Fda 2010 N 0477 0012

Page 1 U.S.
DEPARTMENT OF HEALTH AND HUMAN SERVICES (HHS) + + + + +
FOOD AND DRUG ADMINISTRATION (FDA) + + + + + PART 15 PUBLIC HEARING ON APPROVAL PATHWAY FOR BIOSIMILAR AND INTERCHANGEABLE BIOLOGICAL PRODUCTS + + + + +
WEDNESDAY, NOVEMBER 3, 2010 + + + + + The Panel convened at 8:30 a.m. in Building 31, Room 1503 of the White Oak Campus of the Food and Drug Administration, located at 10903 New Hampshire Avenue, Silver Spring, Maryland, Rachel Behrman, Presiding Officer, presiding. PANEL MEMBERS PRESENT: RACHEL BEHRMAN, M.D., M.P.H., Presiding Officer DENISE ESPOSITO, J.D. JOHN K. JENKINS, M.D. STEVEN KOZLOWSKI, M.D. DIANE MALONEY, J.D. HEIDI C. MARCHAND, Pharm.D. MARK I. SCHWARTZ, J.D. ROBERT A. YETTER, Ph.D. Neal R. Gross & Co., Inc. 202-234-4433
Page 2 PRESENTERS: JAY P. SIEGEL, M.D. JAMES ROACH, M.D. DIRK REITSMA, M.D. ANSHUMAN PATWARDHAN, Ph.D., M.B.A. MARK McCAMISH, M.D., Ph.D. NIKHIL MEHTA, Ph.D. MICHAEL WENGER, M.D. CHARLES D. EBERT, Ph.D. CRAWFORD BROWN, Ph.D. VIJAY TAMMARA, Ph.D., F.A.A.P.S.
TERENCE E. RYAN, Ph.D. ARTHUR TZIANABOS, Ph.D. JOSEPH P. MILETICH, M.D., Ph.D. RICHARD KINGHAM JUDY RUCKMAN, Ph.D. BRUCE BABBITT, Ph.D. ROBERT BAKIN, Ph.D.
BERNARD RHEE, R.Ph., ESQ. MARY GUSTAFSON JOERG WINDISCH, Ph.D. MARIE VODICKA, Ph.D. RASMUS ROJKJAER, M.D., Ph.D. SARA RADCLIFFE Neal R. Gross & Co., Inc. 202-234-4433
Page 3 TABLE OF CONTENTS Presiding Officer Opening Remarks Rachel Behrman. . . . . . . . . . . . . .5 Johnson & Johnson Jay Siegel. . . . . . . . . . . . . . . 12 Momenta Pharmaceuticals, Inc. James Roach . . . . . . . . . . . . . . 32 PPD Dirk Reitsma. . . . . . . . . . . . . . 52 Dr. Reddy's Laboratories, Inc. Anshuman Patwardhan . . . . . . . . . . 66 Novartis Mark McCamish . . . . . . . . . . . . . 87 Merck and Company Nikhil Mehta. . . . . . . . . . . . . .108 Hoffman-La Roche, Ltd. Michael Wenger. . . . . . . . . . . . .123 Watson Pharmaceuticals Crawford Brown. . . . . . . . . . . . .140 Charles Ebert . . . . . . . . . . . . .144 Nuron Biotech, Inc. Vijay Tammara . . . . . . . . . . . . .155 iBio, Inc. Terence Ryan. . . . . . . . . . . . . .167 Shire Human Genetic Therapies Arthur Tzianabos. . . . . . . . . . . .182 Amgen, Inc. Joseph Miletich . . . . . . . . . . . .199 Covington & Burling, LLP Richard Kingham . . . . . . . . . . . .217 Neal R. Gross & Co., Inc. 202-234-4433
Page 4 TABLE OF CONTENTS (CONTINUED) CBR International Corporation Judy Ruckman. . . . . . . . . . . . . .238
PAREXEL Consulting Bruce Babbit. . . . . . . . . . . . . .255
Technology & Business Law Advisors, LLC Bernard Rhee. . . . . . . . . . . . . .274 Robert Bakin. . . . . . . . . . . . . .275
Plasma Protein Therapeutics Association Mary Gustafson. . . . . . . . . . . . .292
European Generic Medicines Association Joerg Windisch. . . . . . . . . . . . .301 PhRMA Marie Vodicka . . . . . . . . . . . . .317 Generic Pharmaceutical Association Rasmus Rojkjaer . . . . . . . . . . . .328
Biotechnology Industry Organization Sara Radcliffe. . . . . . . . . . . . .339
Open Public Comments Russ Lehrman, Lehrman Consulting. . . .360 Eric Katz, Katz and Company . . . . . .364
Closing Remarks/Adjournment Rachel Behrman. . . . . . . . . . . . .373 Neal R. Gross & Co., Inc. 202-234-4433
Page 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. BEHRMAN: P-R-O-C-E-E-D-I-N-G-S 8:32 a.m. Good morning to both
the attendees in the conference center and those viewing the hearing through our live webcast. Welcome to the Part 15 hearing on
the approval pathway for biosimilar and interchangeable biological products, the second day. I am Rachel Behrman, Associate Director for Medical Policy, Center for Drug Evaluation and Research. I will serve as the
presiding officer for this hearing. Before we begin, I will provide a few housekeeping announcements. Please turn
off any mobile devices as they may interfere with audio in this room. We ask that all attendees sign in on both days. I guess you already know this.
The doors were opened at 7:30 a.m. and we're beginning promptly at 8:30. until 4:30 p.m. today. Neal R. Gross & Co., Inc. 202-234-4433 We are scheduled
Page 6 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 The restrooms are located in the lobby to the left and right of the hallways. We are planning for one 15-minute break during the morning and one 15-minute break during the afternoon session. Please note there are trash receptacles located in the back of the conference room and the in the hallways and please we encourage you to use them. Today's lunch break is scheduled from 11:55 to 12:55. There will be
sandwiches, salads, beverages for purchase in the lobby. Concerning the hearing, the purpose of the hearing today is to create a form for interested stakeholders to provide input regarding the Agency's implementation of the subtitle of the Patient Protection and Affordable Care Act, the Biological Price, Competition and Innovations Act of 2009. The BPCI Act amends the Public Health Service Act and other statutes to Neal R. Gross & Co., Inc. 202-234-4433
Page 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 create an abbreviated approval pathway for biological products shown to be biosimilar to or interchangeable with an FDA licensed reference biological product. FDA will take the information obtained from the public hearing into account in its implementation of the BPCI Act. The Agency's interested in hearing from stakeholders regarding the Agency's implementation of the statute on all issues. Chief among them, scientific and technical factors related to a determination of biosimilarity or interchangeability, the type of information that may be used to support a determination of biosimilarity or interchangeability, development of a framework for optimal pharmacovigilance for biosimilar and interchangeable biological products, scope of the revised definition of a biological product, priorities for guidance development, scientific and technical factors related to reference product exclusivity, scientific and Neal R. Gross & Co., Inc. 202-234-4433
Page 8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 technical factors that may inform the Agency's interpretation of a product class as it relates to available regulatory pathways for certain protein products during the ten-year transition period following enactment of the BPCI Act and the establishment of a user fee program for biosimilar and interchangeable biological products. I would now like to ask the FDA Panel Members to introduce themselves. DR. KOZLOWSKI: Hi, Steven
Kozlowski, Director of the Office of Biotechnology Products in CDER. MS. ESPOSITO: Denise Esposito,
CDER Office of Regulatory Policy. DR. JENKINS: John Jenkins. I'm
the Director of the Office of New Drugs in CDER and also the Chair of the CDER Biosimilars Review Committee. MS. MALONEY: I'm Diane Maloney.
I'm the Associate Director for Policy in CBER. DR. MARCHAND: I'm Heidi Marchand.
Neal R. Gross & Co., Inc. 202-234-4433
Page 9 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 I'm the Director of Health Professional Liaison Program in the Office of Special Health Issues in the Office of the Commissioner. MR. SCHWARTZ: Mark Schwartz,
Associate Chief Counsel, Drugs and Biologics. DR. YETTER: Bob Yetter. I'm the
Associate Director for Review Management in the Center for Biologics Evaluation and Research and the Chair of CBER's Biosimilars Committee. DR. BEHRMAN: speakers on the agenda. Turning now to the We have an agenda of
speakers from 21 organizations today with scheduled presentation slots. In order to keep to the agenda as closely as possible, I will go over some ground rules. First, this meeting is informal. The rules of evidence do not apply. No
participant may interrupt the presentation of another participant. Only FDA Panel Members
Page 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 will be allowed to question a presenter. FDA may recall a presenter for additional questions assuming time allows and the presenter remains available. Public hearings under Part 15 are subject to FDA policy and procedures for electronic media coverage of FDA public administrative proceedings. Representatives
of the electronic media may be permitted subject to certain limitations to videotape, film or otherwise record FDA public administrative proceedings including a presentation of the speakers today. The meeting will be transcribed and copies of the transcript may be ordered through the docket or accessed on our website approximately 30 days after this public hearing. Each registered speaker has been given an eight-minute time slot on the agenda with seven additional minutes allotted for FDA panel members to ask questions. If a speaker
Page 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 goes over the eight-minute time slot, the time allotted for questions will be reduced accordingly. For those of you who did not register to make an oral presentation but would like to present your comments, you may speak during the open comment period at that conclusion of the hearing if time permits and I would just ask you at some point to see Sandy Benton who's standing in the back of the room and waiving her hand just so we have a sense of how many people want to speak so we can allot the time accordingly and I'll remind you of that at the lunch break. This hearing is not your last chance to comment. The docket will stay open
until December 31st and we strongly encourage all interested parties to comment. We take
these comments obviously very seriously and study them very closely. Please see the Federal Register notice for details. The majority of speakers
Page 12 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 will be addressing the questions listed in Section 2 of the Federal Register notice for this hearing. And again, given the full agenda, we request that each speaker keep to the allotted time so that we are able to keep to our tight time schedule. We thank you for your interest and your participation. We look forward to a very
productive public hearing. We will proceed with the presentations and our first speaker is Jay Siegel from Johnson & Johnson. DR. SIEGEL: Thank you and I want
to thank the entire panel and the FDA for holding this hearing on this very important matter and seeking broad public input. I'll address a select subset of the issues raised and questions asked in the Federal Register notice and I want to start with if I might paraphrase one of those questions. Neal R. Gross & Co., Inc. 202-234-4433
Page 13 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 In a determination of biosimilarity, what differences in analytic testing may be acceptable? We firmly believe that a standard should be that biosimilar should be as similar as is reasonably achievable. The standard of
sameness has worked well for generics, but as we all know, it's neither achievable nor measurable or demonstrable for biosimilar. So, the legal standard in order to increase access and affordability has been set at highly similar. Now, the highly similar standard has some intrinsic risk. Any differences
between products could have some clinical significance. When applied properly, that
risk can be appropriately controlled and managed so that we can ensure that access is improved and it's access to safe and effective products. But, intentional differences, avoidable, unnecessary differences create Neal R. Gross & Co., Inc. 202-234-4433
Page 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 be needed? unnecessary risks and should not be permitted. Another question asked when are clinical data unnecessary? When might the
requirement for clinical data be waived? We believe that some clinical testing will be essential always to exclude or detect clinically meaningful differences. Even for major manufacturing changes by a innovator, clinical data are often needed and the types of differences that can arise when you completely change the manufacturer are quite major. What types of clinical data would Well, immunogenicity is something
that now and I think for the foreseeable future, certainly the next few years, cannot be predicted without clinical data. So, it
would be important to test immunogenicity and other parameters when there are tests I should add in head-to-head clinical trials and in the case of immunogenicity, also important to determine whether any antibodies that do arise Neal R. Gross & Co., Inc. 202-234-4433
Page 15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 important. against the products cross react between the biosimilar and the innovator and whether they give rise to antibodies to the same or different epitopes. Human pharmacokinetics is Relatively easy to measure. It's
unpredictable from structure and it's relatively sensitive to some changes that may exist between products. measured. The amount of safety data needed may vary depending on the setting, but it's hard to conceive of allowing a product to be broadly marketed to large numbers of patients before some collection of safety data in the controlled setting particularly as clinical studies will be done for immunogenicity and PK in any case. The issue of the desired or intended effects or efficacy if you will is a very complex issue in terms and many of the answers will need to be on a product by Neal R. Gross & Co., Inc. 202-234-4433 So, it should also be
Page 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 product or product class by product class basis. But, there are some general points
that I would like to make in this regard. One is that clinical outcome endpoints are the most meaningful ones and often relied upon as the most meaningful ones and thus are important to measure, but in this setting, pharmacodynamic endpoints even when they're not validated surrogates play a very important role. Because these measures, lab tests, cell count changes that occur with many biologics are often more precisely measured and more rapidly measured and as such, they can be much more sensitive measures of whether there are or are not differences than clinical outcomes endpoints which often require extremely large and long trials in order to exclude all differences that might be clinically meaningful. An issue that has had much discussion in Europe with implementation and Neal R. Gross & Co., Inc. 202-234-4433
Page 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 here has been about whether when there are clinical data supporting a finding about a similarity and one of an innovator's indications, there might be extrapolation to another indication without additional clinical data and it's been noted that that indication would have to have the same mechanism of action. We would assert that the same mechanism of action is necessary but not sufficient. It's one critical determination,
but there are other scientific determinations that need to be considered. Experience both with biosimilars in Europe and with drug products of the same class have shown that two highly similar products with similar clinical effects in one indication may have differences that emerge in a new indication when, for example, the dose or route differs and that's been seen in Europe with biosimilars. A biosimilar EPO.
A deemed biosimilar by the IV route had Neal R. Gross & Co., Inc. 202-234-4433
Page 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 additional safety issues when given by the subcutaneous route. Differences may also emerge when the new target population has different susceptibility to an effect. or is not immunosuppressed. For example, is When different When the
concombinant medications are used.
effects of the drug depend on multiple parts of a molecule such as is the case with antibodies where in one indication may rely on similarity in one area. A new indication may
require a similarity in other areas as well and when tissue penetration to the sites of action differs as can happen with modest changes to any molecule. In different diseases, the same product may be necessary to arrive in different -- may be required to be present in different tissues. A few comments on the much discussed issues of switching interchangeability in front of covigilance. Neal R. Gross & Co., Inc. 202-234-4433
Page 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Switching can increase immunogenicity risk compared with taking either product alone. So, we welcome the requirement to test for switching as part of a determination of interchangeability. Switching can also impair both the detection and the attribution of pharmacovigilant signals, of safety signals that can and will emerge even years after products are on the market. With our own experience with the erythropoietins in Thailand, we have found that in settings where patients have been switched across many products, where all those products are called by the same name, it's extremely difficult to determine any meaningful information about changes in adverse profile trends, attribution of new cases and so forth. That should be avoided here. Naming should discourage inadvertent switching of patients. Naming should facilitate Neal R. Gross & Co., Inc. 202-234-4433
Page 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 tracking signals and with regard to comments that perhaps numbers, NDCs, lot numbers could be included in adverse event reports to ensure appropriate tracking. Something that I'm not
sure the implementation of is really feasible. I would note that we need to focus for pharmacovigilance not only on adverse event reports. That increasingly electronic
medical records, insurance claim databases can be powerful sources of information where we might even be able to look at large numbers of patients receiving an innovative product, a biosimilar for differences in safety effect. We will only be able to use that if all of those databases enable us to know which product the patient had received. I see I have a yellow light and I'm near the end of the my talk. So, I'll just say quickly that we strongly support the development of FDA guidance through a transparent, timely and open scientific product. We believe these are
Page 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. important public issues that should have public input. That the sponsors of innovator
products can greatly help in understanding what are the critical attributes of a product. That the manufacturers of biosimilars will also benefit from such guidance. And I will forego reiterating my key points at the end in order to allow time for questioning. Thank you very much. DR. BEHRMAN: Thank you for your
Are there questions from the panel?
Dr. Jenkins. DR. JENKINS: presentation. Thanks for that
Yesterday, we heard about the
approvals in Europe and that included some products that I think J&J either markets or manufactures. So, I'm interested in hearing what's your perspective on the European experience? I think they have approved upward What's your view
of close to 20 biosimilars.
Page 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 on any safety or efficacy concerns, immunogenicity concerns of the products already approved under their system? DR. SIEGEL: I would say in
general in almost all regards we have a very positive view of the European system. The
process for developing it was an open one. It's a science-driven system. There's been
substantial public commentary and input and those have been considered well in developing the system. You know, one could find individual aspects of it that one might wish were done differently, but I think in general they've done a good job in implementing a biosimilars program. DR. JENKINS: If I could just
follow up, one of the suggestions we heard yesterday is that the data that were used to support the approvals in Europe should be applicable and usable here in the United States. Neal R. Gross & Co., Inc. 202-234-4433
Page 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 issues. So, do you have a view on that? On use of non-U.S. approved reference products for some or all of the data packets that would come to the U.S. for approval and any problems you've seen with the approved biosimilars in Europe that should give us pause? DR. SIEGEL: Well, with regard to
the first part of your question, you know, the issue will depend on how similar the reference product is to the product sold in the U.S. That's a determination I suppose could be made. It does raise certain pragmatic Because if you can approve a product
on the basis of being similar to a product that's marketed in Europe but not in the U.S., than that product that's marketed in Europe but not in the U.S. would also seem to be indirectly deemed to be marketable in the U.S. because it's quite similar to itself. Could a European product show biosimilarity to itself and thereby get Neal R. Gross & Co., Inc. 202-234-4433
Page 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 approved in the U.S.? think that would arise. I think the second part of your question was -DR. JENKINS: Whether you're aware That's a question I
of any problems that have been identified with the European approved biosimilars? Safety
problems, efficacy problems, immunogenicity concerns? DR. SIEGEL: Yes, and I alluded to
one of those which is erythropoietin that was approved only for use by the intravenous route which subsequently was tested by the subcutaneous route to support potentially that use and in the subcutaneous route, there were a couple of cases of PRCA which is a far higher incidence than when it's used with the innovator product and so, that was not approved. As to approved uses and indications, I'm not aware of any problems that have arisen. That was pre-market testing
Page 25 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 that determined that. DR. BEHRMAN: DR. KOZLOWSKI: Dr. Kozlowski. Dr. Siegel, you
mentioned mechanism of action is not sufficient to extrapolate indications and you listed some potential factors. So, do you
feel that if there's appropriate consideration of the right risk-based factors that indications can be extrapolated? DR. SIEGEL: Yes, I didn't mean to
imply that if any of those factors exist you need to do full and complete clinical trials. I think this is a matter of scientific judgment. I think careful consideration needs
to be given to any of those potential differences in the indication. You know,
we've gone from a immunosuppressed population to an immunocompetent population. be an immunogenicity. What would be needed clinically or otherwise to address those. So, Might there
extrapolation, it could be possible, but not Neal R. Gross & Co., Inc. 202-234-4433
Page 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 necessarily. question. simply based on mechanism of action. DR. KOZLOWSKI: And another
You mentioned a standard -- you
know, as similar is reasonably possible and you stated one of the purposes of that is to avoid intentional changes. But, as similar as
reasonably possible will vary with the type of product, how easy it is to characterize, its complexity. So, do you envision, therefore, very different standards across different products? DR. SIEGEL: Well, not
I think as the law envisions,
there may be some classes where as similar as reasonably possible cannot meet the standard of excluding clinically meaningful differences and you may not be able to go there. I do think, however, that there will be cases where standard may even in that sense migrate over time. Where it might be
acceptable to have certain types of Neal R. Gross & Co., Inc. 202-234-4433
Page 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 differences, but as one learns how to avoid those differences, you know, it might be acceptable and it might create a risk that as I said is a risk that can managed with some amount of clinical testing, the pharmacovigilance. But, if it can be avoided,
it should be avoided. MS. ESPOSITO: Dr. Siegel, in your
presentation, you indicated that early and transparent guidance from the Agency would be very useful to the industry. Has Johnson & Johnson given thought to what topics would be most useful and what topics you believe would facilitate the use of the biosimilars pathway in terms of issuing early guidance? DR. SIEGEL: Well, I don't know
that we have a company position on that, but I would say this -- and, of course, some of the comments yesterday I think we all know that the law appropriately precludes guidance delaying the FDA's ability to implement, which Neal R. Gross & Co., Inc. 202-234-4433
Page 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 question. we support and also regarding another comment, we all know that guidance is guidance. not binding. But, one area, you know, if you -one of the things they talked about is product specific guidance and I think in that regard it is through the experience of making a product, through the experience of seeing variations in that product, the experience of clinical testing, that one develops insights that often go beyond the published specifications about what really matters in terms of the quality of the product. We It's
believe that the sponsor can communicate that information through an open process to the FDA that will assist the FDA in assuring that the biosimilars manufacturers know what they need to do. So, that's an area in particular that we'd have interest in doing. MS. ESPOSITO: One follow-up
Are there particular product Neal R. Gross & Co., Inc. 202-234-4433
Page 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 classes that you would view as ripe for early guidance from the Agency? DR. SIEGEL: Well, I think that it
would be a general and reasonable expectation that policy would begin with some of the simpler, smaller, less complicated in structure biologics. That's what has happened in Europe and Europe is now having discussions for policy development regarding antibodies. But, I do think that it's not a bad idea to start with those better defined, better characterized antibodies and products and so, that would probably be the first places to look to issue guidance. But, part
will be what demand you're seeing in terms of what companies want to make biosimilars for. DR. BEHRMAN: I'm going to ignore Do
the red light and ask you one question.
you have any comments on the discussions we had yesterday on drift in terms of interchangeability? Neal R. Gross & Co., Inc. 202-234-4433
Page 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 issue. drift apart. drift apart. DR. SIEGEL: Yes. Products can
Products that are the same can Products manufactured by the
same company in two different facilities can drift apart. That's something that we pay
close attention to monitoring for. Even when you do comparability testing, comparability is not transitive. Meaning, you know, A may be biosimilar to B or interchangeable with B. But, when A becomes A double
A prime, they may be comparable.
prime may be comparable to A prime, but you can no longer know that A double prime is interchangeable or similar to B. Because depending on the nature of comparability, it generally will allow some margin. If you're talking PK20 to 20 percent
in PK parameters, the next change may also increment change and other drifts occur over time. So, I do think it's an important I think it's an important issue for Neal R. Gross & Co., Inc. 202-234-4433
Page 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Thank you. DR. BEHRMAN: Our next speaker is interchangeability. Because
interchangeability requires a determination at a single point in time that they're interchangeable and that switching is safe. I think consideration needs to be given as to whether that will hold up over time. I do not think the solution as one speaker proposed, however, is to therefore not let products change once there is a biosimilar on the market. Many of the changes reflect --
how products are made reflect new technologies that often bring new efficiencies and if we're interested in affordability, we shouldn't be locking into old technologies for our products. DR. BEHRMAN: your comments. DR. SIEGEL: You're welcome. Okay. Thank you for
James Roach from Momenta Pharmaceuticals. DR. ROACH: Good morning. I am
Page 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Jim Roach, Chief Medical Officer at Momenta Pharmaceuticals. Momenta is a biotechnology company that belongs to both GPhA and BIO and we develop analytical tools and methods that advance the science of thorough product and process characterization and knowledge. We apply these methods to develop generic versions of complex products such as enoxaparin and glatiramer acetate and also to develop biosimilar and potentially interchangeable products. We seek to further define product structure and use this enhanced product knowledge to lead to an increased understanding of structure function and process product relationships, tighter control of process development and greater assurance of purity, potency and sameness. We believe that innovation in the analytical methods and tools offers the biologics industry the opportunity to improve Neal R. Gross & Co., Inc. 202-234-4433
Page 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the quality of all biologics whether branded or biosimilar. A goal that all should pursue.
The industry has historically taken the approach to characterizing proteins by evaluating identity, size, charge and glycosylation profile into various methods. We believe generally this is limited and perhaps doesn't capture the complexity of most glycoprotein products. Though it is beyond the scope of this forum to delve into a detailed technical presentation, or spend too much time on slides like this, we believe that the ability does exist to much more thoroughly characterize the entire structural space of the biologic by applying a variety of additional and orthogonal high resolution analytical methods and data integration techniques. As an example of how this technology may be applied, I would refer you to a paper being published in the next week or two in Nature Biotechnology entitled Chinese Neal R. Gross & Co., Inc. 202-234-4433
Page 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Hamster Ovary Cells Can Produce GalactoseAlpha-1,3-Galactose Antigens on Proteins by Carlos Bosques, Brian Collins, James Meador, et al. Patient access to biologics is increasingly limited by high cost and growing demand. Many emphasize the potential risks to
patients if we rush too quickly to bring biosimilars to the market. However, equal emphasis should be placed on the potential benefit to patients by implementing the pathway in a way that ensures the introduction of safe and effective biosimilars into the marketplace. The BPCI Act offers the opportunity to extend the significant benefits that the Hatch-Waxman legislation provided to patients in need of biologics by permitting appropriate reliance on what is already known about an existing biologic. Unnecessary
duplication of human or animal testing can be avoided and access to these potentially life Neal R. Gross & Co., Inc. 202-234-4433
Page 35 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 altering or lifesaving medications will be significantly increased. With this in mind, I would like to emphasize the following points. If the rules
establish burdensome limitations on the application of new scientific approaches, the goals of this legislation will be undermined and investment will be further directed away from the development of technologies intended to enhance product understanding and safety. The Agency's statutory scientific discretion was presumably enacted for precisely this purpose: To accept
applications that may offer new solutions and scientific approaches to the traditional drug development paradigm. It is critically important to allow the Agency the broad scientific discretion needed to make determinations on data required for approval on a case-by-case basis and not to implement unnecessary obstacles to use of the pathway such as Neal R. Gross & Co., Inc. 202-234-4433
Page 36 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 issuing guidances which perhaps mandate certain requirements for approval. To offer the most potential benefit to patients, the Agency's implementation of the BPCI Act must allow for the practical and feasible development of both biosimilars and potentially interchangeable biologics. It will only make sense for
companies to pursue approval via the 351(k) pathway if requirements for pre-clinical and clinical studies are reduced relative to a traditional BLA pathway. The degree of analytical data and knowledge of product quality attributes will help to inform the Agency in deciding the nature and scope of pre-clinical and clinical trials required to support approval. The state of the science with respect to the enhancement of product understanding has evolved considerably in the last decade and will continue to do so. We
need to set policy that is flexible enough to Neal R. Gross & Co., Inc. 202-234-4433
Page 37 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 to conduct. allow the Agency to consider scientific advancements on an ongoing and real-time basis. Pre-clinical and clinical trials clearly have an essential role in assuring the safety and efficacy of novel products. It is
certainly appropriate for both pre-clinical and clinical trials to potentially play a role in determination of similarity. However, this data requirement should be implemented in the context of the existing product knowledge data set. Clinical
trials could be positioned as supportive and designed to provide adequate safety and efficacy information to establish comparability to the reference product. These trials must also be feasible Establishing statistical non-
inferiority or equivalence of a biosimilar relative to a branded product in clinical studies may be impractical for many products and indications. Neal R. Gross & Co., Inc. 202-234-4433
Page 38 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Additionally, switching studies to assess the potential immunogenicity, efficacy and/or safety of a biosimilar relative to a branded product may neither be feasible nor particularly informative in certain circumstances. Immunogenic responses and other safety-related issues may not manifest themselves until well after initial exposure making it difficult to determine the product that may be causing a biological response and similarly biological efficacy may be the result of a long-term cumulative affect with exposure. Again, making it difficult to For
envision the concept of switching.
example, in oncology studies designed to demonstrate an effect on survival. There is certainly lessons to be learned from novel biologics as to how similarity and comparability may be defined. It is important to recognize that existing products may exhibit a considerable amount of Neal R. Gross & Co., Inc. 202-234-4433
Page 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 lot-to-lot variability for a number of product quality attributes. However, as long as each lot falls within certain predefined specifications for these variables, they are considered the same or sufficiently similar to be interchangeable and treated as the same. We believe that the principles articulated in the ICH Q5E Guidance on Comparability of Biologic Products are very relevant to determining the type of data that may be required case-by-case to support approval of a biosimilar product. To quote the guidance, "Determinations of product comparability can be based solely on quality considerations if the manufacturer can provide assurance of comparability through analytical studies and additional evidence from non-clinical or clinical studies as appropriate when quality data are insufficient to establish comparability." Neal R. Gross & Co., Inc. 202-234-4433
Page 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 We support this approach. As the
comparison of a very thoroughly characterized biosimilar to a reference product can be thought of in many instances as analogous to the comparison between a pre-change and postchange product. The burden, of course, will
be on the sponsor to demonstrate that the variability of the biosimilar or potentially interchangeable product falls within a comprehensive set of prospectively defined product quality attributes so that one can reasonably expect that the product will have the same clinical activity as the brand product. Biotechnology companies that have successfully commercialized products are often referred to as innovators. Many of these
companies state the process is the product and replicating biologics is impossible and appear to be advocating for policy requirements that if implemented could effectively render the 351(k) pathway unusable. Many people stated
Page 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 that replicating enoxaparin was impossible as well. I find it interesting generally that an industry which has always prided itself on innovation and the ability to solve complex problems is to quick to emphatically conclude that something is impossible and can't be done. I submit that the technology platforms that we and other biotechnology companies have developed in the interest of advancing product knowledge are every bit as innovative as more traditional drug development platforms and if appropriately applied and supported have the potential to translate into very substantial benefit to patients. So, in summary, there's no arguing with the concept that patient safety is of paramount concern. However, this phrase is
often positioned to support the foregone conclusion that comprehensive non-clinical and Neal R. Gross & Co., Inc. 202-234-4433
Page 42 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 clinical trials must, therefore, be conducted to ensure patient safety. I submit that the patient is of paramount concern and we may not be benefitting patients by conducting redundant and arguably unethical trials should criteria for similarity and/or sameness be otherwise met. I sincerely hope that as the debate moves forward that sound bites and rhetoric will be replaced with fact, objectivity and solid science that enables the use of this pathway in a responsible way. Although the pathway presents challenges to both sponsors and regulators, it also presents a tremendous opportunity for all involved. Most importantly patients. In conclusion, I would like to borrow a quote from a presentation given by Dr. Daniela Verthelyi, Chief of Laboratory of Immunology in the Division of Therapeutic Proteins and OBP at FDA. Neal R. Gross & Co., Inc. 202-234-4433
Page 43 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. "The regulatory process must render a balance between the desire for rapidly available novel therapeutics and the need the carefully evaluate potential safety risks and clinical efficacy." We agree, and hope the Agency finds these comments useful as you move forward to implement the BPCI pathway and thank you very much. Happy to answer any questions. DR. BEHRMAN: Thank you for your
Are there questions from the panel?
Dr. Kozlowski. DR. KOZLOWSKI: Dr. Roach, one
should use a standard of within manufacturer comparability for doing a biosimilar evaluation and the previous speaker mentioned in his presentation some issues that are different like access to intermediates. So, could you comment a little on the actual differences or lack of differences in your view within manufacturer change and a Neal R. Gross & Co., Inc. 202-234-4433
Page 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 biosimilarity evaluation? DR. ROACH: Sure. It's a great
question and I think we would have to evaluate certainly on a product by product basis the differences that we're observing. But, I think the main point is if you can apply analytical technologies at various points in time in process development with your own biosimilar, you learn certain things about how the process may affect the product. Such that by the time you get to
drug product, you can see certain structural fingerprints that you think perhaps were influenced by the process. So that, by the time you get to drug product through these learnings, you may, in fact, have a drug product that may be more similar to the reference product that the differences you observed between lot-to-lot in the reference product. Obviously, this is an evolving science, but that's kind of how I would Neal R. Gross & Co., Inc. 202-234-4433
Page 45 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 approach it. DR. KOZLOWSKI: So, to follow up,
that assumes that you can characterize anything of importance. DR. ROACH: I don't know that I
want to be so bold as to make that statement here today, but what I will say is that our technology platform and I'm sure other people that are working on this bring a whole other degree of resolution to these compounds. DR. KOZLOWSKI: And to follow up
on another note, in your first slide, you had sort of Dr. Nasr's wheel of quality by design. DR. ROACH: Yes. And I think the
DR. KOZLOWSKI:
concept of more advanced pharmaceutical manufacturing that can deliver targeted sets of attributes very consistently I think is something the Agency would like everybody to do. You know, innovators and biosimilar
industries. And I guess if manufacturing can Neal R. Gross & Co., Inc. 202-234-4433
Page 46 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 really advance to be much more targeted, how do you think that relates to the question of drift? Because that's something which has
come up I guess yesterday and today. DR. ROACH: No, absolutely and I
think I made the point early on that I think these technologies that we and others are working on can be applied certainly both to development of biosimilars and to ensure a higher degree of quality for branded products. So, to me the product drift question, I think if I'm the manufacturer, I would embrace these kind of technologies to ensure that your product is not drifting very much rather than to try and position it as what happens if you get a biosimilar on the market and the reference product drifts. To me, the problem or the potential situation could be that there's more issues with product drift than there is from the biosimilar being comparable to the reference product that's approved. Neal R. Gross & Co., Inc. 202-234-4433
Page 47 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. BEHRMAN: DR. JENKINS: Dr. Jenkins. I'd like to follow
up on some of your comments about the role of clinical data. You said that clinical trials in this context should be positioned as supportive to the existing data set and designed to provide adequate safety and efficacy information to establish comparability to the referenced product. We heard a lot of comments yesterday from patient groups and prescribers that they wanted to be very certain that the biosimilar would be highly similar to the clinical effect of the branded product. So,
I'm interested, how do you reconcile those two viewpoints as far as where we should set the bar on determining the role of the clinical trials in establishing, you know, that there's no clinically meaningful difference as the statute requires between the biosimilar and the reference product? Neal R. Gross & Co., Inc. 202-234-4433
Page 48 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. ROACH: Yes. Well, I do think
again it would be on a case-by-case basis. But, I also think that as you develop more product knowledge through various analytical and biocharacterization techniques, we can't underestimate the benefit to patients, right, by getting the products on the market without having to replicate trials conducted by the sponsor or in some instances, quite frankly, depending on how you set this, you could envision a scenario where if you're requiring establishment of non-inferiority or equivalence, you might end up having to run a trial that's 4X or 5X greater in size than what the innovator needed to do to get the product approved in the first place. So, I would emphasize that the burden is clearly on the sponsor to make the arguments as to why it is that their collective package including, you know, certainly all the analytical and biocharacterization data, in vivo data animal Neal R. Gross & Co., Inc. 202-234-4433
Page 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 studies support a more limited clinical data set. At the end of the day, I think everybody needs to be very comfortable with the understanding that if sponsors are presenting package X and the FDA has reviewed it and in your opinion based on this collective data set, it's safe and effective, I mean I think you'll be the ultimate arbiter of where you draw the line based on that package. But, I do think it's possible to provide a limited clinical data set in conjunction with the entire existing data package to get a product approved. DR. JENKINS: There is a model
that's used in the Office of Generic Drugs in certain situations where you can't determine bioequivalents for small molecules based on either pharmacokinetics which is their preferred approach or pharmacodynamics. DR. ROACH: Yes.
Page 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 on that. Neal R. Gross & Co., Inc. 202-234-4433 DR. JENKINS: They do use clinical
trials in some settings such as for topical products. Are you familiar with that model and if you are, do you have any thoughts how that should apply to biosimilars? DR. ROACH: I'm only vaguely I understand the
familiar with that model.
model in concept, but I think the concept still applies that you work out -- you know, the sponsor will propose a study that they think makes sense in conjunction with their package to support approval. Above and beyond that, I guess I'm not that, you know, familiar with the specifics of the model. But, it is a limited -- it's not necessarily the same kind of study that de novo you would be obviously putting forth for an NCE. DR. KOZLOWSKI: One more follow up
Page 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 So, you do mention that there should be supportive clinical trials, but you suggest a non-inferiority trial or a two-sided equivalence trial or a switching trial may be inappropriate. So, I guess I'm wondering what would you envision the design of a supportive trial other than those looking like? DR. ROACH: You know, how much is
enough and where do you set the bar I think relative to the package that you submit? I guess to be clear, I'm not suggesting that non-inferiority or equivalence are necessarily not appropriate for products like this, but it may be, as an example, how you define the non-inferiority or equivalence margin for a product like this relative to an NCE. Might you allow a wider margin as an
example to provide evidence of comparability. DR. BEHRMAN: Just a quick It seems to
question on your slide eight.
imply that you believe that interchangeability Neal R. Gross & Co., Inc. 202-234-4433
Page 52 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 can be established without any clinical data. Is that your position? DR. ROACH: I guess my position is
I would like to believe that over time as the science evolves that it's certainly possible at some point in time and maybe for some products very soon and maybe for others not so soon that possibility exists and so, my main point was more to allow the policy to be flexible enough to able to respond to that kind of data package. DR. BEHRMAN: That's very helpful.
Thank you for your comments. DR. ROACH: DR. BEHRMAN: Dirk Reitsma from PPD. DR. REITSMA: name is Dirk Reitsma. Good morning. My Thank you. Our next speaker is
I am the Vice President
of Global Product Development at PPD and I would like to thank the FDA and particularly the panel for this public comment meeting on the Approval Pathway for Biosimilar and Neal R. Gross & Co., Inc. 202-234-4433
Page 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Interchangeable Biological Products. As a Global CRO, PPD has become involved in the development of biosimilars and to further the interest of our clients, we hope to be able to contribute to the discussion about feasible trial designs for the developments of biosimilar and interchangeable biological products. We were curious what would happen if you actually tried to design a biosimilar trial to show interchangeability. We wanted
to find out if it would be feasible numberswise and what the assumptions would be that you would need guidance on as you went through. So, the key definitions that we took were that an interchangeable obviously first has to be a biosimilar which means it has to be highly similar as the definition states with minor differences in clinically inactive components. There should be no
meaningful differences in safety, purity, or Neal R. Gross & Co., Inc. 202-234-4433
Page 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 potency, and that the same mechanism, vaccinal mechanism, actions should apply as the referenced biologic product. So, once the biosimilarity has been established, you would then add the criteria that if administered more than once or switched, there would be no decrease, no loss of safety or activity or increase of immunogenicity as compared to the reference biologic product. And so, the first point that we discussed was the switch itself. We assumed
that that meant the patient would be receiving one treatment and then would be switched to the other and for the purpose of the discussion, the exercise, we said the patient would switch once. We didn't go into
alternating back and forth and we also didn't think that that would be as common a clinical situation. We also discussed the point at which you would switch. You'd need to switch
Page 55 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 at a point when the patient had had adequate exposure to the first compound before going to the second one, but they would also have to have sufficient exposure to the second compound before they had their assessment. So, the timing of the switch is something that you would need to discuss and need to understand. As Dr. Chow pointed out yesterday, there are issues about the pharmacokinetic and pharmacodynamic profiles of biosimilars that you would need to take into account. By and
large, the first generation of biosimilars has been characterized for having a short halflife and in many cases, you're able to explore single dose pharmacokinetics and single dose pharmacodynamics. Which does allow cross-over
designs which are feasible and which should be conducted particularly if the subject can serve as their own control. fairly compact designs. On the other hand, the monoclonal Neal R. Gross & Co., Inc. 202-234-4433 It allows for
Page 56 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 antibody biosimilars that are coming through tend to be characterized by having a long half-life. Because of the indications being
treated, there's the need to sustain minimal blood levels so that you cannot stop and have a washout period between repeated ministrations. Not always feasible and so,
that means that a perfectly satisfactory trial design may not always be possible. But, in going through this exercise, we did refer back to some of Dr. Chow's publications. So, on the interchangeability criteria, the ones that we focused on for this exercise were, of course, safety. Any
clinical trial needs to have safety first and foremost and then we also took into account pharmacokinetic and pharmacodynamic comparability as well as activity or efficacy for the clinical. We didn't take into account nonclinical or manufacturing comparability Neal R. Gross & Co., Inc. 202-234-4433
Page 57 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 although we understand that the degree of comparability influences the type of clinical trial you would do and the type of data you'd go after. Particularly, if you don't have
very tight comparability, you might even need to do some sort of dose escalation before you actually compare the drug at the level the referenced drug is used at and there have been many comments at this meeting about the impact of product variability on the selection of which biologic reference compound which you use. So, this outlines our thoughts on the trial design for interchangeability. Because it's a clinical trial, it has to be relatively simple and robust. What we
selected was the four parallel design trial with a crossover point in two of the arms and the crossover point is somewhat arbitrary, but we selected that to be at steady state because then at least there would be full exposure to the minimal trough level for the first Neal R. Gross & Co., Inc. 202-234-4433
Page 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 arms. compound. And so, we have four sequences. The first two sequences are that the patient stays on the reference compound so it goes from to A to A past the switching point. second is that the patient receives the biosimilar all the way through going from B to B through the switching point. And then we have the two switch So, the one that we thought was most The
clinically relevant was the switch from the reference compound to the biosimilar since that is probably what would happen most often in practice. But, we also thought that once
the biosimilar's available patients might start out on the biosimilar, have a disappointing benefit or result from being on the treatment and might be switched to the reference compound. So, we felt that to be
complete we should include that change in the trial as well. Just as a model to get our heads Neal R. Gross & Co., Inc. 202-234-4433
Page 59 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 around, we selected a rheumatoid arthritis model because it has fairly early and clear outcome and we selected Humira as the drug to think about which gives us a switching point for steady state at about 12 weeks. So, the endpoint we selected was a measure of joint inflammation, ACR 20, response at 24 weeks. Of the
interchangeability endpoints that we could pick from acute and chronic safety, early activity and immunogenicity, for the purposes of this exercise, we looked at early activity. So, if you would power the trial at 80 percent and you were to take a 5 percent significance level and an equivalence margin which you probably need to do with a compound like this where you could go up in dose and perhaps increase the activity, of 12 percent which is half of the lower limit of the 95 percent confidence interval of the difference between Humira and placebo in the original trials, and we did a pulled analysis for this, Neal R. Gross & Co., Inc. 202-234-4433
Page 60 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 if you do all of that, you come up with a sample size of exactly 1228, but about 1200 patients. So, we then asked what would change about that because you want to try to get your head around whether these trials would even be feasible. If you went from
equivalence to non-inferiority in this setting, you would drop the patients sample size by about 300. Depending on the type of analysis you do, the patient numbers could go up. We
assumed a sequential analysis where you would first do the biosimilarity comparison. Then
compare the reference to biosimilar switch and then the biosimilar to reference switch. If you want to do a really deluxe trial and you wanted to do 90 power and you wanted to do a multiplicity analysis where you could do all the comparisons, your trial would end up being about 2,000 patients and that would be about 2 to 4 times the size of trials Neal R. Gross & Co., Inc. 202-234-4433
Page 61 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 we're seeing for biosimilarity in these indications. So, I think what we and our clients would benefit from as priorities through guidances is first good guidance on what needs to be demonstrated for PK and PD and clinical comparability in interchangeability and then also in nonclinical and manufacturing in order to set the type of clinical trials you would need to do in the first place. We then would need to know what's acceptable as far as the reference compound goes. There's been a lot of discussion about
that, whether ex-U.S. base could be taken. And then specifically as it was referenced this morning, there are guidelines in existence for the earlier biosimilars, but there are no guidelines yet for monoclonal antibody. So, we'd be very eager to receive
those as well. Thank you for your attention. Neal R. Gross & Co., Inc. 202-234-4433
Page 62 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. DR. BEHRMAN: Thank you for your
Are there questions from the panel? I have one. You made a decision
to think about only a single switch. DR. REITSMA: DR. BEHRMAN: Yes. Although that's not
quite what the statute anticipates and certainly, we have said publicly we're very concerned in terms of the way health care is delivered in this country. fact, would be repeated. Can you explain a little bit why you chose a single switch? DR. REITSMA: Basically, it was to We That switching, in
get through a feasibility exercise.
weren't sure when we started out whether we would even come up with a number that would work. Because in our experience in modeling
these studies, you sometimes come up with very high numbers. I'm not sure whether the numbers per se would change very much if you allowed Neal R. Gross & Co., Inc. 202-234-4433
Page 63 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Dr. Jenkins. DR. KOZLOWSKI: The calculation alternating. It was just for the ease of
setting the switching points so that we could get on the exercise that we picked one. DR. BEHRMAN: Dr. Kozlowski and
you I assume would have been valid had these products not had any biochemical similarity demonstrated. It was basically what you would
need to do to compare switching from one product to another. So, I want to ask do you think there is any way in which the prior knowledge, you know, as you mentioned, the level of characterization and the level of similarity could somehow be utilized in the design of the clinical trial? DR. REITSMA: I think that is a
very interesting and a very relative question and I think it's something that I hope to see as we get more into development of biosimilars. Which is being able to take the Neal R. Gross & Co., Inc. 202-234-4433
Page 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 existing information as it was discussed yesterday and again this morning and incorporating that into your assessment of biosimilarity and interchangeability and perhaps even extrapolation and obviously, Bayesian techniques would lend themselves very well to that. So, I would be very interested to, you know, take some of that information and see what modeling would deliver on that and whether it would save you significantly on sample size. DR. BEHRMAN: DR. JENKINS: Dr. Jenkins. Staying on that same
slide where you developed a model for both biosimilarity and interchangeability, I was confused. Are you thinking that would be 24So, just You switch it
week study or a 48-week study? taking you're doing to A to A.
24 weeks or you switch it 12 weeks? DR. REITSMA: The switch in this
example would be at 12 weeks because that's Neal R. Gross & Co., Inc. 202-234-4433
Page 65 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 more or less when steady stage is reached and we picked the 24-week endpoint as something we would measure across the arms for the primary activity. In reality, the trial would probably continue. You would look at the time
code of response to make sure that that was the same because that's well known and there are many ancillary measures you would take including PK/PD measures to support the biosimilarity and interchangeability of the compound. DR. JENKINS: We heard a comment
earlier about concerns that the standards for biosimilars might lead to a program that so much larger than what it took to get the innovator approved and it might drive people away from the 351(k) pathway. I don't know how much data were required for the original Humira approval, but what's your thinking about whether this would be such a large trial that might drive Neal R. Gross & Co., Inc. 202-234-4433
Page 66 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 everyone. Neal R. Gross & Co., Inc. 202-234-4433 sponsors away from this pathway. DR. REITSMA: It is possible if
you can't apply mitigating factors to bring the trial size down and I'd be surprised if you couldn't do that because now we just look at the clinical data. Generally, when a drug gets approved, there are more studies done obviously than just the pivotal study. In
this development, the pivotal study itself may be bigger than individual pivotal study for some of the originator approvals, but I think the total size of the program by the nature of the biosimilarity development and the spirit of that might still be smaller. DR. BEHRMAN: Other questions?
Thank you for your comments. DR. REITSMA: DR. BEHRMAN: Anshuman Patwardhan. DR. PATWARDHAN: Good morning, Thank you. Our next speaker is
Page 67 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 My name is Anshuman Patwardhan. I'm here representing Dr. Reddy's Laboratories. I would like to begin by thanking by FDA for giving us a chance to put forward some of our thoughts on the biosimilars pathway in the United States. Dr. Reddy's is a diversified health care organization with global presence and the United States is our largest market. The biologics business of Dr. Reddy's is currently focused on biosimilars where our business strategy is quite simple. We plan to and will launch our biosimilars in every market where the unmet is defined by either limited patient access to lifesaving medications as is the case in emerging markets or there is a disproportionate cross burden on the health care system as in the case in many developed markets. This slide shows an overview of our biosimilars pipeline. We specialize in
Page 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 2001. tackling complex biologics. Our GCSF and
rituximab are already marketed in Asia, Latin America, Middle East and the CIS bloc and our darbepoetin alfa has recently been launched in India. As many of you might know, we have been the first in several of these markets to have gained an approval for a similar version of the originator product and have made significant impact on patient access in these countries as I'll show in my next slide. We launched our GCSF in India in Today, with ten-plus place in the
market, the number of cancer patients receiving GCSF has increased more than 30-fold in India. Similarly in case of rituximab,
just within three years of launch of our Reditux brand, the number of patients receiving this lifesaving therapy has already gone up more than sixfold in India. The evidence is indisputable. Competition does lead to patient benefits Neal R. Gross & Co., Inc. 202-234-4433
Page 69 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 especially in countries like India where there is a wide income disparity and individuals have to bear practically the entire burden of the cost of therapy. Pharmaceutical
monopolies really have no reason to insure affordability of drugs even for lifesaving mediations. The only way to make this happen is for regulatory agencies to create sciencebased pragmatic regulatory frameworks that can encourage healthy competition in the marketplace. We think that the United States
is not too different from India in this regard. In fact, the best example of this phenomenon is right here in our backyard where the FDA's implementation of the Hatch-Waxman law has demonstrated amazing efficiency of the U.S. market and has saved the system literally hundreds of billions of dollars. Before I move into our positions, I wanted to leave you with some snapshots from Neal R. Gross & Co., Inc. 202-234-4433
Page 70 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the basis of the original approval of Reditux in India which was based on a limited singlearm clinical trial, but with the expectation of an extensive post-marketing surveillance in which we now have close to a thousand patients. The figure on the left shows that the objective response rate with Reditux in patients with an aggressive form of nonHodgkin's lymphoma is highly consistent with that shown with the originator product and the graph on the right shows our post-marketing surveillance data where we continue to see not a single case of immunogenic response in any patient. The point I'm trying to make is that today's advancement in process and analytical sciences, it is possible to design biosimilars to be therapeutically indistinguishable from the RMP. Thus, health
care cost savings and patient benefits are no longer expected to be mutually exclusive Neal R. Gross & Co., Inc. 202-234-4433
Page 71 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 propositions assuming that the regulatory framework for the approval of biosimilars is made competition-friendly based on science, common sense and pragmatic approach to risk benefit for the patient. With that preamble, I would like to now present our position on three key questions that we have chosen to speak about today. Question A3 asks, "What the acceptable range of structural differences may be in the absence of any clinically meaningful differences?" We believe that the goal of clinical testing is to separate relevant structural differences from irrelevant ones. Presuming that the development was designed to present a biosimilar product via the use of identical host species to produce identical amino acid sequence and a highly similar glycosignature. Thus, while similarity in the key Neal R. Gross & Co., Inc. 202-234-4433
Page 72 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 critical quality attributes should be a precondition for IND approval, we believe that minor differences in post-translational modifications need not serve as a hurdle to begin clinical testing and we want to reiterate this is for beginning the clinical testing not for the approval of the product. So, here we have shown an example of how such differences in post-translational modifications may be delineated by the FDA on the basis of key considerations. Such as, the
presence of all isoforms in the biosimilar that are present in the RMP, no introduction of any new isoform for the first time in the biosimilar, in the presence of all mechanisms of action in the biosimilar and finally, a detailed explanation and investigation of any quantitative structural differences by the biosimilar sponsor along with the adequate justification of how these differences may not lead to any clinically meaningful differences. We'll go on to the next question. Neal R. Gross & Co., Inc. 202-234-4433
Page 73 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Question A4 asked, "When can animal toxicology studies not considered necessary?" Well, we know that animal tox studies are not statistically powered and do not always predict clinical toxicity. so, we believe that their use as a prerequisite to clinical trials may be justified in case of novel biologics where significant potential risks exist from unknown unknowns. For biosimilars, however, which have been demonstrated to be highly similar to the RMP and the RMP itself has had a long history safe human use, the value of requiring unpowered animal tox studies as a prerequisite for clinical trials in our opinion is marginal and especially so when the biosimilar has already been marketed in other jurisdictions where it has gathered significant clinical post-marketing safety, efficacy and immunogenicity data. We believe that the only time nonNeal R. Gross & Co., Inc. 202-234-4433 Even
Page 74 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 clinical tox studies may be justified is when there exists a relevant animal model for the indication that can differentiate between the toxicities of two highly similar molecules. An example of this may be a case where a mouse model is found to be relevant and can ethically be used with sufficient power. Moving on to the last question on our list, Question D asked "When would studies against RMP approved in other jurisdictions may be considered acceptable to the FDA?" We all know that clinical costs represent by far the largest proportion of the cost for biosimilars development and that the burden of having to repeat clinical trials for every major market is guaranteed to be a major entry barrier for a majority of biosimilar manufacturers. We fully realize that it is not the job of the FDA, but the job of lawmakers to create competition in the marketplace. Neal R. Gross & Co., Inc. 202-234-4433
Page 75 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 However, we also know that the BPCI Act as it is worded today is fairly broad and thus at the end of the day, it will be the FDA guidelines that will define whether or not health care savings and the patient benefits envisioned in the BPCI Act are brought to reality. Specifically in this case, our position is that studies with a RMP approval in other jurisdictions should be acceptable to the FDA based on (1) a clear demonstration by the sponsor using high resolution in vitro structural and functional assays that the two RMPs are similar and (2) the quality of the studies conducted in other jurisdictions is acceptable to the FDA based on compliance with GMPs, GLPs and GCPs. I would like to begin my summary with this graph that shows health care spending in various countries and say something that we all already know. That the
U.S. patient pays more for health care that Neal R. Gross & Co., Inc. 202-234-4433
Page 76 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 any other patient in the world. With current
monopoly pricing routinely in the range of $10,000 to $100,000 per patient per year, biologics truly represent the extreme end of the health care costs spectrum. Dr. Reddy's has first-hand experience that health competition in the biologics market even without automatic substitution can result in dramatic increase in patient benefits without affecting the quality of care. I would like to reiterate the 30fold and sixfold expansion in patient access in India after the launch of similar GCSF and rituxima versions respectively in combination with the excellent safety, efficacy and immunogenicity profile of our similar biologics without extensive post-marketing surveillance. I would like to conclude by saying that we fully support the FDA in adopting biosimilar approval guidelines that employ Neal R. Gross & Co., Inc. 202-234-4433
Page 77 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Jenkins. DR. JENKINS: I'd like to go back science to realize the goal of the BPCI Act of creating health competition to cause a reduction in monopoly pricing of biologics and a break to the runaway cost of our health care. I would like to end my presentation with this slide and I thank you. DR. BEHRMAN: Thank you for your Dr.
Questions from the panel?
to your slide where you describe the approval pathway for your rituximab product in India and try to better understand what the clinical trial database actually consisted of. you said it was a single-arm trial. I think So, can
you say more about the figure on the left? I'm having trouble sorting through exactly what I'm seeing there. DR. PATWARDHAN: Yes. Basically,
in the figure on the left, we are showing in blue the objective response rate with our Neal R. Gross & Co., Inc. 202-234-4433
Page 78 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 trial in 67 patients in India. It was a
single-arm trial and in, I guess, orange boxes, we are showing all the literature with the originator product and what objective response rate they have gotten in the same indication. The point of the slide was that yes, we had to go to a single-arm trial, but that objective response rate is basically identical to what has been MabThera Rituxan experience. Regarding your point about singlearm trial, I just want to out that when we launched or when we were trying to launch Reditux in India, because of the price of Rituxan or MabThera in India, the number of patients, overall number of patients in India receiving Rituxan was less than a thousand. So, in a country like India, for the regulatory agencies to mandate powered clinical trials against the brand was just simply not possible and, in fact, I mean, we Neal R. Gross & Co., Inc. 202-234-4433
Page 79 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 wouldn't be -- in fact, in India, that wasn't the standard of care at that time. Of course, now that we have launched, the prices have come down and as I said, the patient access has increased sixfold since the time we launched. So, that was a
justification why the single-arm trial was asked. However, there was an expectation that there will be extensive post-marketing surveillance in which we now have a thousand patients. DR. JENKINS: So, basically, on
this slide, the 94 that's in the blue box is your single-arm trial data and the other boxes represent other historical trials -DR. PATWARDHAN: DR. BEHRMAN: Articles --
-- published. Correct.
DR. PATWARDHAN: DR. JENKINS:
Then what's the
dotted-line box that captures some of the smaller boxes, but not all? What does that
Page 80 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 refer to? DR. PATWARDHAN: Yes, the dotted
line is the confidence interval around our objective response. What we are saying is that that confidence interval, 95 percent confidence interval, around our objective response is falling within the range of the historically observed. So, it's not just the 94 percent,
but even the variation of our -- although, I guess, some measure of variability of our objective responses falling within the historical range. DR. JENKINS: Okay. So, would you
be advocating for a noncomparative trial for U.S. registration? DR. PATWARDHAN: What we would be
advocating is an eye on the benefit versus the risk. So, in India, for example, the benefit was clearly that patients were not receiving the product and it was impossible to Neal R. Gross & Co., Inc. 202-234-4433
Page 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 do a power trial because the number of patients on the branded version was just simply not enough. In the U.S., the risk/benefit ratio may be different, but always eye on the benefit has to be there before requesting the trials. So, we're not envisioning a singleWe think, in fact, that that
arm trial.
probably won't fly with the FDA. But, again, the size of the trial, the endpoints, the length of the trial, these things have to be kept in perspective of a new -- vis-a-vis the benefits to the patients as opposed to just sticking with the prior practice. DR. BEHRMAN: Could I just follow
up on Dr. Jenkins' question before we get to Dr. Kozlowski. So, patients were not on in the post-market setting or in the clinical practice the product, but you would not have been prohibited from doing a randomized trial. Neal R. Gross & Co., Inc. 202-234-4433
Page 82 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Kozlowski. DR. KOZLOWSKI: To keep to this trial? DR. PATWARDHAN: DR. BEHRMAN: No. Thanks. DR. PATWARDHAN: DR. BEHRMAN: Correct.
So, you made a Is that
decision to do a single-arm trial. correct? DR. PATWARDHAN:
No, so the
requirement in India for approval was that we can be marketed with a single-arm trial. DR. BEHRMAN: You would not have
been prohibited from doing a -DR. PATWARDHAN: DR. BEHRMAN: No.
-- comparative
Okay.
DR. PATWARDHAN:
But, doing a
power trial at that time in India with less than a thousand patients on the brand was just even for us -- even you wanted to, wouldn't have been possible. DR. BEHRMAN: Thank you. Dr.
Page 83 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 same slide, so on the right of this slide, you talk about evaluation from immunogenicity. So, just to clarify, is that using an assay for antibody or is that looking for immune-related adverse events? DR. PATWARDHAN: against Reditux. DR. KOZLOWSKI: Okay. And did you No, this is assay
have controls to sort of make sure the sensitivity of that assay was similar to, for instance, what the innovator would be using to get their data? DR. PATWARDHAN: The assay has
been validated in our shop, but I don't think we have done a comparison with the assay that has been used by the branded company. DR. KOZLOWSKI: access to that, but -DR. PATWARDHAN: DR. KOZLOWSKI: Right. -- based on their You wouldn't have
sensitivity to their product. DR. PATWARDHAN: Yes.
Page 84 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. KOZLOWSKI: And then, you
know, in your presentation you had mentioned, you know, making sure that you have the same isoforms. So, is there an extensive
biochemical characterization to look for differences in glycoforms in other posttranslational modifications? DR. PATWARDHAN: Sure. So, the
effect of -- well, our position is that all glycoforms must be present in the biosimilar that are present in the RMP. There should not
be any new isoforms that we have introduced and you can expect a high level of similarity in the major isoforms between the -- in the quantitativeness of the major isoforms between the RMP and the biosimilar. But, to expect even a minor isoform that they have to be exactly on top of each other is -- in our opinion is not consistent with the biosimilar concept. Regarding the position, you can always do functional. You always have
Page 85 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 that trial? functional bioassays that can measure the impact of differences in minor glycoforms on the bioactivity and even beyond that, you also have biomarker studies that without going into patients or animals, you can still predict the effect of differences in minor glycoforms on the activity and on the PD markers. can recreate using those studies. DR. BEHRMAN: DR. MARCHAND: comments today. I wanted to ask the question with regard to the single-arm clinical trial, you have an n of 67. You made the comment -Dr. Marchand. Thank you for your So, we
mention that in your post-marketing trial. It's extensive that you have a thousand patients enrolled. Can you talk a little bit about If it's a registry or if it's an
actual trial and would you advocate that for products as we implement biosimilar in the U.S.? A similar type of system. Neal R. Gross & Co., Inc. 202-234-4433
Page 86 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. PATWARDHAN: Yes, so In fact, in
definitely, we would advocate.
our opinion, clinical trials are really designed to separate -- the resolution of clinical trials -- while the relevance is very high, the resolution of clinical trials is significantly lower than the very high resolution bioanalytical techniques we use in the front of the development. So, our view is that the clinical development is really designed to separate or see kind of major differences. If there are
any major differences between -- at the clinical level between the RMP and the biosimilar. The final proof of whether
they're exactly the same or whether there are any minor differences are only going to come from post-marketing studies. So, our view is that the clinical studies can be designed in a pragmatic fashion with the expectation that there should be extension post-marketing surveillance so that Neal R. Gross & Co., Inc. 202-234-4433
Page 87 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. over time the FDA has the ability to take further action if necessary. And the same thing probably can apply towards some of the other questions that have been posed before regarding the drift of interchangeables. I mean you can approve, you
know, A prime based on all the due diligence, but then there should be an expectation on the sponsor that in post-marketing phase whole studies they show clear differences between A prime and B and very well would be that, then interchangeability will be taken away for the brand. DR. BEHRMAN: Thank you for your
Our next speaker is Mark McCamish
from Novartis. DR. MCCAMISH: Thank you. It's my
privilege to represent the Novartis Group of companies and sharing with you our worldwide experience in development and commercialization of biosimilars. I'll be addressing three items Neal R. Gross & Co., Inc. 202-234-4433
Page 88 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 today: biosimilarity, interchangeability and
use of non-U.S. licensed products in support of clinical development programs. We'll
address all remaining issues in our support to the document. Novartis speaks with 30 years of experience in development of biologics including functioning as a contract manufacturer, developing diagnostics, vaccines, novel products as well as biosimilars. We feel that competing in all
sectors is completely compatible and that in doing so, we will encourage innovation. Access is an unmet public health need that lower-cost biosimilars will and have already addressed. I have to pause here and just address the access issue. It's a fundamental
stimulus for me and many families that you are aware of deal with this issue in terms of decrease access. My wife of 35 years has ankylosing Neal R. Gross & Co., Inc. 202-234-4433
Page 89 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 spondylitis for the past 30 years. We have
had good health care coverage in the U.S., now in Europe. She's never qualified for use of
an anti-TNF biologic due to cost issues as a primary factor. So, it's a personal issue for me and from a Novartis perspective, we feel that dealing with all aspects of novel as well as biosimilar products meet unmet medical needs including access moving forward. A theme we will have is that standards should apply. High standards should That biosimilars
apply to biologics equally.
that demonstrate a high similarity to a U.S.referenced product should have an abbreviated clinical program. A key is that scientific and regulatory consistency should be applied by FDA fairly and irrespective of sponsor. You have got excellent experience with product comparison whether it's in looking at generic products and establishing Neal R. Gross & Co., Inc. 202-234-4433
Page 90 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 equivalents such as the recent approval of enoxaparin by Sandoz and Momenta or looking at manufacturing changes, making a judgment of comparability or with the new legislation looking at high degree of similarity within a biosimilar. Our point is that identical
science applies in these applications and the science is fundamental and universally applicable. This pyramid taken from the published literature shows our foundational principle. That is degree of similarity is
based on analytical characterization and iterative improved processes. You can see that the base of the pyramid is formed by physical chemical biologic characterization supported by worldclass analytics and what we do is reiterate in terms of process development. We change the
process to achieve these highly similar product attributes including posttranslational modifications. Neal R. Gross & Co., Inc. 202-234-4433
Page 91 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 So, we modify the process to achieve the post-translation modifications that we feel are similar to the reference product and that way it is a pyramid and will require less pre-clinical, PK, PD, or clinical trials than would be expected in a traditional BLA approach. Once we achieve what we consider highly similar, then we should have a streamlined pre-clinical and clinical program and if the product quality attributes deviate from the reference product, then more preclinical and clinical studies should be required. You're very familiar with manufacturing process changes. You've
evaluated that as being highly similar in the past. Whether these encompass new master cell
banks, different cell lines, new manufacturing facilities or different purification processes, you've made a judgment call about the pre-change and post-change product being Neal R. Gross & Co., Inc. 202-234-4433
Page 92 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comparable and in doing so, they achieve a level of high similarity in an analytical level and sometimes that requires additional work. When you've made that judgment and the pre and post-change products are deemed comparable, they are interchangeable. The
U.S. market physicians, pharmacists, payers, patients are not even informed about the shift in the product attributes because you've made a judgment that they're comparable. We suggest that similar scientific and technical factors should be used to make a similar decision with biosimilars and that that biosimilar product quality attributes that are within a referenced product goalpost which I'll justify an abbreviated pathway. This slide is probably the critical slide in the deck and it outlines the view of the quality range of the originator that sets the product goalpost. We have an ongoing sophisticated Neal R. Gross & Co., Inc. 202-234-4433
Page 93 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 analytical characterization program for reference products. We follow them over time
through batch-to-batch variability as well as through a process change. There's been a lot of discussion about drift today and yesterday. experience, we don't see "drift". In our We see
batch-to-batch variability and then we see jumps and those jumps are usually sudden. We
assume they're associated with manufacturing changes and we outline here in this graph, for example, the initial originator quality that we look at, batch-to-batch variability. Then
we see new originator quality that's usually associated with manufacturing changes. We feel that this sets up, depicted by this graph here, this arrow, the complete quality range for claiming comparability for a biosimilar and we utilize that as our goalpost to achieve a highly similar biosimilar product and then we iterate that process development as well as analytical Neal R. Gross & Co., Inc. 202-234-4433
Page 94 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 characterization to achieve that. In fact, it takes us twice as long to develop a biosimilar product than it does a novel product because of those iterations and process change to achieve this. Once this is achieved, again, we establish narrow release specs and follow that product through commercialization and then if this is achieved, we petition for an abbreviated clinical development program. In terms of interchangeability, we would use the same scientific approach that I've just outlined in terms of looking at product quality attributes as a core. However, the statute does refer to switching studies. So, accordingly, we feel that we'll
have to demonstrate safety, purity and potency that are not impacted by switching going forward. In this slide, we just outline an approach that we would suggest. We think that
it is scientifically plausible to assess risk Neal R. Gross & Co., Inc. 202-234-4433
Page 95 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 of switching in a phased restudy design. However, it is not scientifically feasible to do this looking at immunogenicity alone. other words, we can't power study if immunogenicity's one or two or three percent in terms of a non-inferiority approach. So, what we proposed and what we've done is we use efficacy as a surrogate for significant clinical immunogenicity. If In
the efficacy is impacted by immunogenicity, you can pick that up through a traditional non-inferiority design and here we're simply using an oncology approach using supportive products such as EPO or GCSF. Patients undergo multiple cycles of chemotherapy with such support and we look at subjects that have been assigned to the reference or the biosimilar product without switching and compare and contrast the efficacy over multiple switches to those patients exposed to switching from the reference to the biosimilar product over time. Neal R. Gross & Co., Inc. 202-234-4433
Page 96 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 You can establish a noninferiority margin in interactions with regulatory authorities to agree upon that and then do such a study to give you confidence in this moving forward. Again, we look at immunogenicity of each of the patients, but it's not powered to show a difference in immunogenicity. The use of supportive data. key to be able to use data from non-U.S. licensed products in moving forward. It's key It is
to have a global development program and we would again take the same approach. We can utilize the same analytical characterization of the non-U.S. licensed product. Compare that to the U.S. licensed
product and if they have overlapping product attributes based on formal analytical characterization and comparability, then we feel that that data can be used in support of a file including pivotal program. The other aspect that can be done, Neal R. Gross & Co., Inc. 202-234-4433
Page 97 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 you in collaboration with EMA can look at where products have been manufactured and make a determination of whether it's in the same manufacturing site for drug product growths drug substance and that could be helpful in limiting repeated development in every region. So, finally, in summary, Novartis urges FDA to use past experience with comparability exercises to evaluate biosimilars. Foundational principle is that
the product attributes within the origin product variability should mandate an abbreviated clinical development program. Current analytical technologies allow robust analytical and biologic characterization of even complex biologics. They can't pick up everything, but they pick up most issues that can be looked at and certainly the same issues you've evaluated with comparability exercises. Solid regulatory science is a basis for determinations of what additional Neal R. Gross & Co., Inc. 202-234-4433
Page 98 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Schwartz. MR. SCHWARTZ: presentation. Thank you for the data beyond characterization is necessary and for biosimilars, the product attributes that are within the distribution of the product attributes of the reference product would justify an abbreviated pre-clinical and clinical program to address biosimilarities, use of supportive data and interchangeability. The more it drifts, the more data is necessary. Thanks for your time. DR. BEHRMAN: Thank you for your Mr.
Just a quick seeking
clarification in this admission that you made. Can you elaborate a little bit on why you take issue with the reference to interchangeability being a higher standard in the statute towards the end of your submission? DR. MCCAMISH: Yes, sir. The main
Page 99 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 issue there is that we don't create a product from an analytical perspective or actual development of the product. That would be
different for the biosimilar or the interchangeability. So, the higher standard that is referred to is really more data necessary to get that approval, but it's not a higher standard for the product per se. Because when
we develop the biosimilar, we don't anticipate developing a lower standard biosimilar for biosimilarity and then a higher standard product for interchangeability. So, it's mainly around there's more data required based on the statute for justification of interchangeability, but the product itself is high quality moving forward. MR. SCHWARTZ: It's just that it's
a more exacting standard, not a higher or lower standard. DR. MCCAMISH: DR. BEHRMAN: Correct. Correct.
Dr. Kozlowski.
Page 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. KOZLOWSKI: So, I want to
follow up on your comment on goalposts. DR. MCCAMISH: DR. KOZLOWSKI: Yes. So, you're
suggestion is the entire range of attributes that the product has had throughout the market are a legitimate target for biosimilarity. So, would that also in your view be a legitimate target for interchangeability? DR. MCCAMISH: Yes, and the issue
there is that the products as illustrated here, they've been exposed to patient populations and so, the product attributes that you're looking at have been exposed in patient populations and so, when that originator changes in terms of manufacturing process, you've made a determination of the comparability of those products. Those
products at times have been on the market at the same time depending on the expiry date of the old versus new, et cetera. Those have been used Neal R. Gross & Co., Inc. 202-234-4433
Page 101 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 interchangeably. They've been exposed to
patients and we feel that entire area is not only valuable from a biosimilar perspective, but also for an interchangeable biosimilar. But, again, that's an analytical base approach. DR. KOZLOWSKI: So, to follow up
on your answer, so, if you make a manufacturing change, you have a step function change and you have crossover for a short period of time. So, the patient population
would be exposed to the different products for some level of time and then, you know, much more similar batch-to-batch variation within products. So, when you have two products on the market at the same time though that have that same range of difference, you're exposing the population to this larger difference between products all at once and I guess I want your sense about whether that's a consideration for interchangeability. Neal R. Gross & Co., Inc. 202-234-4433
Page 102 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 before this. understand. Ms. Maloney. MS. MALONEY: It was on the slide I just want to make sure I Where you talk about for DR. MCCAMISH: And again, my
response would be it is a consideration that should be evaluated, but when we're talking about this, this is not an easy thing to be able to create a product that has all attributes within this range. huge range going forward. This is not a
This is not
products that are licensed outside of highly regulated areas or regions. So, it is very difficult and challenging to get these product attributes within this range and the expectation is that not often can you achieve that. If you do
achieve it, it should give you more comfort in terms of the biosimilarity, extrapolation and interchangeability. DR. BEHRMAN: Other questions?
manufacturing process changes and how and I Neal R. Gross & Co., Inc. 202-234-4433
Page 103 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 think your opinion is that they're actually for the same company's product treated as interchangeable. My understanding is when the change is made the old product is no longer on the market. So, I'm not sure if I understand
the interchangeability. DR. MCCAMISH: Simply that
interchangeability meaning that you could use either and for a period of time, again, depending on the expiry of the products because when a manufacturer changes, there is usually a lifetime of the product, the preproduct and the post-product and depending on whether that's in Europe or the U.S., there is the potential for being exposed to both of those products. And there's no labeling. First,
there's no labeling that says the product's been changed. So, it's not communicated to
the clinician or the user or the payer and secondly, there's no difference in terms of Neal R. Gross & Co., Inc. 202-234-4433
Page 104 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 next slide. slide. whether you order a product pre and postchange. They can be interchangeable because
the pharmacist doesn't know that that batch or whatever is the new product quality. DR. BEHRMAN: DR. JENKINS: Dr. Jenkins. A couple of First, within
questions along that same line.
innovator changes, they have access not only to the product, but also to the API which will be different for the biosimilar who's trying to compare himself to the innovator. only have access to the product. So, does that have any implications in your mind about the ability to demonstrate comparability? And secondly, I think it's on your If you could advance to your next They
How will the biosimilar product know
about those ranges of changes that have occurred to the innovator? range? How will know that
You're saying that's a range that you
should be able to target your biosimilar to Neal R. Gross & Co., Inc. 202-234-4433
Page 105 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 to develop. program. fit in, but how will you know what those ranges are? Those are not publicly available Are they? Good questions.
information I don't think. DR. MCCAMISH:
Let me address the first -- the second first. In terms of the range, what I mentioned is we have an ongoing screening program. So, we follow this over time. I can
only comment about what we do and so, we have access to our own characterization of products over years, over batches, over manufacturing changes. So, we accumulate this data. is not publicly available data. It's data This
that we generate and accumulate in comparison to our product as it's going through the development phases. Biosimilar takes about seven years It's not an overnight development
So, we do this over time and so, it It's our own that
is not a public database. we generate and compare.
Page 106 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 In terms of the first question, in terms of looking at the API or the drug substance, what we use is a fairly sophisticated deformulation strategies. have our product that we have made. We
We put
that product in the identical formulation of the originator product and then we deformulate that and we look at if there's any product changes to that based on our API drug substance compared to what we utilize and then we modify that deformulation process to achieve that with the originator to give us confidence in that capability. DR. BEHRMAN: Okay. We're not
doing as well as yesterday. more questions. DR. KOZLOWSKI:
Dr. Kozlowski has
So, in your
switching study for immunogenicity basically relying on decreased efficacy, so, I think you had a number of 50 patients per arm. So, that
would be sensitive only to a very large percentage of patients having neutralizing Neal R. Gross & Co., Inc. 202-234-4433
Page 107 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 antibody. So, I guess I'm wondering where that number came from and what level of sensitivity to neutralizing immunogenicity do you think is appropriate? DR. MCCAMISH: great question. Sure and that's a
What we're trying to
demonstrate is a pragmatic scientific approach going forward. We've recognized and I've
mentioned that you cannot feasibly do a study powered on immunogenicity. powered on immunogenicity. So, this is not This is powered on
whether there's a significant effect that immunogenicity alters the efficacy. And you're absolutely correct that you would not be able to pick up from such a small study issues regarding immunogenicity if there's a 1 or 2 or 3 percent, but you can pick up a major impact in terms if it has an efficacy. Each patient would be monitored for screening antibodies as well as Neal R. Gross & Co., Inc. 202-234-4433
Page 108 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 neutralizing antibodies if the screening antibody test is positive. But, the question becomes how can you balance moving forward with developing a biosimilar in a efficacious and efficient way. Because it takes about $200 million to develop these and even the cost of the originator product that we have to purchase can be between $70 and $100 million. So, these are the issues we have to deal with. DR. BEHRMAN: your comments. We're going to take a break. We'll resume at 10:15. Thank you. Okay. Thank you for
(Whereupon, at 10:03 a.m. the above-entitled matter went off the record until 10:18 a.m.) DR. BEHRMAN: will be Nikhil Mehta. DR. MEHTA: Good morning. My name Our first speaker
is Nikhil Mehta and I'm here on behalf of Neal R. Gross & Co., Inc. 202-234-4433
Page 109 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Merck and Company. We appreciate the opportunity to comment on the approval pathway for biosimilars and interchangeable products. Merck has a broad portfolio of biologics products. We have been and continue
to be a leader in the disease prevention space through the development of vaccines including several that are listed here and many others that aren't. In the innovative biologic space, our products include Intron A, Remicade outside the U.S. and Follistim. We also have
significant experience in development of second generation products in each case. include PEG Intron, Simponi and Elonva. Merck is our business here that focuses on the development and commercialization of biosimilars. We They
currently have several biosimilars in development and anticipate having five biosimilar programs in advance development by Neal R. Gross & Co., Inc. 202-234-4433
Page 110 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 2012. Our approach is to develop both innovative biologics and biosimilars to the same consistent high quality standards and scientific standards. We believe that consistent high scientific integrity standards should be used in assessment of similarity in the development of biosimilars and innovative biologics. Have
the experience that industrial agencies have had over the years. In the biosimilars, however, you should keep in mind and factor in the extensive nature of the change which includes cell lines, manufacturing processes, manufacturing facilities, analytics and process controls and on and on. That's a
significant change and based on that, the rigor of the comparability exercise should be significantly higher. We'll focus today on showing our perspective on three key issues which are Neal R. Gross & Co., Inc. 202-234-4433
Page 111 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 likely to have a major impact on the development of biosimilars from our perspective: Establishment of quality
standards, the need for clinical trials for approved biosimilars and clear and stringent basis for extrapolation of indications and the use of ex-U.S. supporting data. Setting private quality standards for comparability demonstration poses a challenge for biosimilar development and the previous speaker Dr. McCamish also shared the same thinking. We have similar thought
process actually. Product variabilities inherent to biologics and this includes both batch-tobatch variability and product microoriginating. Further, more reference product
quality attributes change over time due to drift and manufacturing process changes. From a perspective of developing biosimilars, we can say that it starts with a -- it's a very targeted activity with a Neal R. Gross & Co., Inc. 202-234-4433
Page 112 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 thorough analysis over the years of multiple lots of reference products to generate a range of results. We believe that the entire
analytical range for reference products that we have been able to generate from those analysis should constitute a private window for the development of biosimilars as the originator has already qualified them through their clinical or other trials or other studies as relates to patient exposure. We also acknowledge that the actual range of the quality attributes for the biosimilar would be a subset of this window keeping in mind the quality attributes within the manufacturing capability of the biosimilar process. In spite of these targeted efforts to insure product comparability, it's likely that differences will be observed due to complexity of the products and the process and analytics. The current state of science does Neal R. Gross & Co., Inc. 202-234-4433
Page 113 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 not allow to credit the impact of these changes. Therefore, we strongly believe that
beyond the determination of CMC comparability demonstration of similarity of safety and efficacy profile for the biosimilar should be required. To that end, clinical trials demonstrated bioequivalence necessary. We
also believe that a robust non-inferiority study comparing biosimilar to reference products should be required in one key sensitive indication. Extrapolation to other indications could be supported by open and safety studies in each of these indications as the mechanism of action is well understood. Regarding the use of supporting data from studies with ex-U.S. comparator, it's important to note that in most cases the originator product approval is in different regions especially the ICH regions and notably in the EU are based on the set of trials by Neal R. Gross & Co., Inc. 202-234-4433
Page 114 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the innovator and consequently use the same drug product, i.e., a common original reference product. We also have to keep in mind that over time there's a risk of divergence of quality attributes that can be U.S. and exU.S. product and the differences in approved indications and patient populations. With that in mind, the biosimilar sponsor should be required to justify their allowance update out of the ex-U.S. sponsor. It will be very valuable to insure that the ex-U.S. reference product could have been approved based on the same set of clinical trials at least in the initial case as a U.S. reference product as that insures good -- of a common reference to the biosimilar. Bridging data furthermore between the biosimilar and the U.S. and ex-U.S. reference should be provided and this could include CMC comparability using sensitive physicochemical and biophysical and in vitro Neal R. Gross & Co., Inc. 202-234-4433
Page 115 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 testing. Clinical PK, PD and immunogenicity comparability will also be valuable to demonstrate. And finally, it's also important that the studies with the non-U.S.-licensed comparator be performed on the same population, U.S. population, for the same indication using the same administration as those of the U.S. as to make them into critical. Finally, on the subject of safety, biosimilar manufacturers should have a robust PVG system capable of tracing adverse events at the patient level with individual lots of products and some solutions were provided yesterday and I realize it's a complex problem, but I think it's an important one. The use of proprietary unique identifiers and physician/pharmacist education programs should mitigate inadvertent substitution or interchangeability. Neal R. Gross & Co., Inc. 202-234-4433
Page 116 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 And finally, all constituents should receive educational updates to manage the unique nature of pharmacovigilance as we embark on this effort to introduce biosimilars into this system. In conclusion, patient safety is certainly paramount in our efforts to commercialize biosimilars. Regulations should
be based on clear scientific and clinical evidence of similarity and safety. We believe that one positive control clinical trial and a key indication should be required to support the approval of a biosimilar and that there could be ways including the one which we suggested, possible way, whereby we could allow the ex-U.S. data to support the approval in the U.S. And finally, extrapolation of indications should be allowed for all that clinical evidence including control trial and indication and supplemented with open-label safety studies and other indications. Neal R. Gross & Co., Inc. 202-234-4433
Page 117 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Jenkins. DR. JENKINS: I'm trying not to. Thank you. DR. BEHRMAN: Thank you for your Dr.
Unfortunately, they took away your last slide, but okay, there it's back. That one positive controlled clinical trial that you're recommending for the initial approval, what's your proposal for how that should be designed and analyzed? We've heard various proposals yesterday and today. Some concerns about a
strict non-inferiority or equivalence analysis leading to a sample size that would be not feasible or economically a disincentive. what's Merck's proposal for how that one positive clinical trial would be designed and analyzed? DR. MEHTA: We believe that the -So,
we do believe that it is feasible to run a control trial and we believe that the nonNeal R. Gross & Co., Inc. 202-234-4433
Page 118 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 inferiority margin that essentially preserves a substantial portion of the difference in a trial of potential biosimilar and referenced products should be essential. I take that a equivalence trial is certainly also -- from our experience, an equivalence trial is not going to be substantially larger and certainly provides a greater assurance that the product is going to be biosimilar. DR. JENKINS: Does Merck have any
thoughts on how we would set those margins? You know, I mentioned yesterday non-inferiority analyses are often used in the setting of active control trials to establish that the new product is safe and effective for approval. Which is different from saying that it's not clinically meaningfully different from the active control. So, are you talking about retaining 50 percent of the estimated effect size of the active 80 percent/90 percent? Neal R. Gross & Co., Inc. 202-234-4433
Page 119 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Have you given any thought to where you would set that bar to be a reasonable standard for not clinically meaningfully different, but also not so burdensome that it would be infeasible to conduct the study? DR. MEHTA: We think that it's --
I don't believe we are -- the exact number where the bar should be set. However, we do
acknowledge that if the bar is set too low and your trial comes out at the lower end and passes through, it will still be difficult to convince prescribers to use the product. So, I think that needs to be a reasonable balance. I don't think we have an
actual number in mind as to where it should be. DR. KOZLOWSKI: To follow up on
the idea of one trial for a key sensitive indication, so, I'm assuming by key sensitive indication that there is one indication most sensitive to structural variation and potential differences between the biosimilar Neal R. Gross & Co., Inc. 202-234-4433
Page 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Ms. Maloney. MS. MALONEY: I just wanted to go and the innovator. So, is there always a key
sensitive indication? Because you can worry about different adverse events in different populations. You know, you might have
different mechanisms of efficacy. DR. MEHTA: I think the selection
of the key sensitive indication would be dependent on the response in that indication. I think some are very sensitive through the dose response. Would be one way to look at it
from our perspective. Certainly, it will also be useful to pick it in an indication where there's a substantial uptake of the product. DR. KOZLOWSKI: And would
mechanism or other potential safety risks in a population play a role in that? DR. MEHTA: DR. BEHRMAN: Absolutely, yes. Other questions?
Page 121 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 to the slide that had to do with safety and monitoring and the naming issue. I'm not sure
if I heard you take a position on the need for a unique name or not from a pharmacovigilance point of view. We've heard some people speak to the fact that maybe the NDC number is sufficient because it's detailed enough. So, can you just comment on that? DR. MEHTA: We believe that having I think it's going
a unique name is valuable.
to prevent inadvertent substitution and certainly, we also believe that it's useful for patients' awareness of what they are using as well as physicians awareness. There are NDC codes and other ways where we can track pharmacovigilance, but I think having unique names provides other benefits other than just pharmacovigilance. DR. BEHRMAN: DR. JENKINS: Dr. Jenkins. I want to follow up
on that because I misread your slide earlier. Neal R. Gross & Co., Inc. 202-234-4433
Page 122 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 It says the use of proprietary unique identifiers. Yesterday, we were talking about nonproprietary unique identifiers. So, are
you suggesting that they would have the same nonproprietary names. Say Filgrastim, but you
would differentiate by the trade name? DR. MEHTA: I think that we should
have -- it would actually be useful to have different names other than -- not just the proprietary name, but even the -DR. BEHRMAN: I have one question
back to drift or jump or whatever term. To you have any recommendations to the agency in terms of how we can assure over time that if, indeed, products were determined to be interchangeable that the soundness of that decision remained? DR. MEHTA: I think it's a
challenging question for an interchangeable product. I'm not sure that we have an answer. DR. BEHRMAN: Okay. Thank you.
Page 123 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Genentech. DR. WENGER: name is Michael Wenger. That's correct. My Still four? Wenger. DR. WENGER: DR. BEHRMAN: Yes. Hoffman-La Roche and Thank you for your comments. Our next speakers, we have four. Oh, just one. Okay. Michael
I work in late-stage
development for La Roche and Genentech and I would like to thank the FDA for giving us the opportunity to express our views on this guideline. So, many speakers have already alluded to that safety should be the primary concern. We concur with this. La Roche supports the development of a regulatory framework for biosimilars and the approval process for biosimilars in our view must be based on the concept of similarity. Comparison with the reference and
innovative product, i.e., a rigorous head-toNeal R. Gross & Co., Inc. 202-234-4433
Page 124 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 head quality non-clinical and clinical evaluation. Extrapolation of safety and efficacy across indications should not be supported without adequate clinical trials, but a similar entrance must meet the firm criteria for immunogenicity testing and postauthorization risk management including pharmacovigilance. Biosimilars should be uniquely identified and we do not support automatic substitution or interchangeability. Immunoglobulins are highly complex molecules and I would like to focus on immunoglobulins or monoclonals in particular for the remainder of the talk and basically address clinical aspects. Any subtle change in any of these parameters might prompt basically a new biologic or a significant variation in the biosimilar and it continues even with the mode of action for monoclonal antibodies. Mode of
Page 125 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 actions are complex, not at all understood for all monoclonals. Sometimes they are easy.
Sometimes they are more difficult. So, the in vivo net contribution of the mode of action they are often incompletely understood, but as rituximab as been mentioned before, we also need to pay attention that for some monoclonals there's actually more than one mode of action such as apoptosis, such as complement activation or ADCC. For rituximab and each of those three
mode of action might contribute differently regarding different disease states. Demonstration of clinical similarities is, of course, a challenge and biomarkers or well established in vitro potency assays might help us. with the mechanism of actions. Both correlate Sometimes
quite well with the monoclonal antibodies. But, they are not validated surrogates of clinical benefit. For
biosimilars, similarity concerning efficacy Neal R. Gross & Co., Inc. 202-234-4433
Page 126 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 and safety with the reference product has to be demonstrated in adequately powered clinical trials. Now, the demonstration of clinical similarity -- the proof of clinical similarity as said before requires in our view a demonstration of equivalence with predefined margins. While the non-inferiority superior
efficacy is not acceptable because it might be connected with increased safety risks and there might be actually even consideration be given that within the particular product different safety margins need to be implied for different indications regarding only or relating to the differential benefit a drug has in one indication. The focus of the clinical trials for biosimilars will be to demonstrate similarity to the reference product rather than benefit for patients. Proof of effectiveness. In
oncology, these endpoints accepted to be Neal R. Gross & Co., Inc. 202-234-4433
Page 127 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 correlated with survival and -- refer here specifically to oncology. Overall survival is
usually an accepted endpoint of progressionfree survival. There's no justification for
an accelerated approval of biosimilars based on nonvalidated surrogate endpoints such as response rate. Of course, if these endpoints
have been validated, that's a different story. Which endpoints should be used? Activity endpoints such as biomarkers can often be measured faster, cheaper and with more precision than clinical outcomes. However, these should not be taken as a sole basis for judging similarity. Similarity in effects on a biomarker will not always predict similarity in effects on clinical outcome. regulatory implications. This has some
Head-to-head
comparisons of effect of biomarkers might be quite powerful tools in identifying or excluding some clinical differences and may prove valuable in supporting extrapolations to Neal R. Gross & Co., Inc. 202-234-4433
Page 128 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 immunology. other indications. But, the demonstration of similar effects on an easier measured biomarker should be considered necessary, but not usually sufficient to establish equivalence. There's some example in For example, the impact on
circulated levels of cytokines or inflammatory markers is a well-established biomarker that does correlate at least in some instances with clinical outcomes. On the country for B cell diseases, a potential biomarker is the reduction of lymphocytes counts which basically is working for any of the B cell antibodies in development, but does not correlate with the intent of or with the extension of the clinical benefit. Extrapolation of safety across indications may be adversely impacted by any of the following: Concomitant medications,
immune competence of the patient's Neal R. Gross & Co., Inc. 202-234-4433
Page 129 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 immunogenicity, the approved dose or susceptibility in the populations to specific potential toxicities. Against some regulatory implications this might have, safety in immunogenicity data in all target populations and disease should be, in our view, provided. When an innovator drug has safety concerns and a second indication that are different from or greater in magnitude than those in the first, the biosimilar generally should be assessed for those concerns as well. Again, the example of rituximab had three different modes of action and each contribute in a different way to different indications, different lines of treatments. So, from our review, if we take this example, extrapolation from one disease to another, like rheumatoid arthritis to oncology, likely involves different modes of actions, different effective mechanisms and certainly a different immune status exists in Neal R. Gross & Co., Inc. 202-234-4433
Page 130 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 our RA patients as compared to oncology patients. avoided. Extrapolation from line of treatment, first line versus relapsed versus refractory, might put patients at risk again due to an immune system. It is more affected Affected In our view, that should be
in later lines of treatment.
mechanisms such as NK cells necessary for ADCC might be absent. So, in our view, again, this
is not a valid extrapolation mode. Extrapolation from single agent to treatment to combination treatment is in our view also not warranted due to high probability of different net contributions of the mode of actions. What might be a possible way to extrapolate is if one concomitant treatment to another allowing for clinical testing of biosimilar only with one chemotherapy or one additional treatment for the broader approval. So, in summary, for these clinical Neal R. Gross & Co., Inc. 202-234-4433
Page 131 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 issues that we address in this talk and we will address more in our written answer, a strong CMC and nonpolitical data limiting the potential differences are critical. For
complex molecules, in our view, there will always be differences. It's just a function
of how hard you look to detect those. Pre-clinical toxicity studies are essential, but clinical head-to-head trials of the biosimilar product versus an original reference in our view are still essentially required. The goal should be to demonstrate equivalence not just non-inferiority. It's,
of course, difficult to do in small trials. For lifesaving drugs, only a small confidence interval may be allowed. Equivalence needs to be also demonstrated for safety and efficacy. Surrogate endpoints are only acceptable if a clear and clinically-validated correlation exists to the desired endpoint. Neal R. Gross & Co., Inc. 202-234-4433
Page 132 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 questions. comments. Jenkins. DR. JENKINS: I do have two For some of the biosimilar products, maybe an innovator development pathway might be a suitable alternative, but that's, of course, something we leave to the biosimilar companies. Thank you for your attention. DR. BEHRMAN: Thank you for your Dr.
I noted with interest, I don't
think your slides are numbered, but your slide where you talked about the demonstration of clinical similarity. You proposed that the
endpoints that we would use in oncology would not allow for surrogate endpoints like response rate. I found that curious.
Why would it acceptable to approve the innovator on response rate, but not approve a biosimilar on response rate given that there are well-known cases where progression-free survival has not translated Neal R. Gross & Co., Inc. 202-234-4433
Page 133 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 into overall survival and yet, you know, those products are out there? So, I'm just curious
why would you take that position? DR. WENGER: We actually think the
exact same standards should be applied to biosimilars as to innovator products. there is indeed a correlation that is established between say response rate and progression-free survival or progression-free survival to overall survival in the disease for the innovator product, that same pathway should be open also for biosimilars. DR. JENKINS: I would note by the So, if
way that you're going to get 12 years of exclusivity. So, you shouldn't have 12 years
of still having the surrogate and not having the conversion to the regular approval. maybe this is a moot point. DR. BEHRMAN: just for clarity. Yes, but just as -So,
So, you're position is that
if a product is under accelerated approval, has not achieved traditional approval, it is Neal R. Gross & Co., Inc. 202-234-4433
Page 134 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 not a -- and should 12 years have passed, it should not be a candidate for a biosimilar. Being in a reference pack for biosimilar DR. WENGER: So, if an innovative
product has been approved on the basis of the proof that say a surrogate endpoint is actually correlating with the primary endpoint, say progression-free survival, we think this road should be open to biosimilars as well. So, just the same standards and rules should apply to both biosimilars and to innovative products. DR. JENKINS: My second question
related to your rituximab example and I wanted to revisit a question I had asked one of the other sponsors earlier. Which is, you know,
if you're the innovator for that product, apparently there are now biosimilars approved in other parts of the world. So, what's your
experience been in identifying any safety concerns or efficacy concerns that have arisen Neal R. Gross & Co., Inc. 202-234-4433
Page 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 from those approved biosimilars to rituximab? You made the case that it should be a pretty high bar. evidence of a problem? DR. WENGER: So, we have some So, have you seen
experience with India and we can't say that we see a problem, but we also can't see that we or can't say that we have adequate information. Basically, the trial that the colleague was referring to is not published other than in abstract format. So, we don't -
- we are not able to confirm the efficacy information that was shown or demonstrated. With regard to this literature comparison as set in our view in a disease that is potentially life threatening like lymphoma or diffused large B cell lymphoma, we would used the agency to consider that the safety bars or the safety standards need to be very high for the comparative product. In
regards to the possibility that even if the Neal R. Gross & Co., Inc. 202-234-4433
Page 136 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 product is 5 percent less efficacious or has 5 percent or 10 percent more side effects, it might have a detrimental outcome if ultimately the goal of the therapy is cure. This might be different from drug to drug and so, we think actually an individualized approach for particular drugs might be warranted with regards to what actual trial needs to be conducted or not. DR. BEHRMAN: DR. KOZLOWSKI: Dr. Kozlowski. So, in your
presentation, you talk about clinical similarity and talk about the standards for that. So, do you feel that the similarity
exercise should be treated separately? There's structural similarity. clinical similarity. There's
There's pre-clinical
similarity and they don't interact or do you feel, in fact, that, again, information, as has been discussed before, should be leveraged in some way across these different sort of dimensions of similarity? Neal R. Gross & Co., Inc. 202-234-4433
Page 137 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. WENGER: Basically, our view
is we've looked into new forms, new versions of our own antibodies to basically bring the science forward and while we see that there's very high comparability on the pre-clinical end, it does not necessarily correlate with what we see on the clinical side of things Very subtle modifications would not necessarily would be considered relevant from a pre-clinical end might well translate into greater or smaller clinical benefits. So, in our view, this is a separate issue that should be look at specifically. DR. KOZLOWSKI: I think if any of
that isn't public, it should be shared. Because I think that's certainly of interest. And a quick question on extrapolation. So, again, your perspective is
really extrapolations are extremely unlikely except for very limited circumstances. So, to throw out an alternative, Neal R. Gross & Co., Inc. 202-234-4433
Page 138 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 say you had the two most different indications in a product that had five indications and you explored those two, do you believe you could extrapolate the other three? DR. WENGER: So, if you take this
example here where we have two extremely different indications, rheumatoid arthritis and lymphoma oncology, there might be a way to extrapolate within oncology from one disease or from one disease state to another. Again, for us, it depends highly also on the clinical benefit that is achievable with the innovator drug. If this
is a marginable benefit or say it's a benefit that can be achieved with relative ease, we would probably be more comfortable with this. While if we're talking about an overall survival benefit, for example, we would propose to redo the trial in each and every disease state. DR. BEHRMAN: DR. JENKINS: Dr. Jenkins. I'd like to go back
Page 139 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 standard? to your last slide again in your summary. for your clinical head-to-head trials, you wanted a demonstration of equivalence and you wanted a small competence interval. You So,
recommend equivalence for safety and efficacy and the surrogate endpoints are not acceptable unless they've been clinically validated. So, is that really an achievable To have a biosimilar approved under
that paradigm or is that essentially closing the door to a biosimilar? DR. WENGER: So, we've been asked
to comment on the guideline and I think these are our positions. We're not in the position
to comment from a biosimilar perspective on these issues. Having said this, I think there -I explain some scenarios where actually there is a feasible way of having a biosimilar being approved in some of these indications. Again, the perspective that we take here is that we shouldn't need to look at Neal R. Gross & Co., Inc. 202-234-4433
Page 140 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the drugs and what they bring to patients on a case-by-case basis. If the additional
benefit that a drug gives to patients is really very high, then in our view, the safety margins should be very narrow. In case this is a relatively low benefit or if the benefit can actually be say the drug doesn't work, through a subsequent treatment can be recaptured, that might allow for an easier pathway for biosimilars. DR. BEHRMAN: your comments. Okay. Thank you for
Our next speakers are Charles
Ebert and Crawford Brown from Watson Pharmaceuticals. DR. BROWN: Good morning. Watson
Pharmaceuticals welcomed the opportunity offered by FDA to participate in the hearing on biosimilars. The focus of our presentation is on two areas. Firstly, biosimilarity and the
second on the benefits of global development to progress safe and affordable biosimilar Neal R. Gross & Co., Inc. 202-234-4433
Page 141 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 products for the U.S. population. The benefits of global development a reduction in time, a reduction in resource and opportunities to eliminate unnecessary duplication of human and animal testing. In addition to looking to develop local guidance, we believe the Agency can support this global opportunity through regulatory harmonization and indeed FDA has participated actively within ICH that has created a framework for biological products by way of guidance and indeed in the '80s, FDA's pioneering role in evolving guidance for the new technologies based on DNA technology for protein therapeutics formed an excellent basis upon which scientific and regulator experience could then form a guidance under ICH such as ICH Q5E. And we believe that the activities of the European agency, the EMEA, offers a similar opportunity to leverage some of their guidance documents as a basis for scientific Neal R. Gross & Co., Inc. 202-234-4433
Page 142 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 dialogue in order to form a common scientific framework. The Agency can also support global development two further ways. Firstly, the
FDA should accept non-U.S. trials with nonU.S. source innovative product predicated upon ally to the principles enshrined within ICH Q5E, the demonstration of comparability to that -- to the product available in the United States. And lastly, post-approval safety requirements should align with other new U.S. programs when possible and should not exceed those of the innovator products. In seeking to develop regulation for biosimilars, we believe that there is no one size fits all approach. It will be case-
by-case basis and this reflects not only the breathe of complexity of biosimilar products and the range of product types, but also the understanding of the impact of determining there is a different in the relationship to Neal R. Gross & Co., Inc. 202-234-4433
Page 143 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 its structure and function and what that difference might mean in a clinical setting. Nevertheless, within the U.S., the use of comparability protocols has, indeed, permitted evaluations pre and post-change of biotech products to permit the introduction of new processes and indeed the stepwise approach starting from a biochemical, physicochemical methodology moving to non-clinical and if necessary, clinical. That cascade in staffing
has been an essential cornerstone of European approval of biosimilar products. Similarity should be demonstrated based on comparison of multiple lots of innovator and the biosimilar product. In short, a data-driven process whereby for the biosimilar product plus demonstration of similarity is necessary, is not sufficient and needs to be supported by the same set of scientific tools the application, if you will, of good science from day one in terms of manufacturing design, but Neal R. Gross & Co., Inc. 202-234-4433
Page 144 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 has been applied to innovative products, needs to be applied to biosimilar products so that we're able to produce them to predefined specifications within facilities that meet the standards of FDA current manufacturing process. I'll pass you to my colleague Dr. Ebert who will now address issues of nonclinical and clinical testing. DR. EBERT: Chuck. First off,
Thank you.
we think that significant advances have been made on characterizing biosimilars and in developing processes that allow the development of biosimilar products. That said, non-clinical testing and clinical testing to some extent should be conducted. However, having demonstrated comparability through chemical/biochemical similarity, that program for the non-clinical testing should be reduced appropriately. This
is consistent with guidance such as from the Neal R. Gross & Co., Inc. 202-234-4433
Page 145 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 EMEA and also the approval of several recent products. Moreover, unnecessary testing in animals is unwarranted and I might add also that certain animal models probably are not appropriate today. Many models exist and are validated, well recognized. They should be
utilized as part of the non-clinical program. However, there may be a lack of animal models for certain compounds in which case, conducting non-clinical trials let's say in chimpanzees may not be appropriate. However, in vitro methods can be utilized across essentially drugs and this allows us to demonstrate comparable similarity in pharmacology activity and potency. PK/PD should be demonstrated as part of the non-clinical program. There we
would recommend that a single pharmacokinetic trial in a single species should be adequate. Again, in vitro assays can help establish Neal R. Gross & Co., Inc. 202-234-4433
Page 146 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 pharmacology equivalence and similarity and PD safety trials should not be required. Again,
this is not necessary since these are not new molecular entities. A toxicity study in a single species is appropriate. The duration and the
species selection needs to be carefully selected in order to detect relative differences. Immunogenicity being a key
component of that. Other routine tox studies such as chronic toxicity, geno tox, reproductive tox, carcinogenicity should not be required since these have already been established for the innovator product. Additional studies may also be appropriate such as local tolerability and need to be assessed on a case-by-case basis. And as the product progresses through development, it is a cumulative evidence-base that you have shown similarity. If you've demonstrated chemical, Neal R. Gross & Co., Inc. 202-234-4433
Page 147 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 biochemical and non-clinical similarity, full clin pharm testing should not be required. Which is again consistent with guidances from other regulatory authorities. A single dose bioequivalency may be appropriate for demonstrating pharmacokinetic operability. However, other
approaches need to be considered as well have been presented and discussed throughout the last two days. Typically, the standard bioequivalency may be appropriate for most cases. However, the Agency needs to remain
open to other approaches as well. Tmax and other pharmacokinetic parameters such as half-life and clearance, of course, need to be considered when appropriate and PD similarity should be assessed if appropriate. There we need to really look at
the comparability margins and to have it justified on a case-by-case basis rather than picking an arbitrary number. Neal R. Gross & Co., Inc. 202-234-4433
Page 148 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 relevant. Some cases PD markers may not be They may not be appropriate In which
indicators of clinical response.
case, the Agency should exercise judgment in requiring PD testing. And I see we're blinking red. So, I'm just going to quickly go to we think that a single randomized control clinical trial should be adequate. The
efficacy endpoints need to be carefully selected. Surrogate endpoints are Safety comparisons need to be The standard safety
appropriate.
assessed as well.
components specific for that compound should be included as well as immunogenicity. We believe a single trial should support multiple indications when there is a common mechanism action and the size of these studies really needs to be considered in a manner to allow effective development of biosimilars and ICH-type exposures should not be required. Neal R. Gross & Co., Inc. 202-234-4433
Page 149 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 The conclusion is that biosimilars are not new molecular entities and having gone through extensive comparability testing plus limited abbreviated non-clinical/clinical testing, there's necessary assurances of quality, safety and efficacy. The FDA has a history of approving biological products based on comparability testing including several biosimilar-type products in the 505 pathway as well as postmanufacturing changes. We would love to see the FDA engage in harmonization through ICH. It think
that would allow for the development of global programs. A single clinical trial should support approval for all indications with a common mechanism. The acceptance of U.S. trials with non-U.S. source materials should be encouraged and can be based upon comparability testing and the FDA needs to use scientific discretion Neal R. Gross & Co., Inc. 202-234-4433
Page 150 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 that one. comments. Kozlowski. DR. KOZLOWSKI: In an early slide, in establishing requirements on a case-by-case basis. Thank you. DR. BEHRMAN: Thank you for your Dr.
you presented that any post-marketing requirements should be no different than the innovator and I guess I ask is that because you think the purpose of post-market studies for biosimilars will always be the same purpose as for innovators? DR. EBERT: Well, I'll address
We think that really biosimilars
should not be required to have additional post-marketing requirements beyond that of the innovator. I think one of the points there was that there may be post-marketing risk management programs in existence in other territories and that we should try to Neal R. Gross & Co., Inc. 202-234-4433
Page 151 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 harmonize with those, but again, the postmarketing requirements should not be any more onerous than that opposed on the innovator. DR. KOZLOWSKI: So, to follow that
up, it's conceivable that, for instance, the development program could be, you know, modified in some ways by the ability to use certain post-market studies. So, you know, it
may work in a couple of different directions to lock the ability of specific targeted postmarket studies. So, I guess I'm wondering again because if -- the reason to keep them the same is if the purpose is the same. DR. BEHRMAN: Could I ask a When you say
question because I'm not clear?
that they should be the same, do you mean that if there's a REMS program and so forth that it should be the same or do you mean that if the innovator with -- let's say it's been on the market for however many years and had a program of 20,000 patients. Did not have a
Page 152 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 post-marketing commitment study for any pharmacovigilance. That, therefore, perhaps
a biosimilar with an exposure of 5,000 patients should also not have such a postmarketing commitment? DR. EBERT: Well, I hope we don't
need to expose 5,000 patients in a biosimilar program, but I think our intent here was -and maybe we did not communicate properly. is that a biosimilar approved in Europe will likely have some sort of post-marketing pharmacovigilance risk management program. We should be able to -- in fact, I think the Agency would want to see that data coming in and that's what we meant by we would couple onto those programs. In addition, I don't think that additional REMS-type program or expanded programs should be required of a biosimilar that was not required of an innovator. sets the biosimilar up almost as being inferior coming out of the box and it has a Neal R. Gross & Co., Inc. 202-234-4433 It It
Page 153 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 bit further? higher risk which is not necessarily true. DR. BEHRMAN: But, putting asides
REMS for a moment which, of course, is a hot topic, perhaps a registry or other types of safety surveillance, a sentinel study for example, do you feel those would also be appropriate or inappropriate? DR. EBERT: I think it depends on
the particular product that needs to be assessed on a case-by-case basis. DR. BEHRMAN: DR. JENKINS: Dr. Jenkins. You mentioned that
you think that surrogate endpoints should be okay for the clinical study. The previous
speaker suggested that at least in certain indications the surrogate should not be acceptable for the biosimilarity comparison. Can you comment on that a little Why you think the surrogate
endpoint would be okay in the clinical trials? DR. EBERT: Well, I think again Let's say
it's going to be case-by-case.
Page 154 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 you're looking at osteoporosis, then bone mineral density I think is an appropriate surrogate endpoint. If you're looking at MS, I think MRI counting of lesions is appropriate surrogate endpoint. I personally think that overall response, you know, is an appropriate surrogate in oncology, but again, you have to determine that on a case-by-case basis. DR. JENKINS: One other question.
You make a lot of reference to ICH and harmonization and you also talk about FDA should be able to use data generated using non-U.S. referenced products. Would you limit that to ICH region countries for the non-U.S. product is registered or would you broaden that? DR. EBERT: I would in general
yes, limit it to ICH region countries, but I think you also need to be open to other situations based upon what data is available, Neal R. Gross & Co., Inc. 202-234-4433
Page 155 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the quality of the studies that were conducted and how supportive they are. DR. BEHRMAN: Any other questions?
Thank you for your comments. Our next speak is Vijay Tammara from Nuron Biotech. DR. TAMMARA: Thank you. Thanks
for the opportunity to come with our opinion from Nuron Biotech. I'm Vijay Tammara.
My experience -- my personal history is based upon my prior experience at FDA as well as in this field over the last 18 years. I was involved in developing a lot of
guidelines at FDA when I was at the Office of Clinical Pharmacology Biopharmacokinetics. wrote all the FDA guidance inventory and we wrote correlations. I was part of the working We
groups to develop those guidelines and actually, that intravenously -- worked at Merck and currently at Nuron Biotech. So, I'm going to -- an introduction as to what the biosimilarities Neal R. Gross & Co., Inc. 202-234-4433
Page 156 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 and we're going to consider today's presentation only in the biosimilarity factors to consider. We'll leave the comments, the
dockets on the other aspects of the open hearing here today and we will touch upon the comparability of PK/PD and economics biosimilars and what biosimilars mean for the future in general outline. So, biosimilars are defined as a product comparable in quality, safety and efficacy to a different product as has been -everybody has been mentioning the last couple of days. Because it's impossible to show two
protein products to be identical, the term biosimilar was introduced in the UN following biologics or biogenetics in the United States. Biosimilars as everybody has claimed or at least mentioned are not generic drugs because of the complex science involved. They are new non-innovated products and need be supported by every related clinical data at the time of approval and we have been talking Neal R. Gross & Co., Inc. 202-234-4433
Page 157 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 about what's the abbreviated clinical data that's required and how we're going to justify that and I will talk about it a little bit more during my presentation. So, I'm going to talk about the biosimilarity. Particularly the two questions
the forum has addressed us to considered. What scientific and technical data should FDA consider in determining whether a valid product is highly similar to the reference product notwithstanding minor differences in clinically inactive components? That is excipients. Current paradigm predominately realize empirical human data with minimal unity of prior knowledge and mechanistic understanding for decision making in most cases. For biosimilars, probably that's not
the right case because this are based upon prior knowledge and for biosimilars in general process is the product compared to the small molecules because it's a complex science Neal R. Gross & Co., Inc. 202-234-4433
Page 158 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 evolved. process. Once you make the process is Really compare the product in terms
of its comparability, in terms of quality and everything else and explain the design space and specifications and now, we have the process and enacted acceptance that's currently the product in a simple -- there is no other excipient used to really make a product other than just making -- a solution. So, if you are interested in the prior knowledge of the product, innovator product, and how that has been used it will play a lot of account for developing a biosimilar. But, the establishment has specifications based upon the originator product through characterization and lot-tolot variability of the critical characteristics of the drug product to -product profile for the biosimilar product. How you can achieve this not from the product Neal R. Gross & Co., Inc. 202-234-4433
Page 159 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 information, but probably obtain the product from the market and testing it and there bring a private profile so that you can make a biosimilar product meet those target profiles. And then designing of the manufacturer's process of a biosimilar product to the label development of the product to meet those specifications and we've been talking about the drift for the last couple of days and drift will occur. for the innovator product. for the biosimilar product. Drift will occur Drift will occur But, as long as
the drifts are within the space of those recommended target profile you should be okay. Clinical comparability data should be based on adequacy of design and characterization and uncertainly -- so, for the clinical that are actually locking for these, what uncertainties which we cannot address when we're defining the target profile or the target characteristics of the innovator product or the biosimilar product? Neal R. Gross & Co., Inc. 202-234-4433
Page 160 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 What are the uncertainties that we are sure of, but we are not able to address? That's where you need a clinical data to address those uncertainties within a reference product for a biosimilar product. So, what scientific and technical factors should the FDA consider? Analytical
and what is the range of structure difference for example? So, we think major structural
differences permissible will depend on the totality of the entire item and may vary by product type and from product to product. Data derived to demonstrate comparability utilizing comprehensive techniques to illustrate, for example, a natural sequence or a natural composition of mapping or maspec are two identification steps. Outside exclusions are leading the
different quality methods to insure that the analytical tools are matched. Like UV visual
or DSC or AUC, analytical certification. The compound is not quality Neal R. Gross & Co., Inc. 202-234-4433
Page 161 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 characteristics between the biosimilar and the referenced product. The major differences
through the improvement of analytical tools means you may have a different level of impurities, different level of aggregates, something like that. Is because of the
technology developed complicate the innovator product which was established and approved say 1990s or since 2000 at 2010. So, these improvement of technology, improvement of analytical tools thereby which your biosimilar product may have an enhancement in terms of the added goals, impurities and other things. look into that very carefully. And this is based upon the FDA's comparable adjustment which has become as a guidance and which hasn't been applied by all the regions ICH to develop further guidelines to show the comparability. Reasonable pre-clinical and clinical settings are required as per the ICH Neal R. Gross & Co., Inc. 202-234-4433 So, you need to
Page 162 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 guideline Q5E which prorates a baseline. not very helpful here by the ICH Q5E. develops a baseline. you're required. Particularly, you must base this in clinical studies. Limited at the time of It's
But, it
What the minimum studies
approval, but followed by post-marketing monitoring, post-approval monitoring. Post-
approval follow up is essential including an observation study to collect robust adverse data which can come from the CH of the product once it's approved and is placed into the market. So, to confirm that, I think an
observation study in the post-marking area in the pharmacovigilance part is very critical. For example, if you look at the quality differences between biosimilars and different drug products that been approved in the FDA and different products, in terms of the wholesales, there is a difference in wholesales where public data, the biosimilar product is made. For example, Valtropin has
Page 163 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 made with the East compared to the hemitrope. Different levels of impurities in these products. Zarzio and filgrastim, as it is a The change in the
different formulation.
excipients and different glycosylation process for some of these compounds. Still, none of these products which have been in the market so far did not lead to any significant adverse events or safety concerns. Indicating that a minor
change or deviations in the quality differences between biosimilars and different type products should not really consider a concern, a safety concern. Because none of
them are shown to be that to date. So what scientific and technical factors should the FDA consider in determining the analytical and what particularly -- the
question I am answering is, what analytical or clinical activities are necessary for a particular biosimilar application? As
described earlier, comparability testing for Neal R. Gross & Co., Inc. 202-234-4433
Page 164 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the API, which is a drug substance, and the product, is essential. Analytical and
clinical safety activities are necessary but may be abbreviated, notably in the case of PK and the PD. The differences observed in PK
profiles but comparable in PD is demonstrated and clinical events could be established, should be considered. I think I'm running out of time. I'll finish in one minute. So, for example, I'm giving you a graphical presentation here. concentration profile for PD. I have a plasma I have a
product where you give it at two different dose levels and you can see on the right-hand side the PK profiles are different, but if you look at the PD, they're all lacking more or less in the assay variation. So even though
if you see PK differences, if there is no difference in PD, you can still consider that similar and probably you can take it forward with a PD approach. Neal R. Gross & Co., Inc. 202-234-4433
Page 165 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 The economics of biosimilars is cost containment, particularly to reduce the output pressure on healthcare, increase affordable access and would help to reduce R&D development costs, particularly gain in production efficiencies, streamline development programs, generate savings and can be offered at prices below the finished product which can be done. In particular, to conclude, what's the future for the biotechnology industry? It
offers a pathway because it avoids arbitrary, unnecessary or unethical duplication of preapproval studies or clinical trials. Testing
based on comparable differences or proffered extrapolation between indications based on thorough understanding of mechanism action and other relevant factors, while accommodating scientific progress to allow regulators access to the highest-quality and most important data on which to approve a biosimilar product and sponsors can utilize these. They efficiently
Page 166 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Kozlowski. DR. KOZLOWSKI: In your slide on use prior knowledge to enhance their efforts. And I appreciate your time and thanks for the opportunity to present and I'll be more than happy to address any comments or questions. DR. BEHRMAN: Thank you for your Dr.
the procedure to go through comparability testing, I think it's before the graphs you show about PK and PD, you state clinical studies to demonstrate efficacy may not always be needed if the PK/PD or PD is sufficient. So I want to ask, do you also mean no safety or immunogenicity studies? DR. TAMMARA: The safety and
immunogenicity would be following in the postapproval. Because once you have a PD, as part
of the PD study, you can assess immunogenicity in the PD study, and then once you have that information, you can assess the safety Neal R. Gross & Co., Inc. 202-234-4433
Page 167 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 immunogenicity problem in the post-approval. DR. KOZLOWSKI: So, to clarify,
you would say PK/PD comparison if appropriate plus the structural, you know -DR. TAMMARA: DR. KOZLOWSKI: Similarity. -- yes, similarity
would be sufficient pre-market studies and then the rest of the studies would be postmarket? DR. TAMMARA: DR. KOZLOWSKI: That's right. So, I would point
out that I think you disagree with the previous speaker because you would have a very different post-market plan than the innovator. DR. TAMMARA: That's right. I
honestly disagree with that. DR. BEHRMAN: Other questions?
Thank you for your comments. DR. TAMMARA: DR. BEHRMAN: Thank you. Our next speaker is
Terence Ryan from iBio, Inc. DR. RYAN: I'm like to open my
Page 168 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 statement by thanking the panel and the Food and Drug Administration for holding this hearing to receive public comment on the development of guidances for biosimilar drugs. Because of the complexity of biologics and the various means to manufacturer them, current biotherapeutics are often expensive and their availability to patients may be limited by the resources of the patient or insurance co-payor. The existence of biosimilar versions of these front-line branded biologics is likely to have a dramatic effect on patient access and lessen the financial impact of biologics on patient resources and those of the health care system as a whole. These
reasons provide a compelling rationale for the development of biosimilar guidances that will result in the introduction of safe and effective treatments that reach a broader patient population. Because these initial guidances Neal R. Gross & Co., Inc. 202-234-4433
Page 169 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 will have a profound influence on the technology and economics of biosimilar development, we'd like to urge the panel to take the broadest possible perspective on how the specification of highly similar should be interpreted. A perspective that emphasizes
analytical biochemistry as the benchmark for highly similar would be likely to ensure safety and efficacy of a biosimilar through exact mimicry of the branded biologics primary peptide sequences and various posttranslational modifications. However, such an emphasis may restrict the production of a biosimilar to the very specific manufacturing method used to create the branded biologic, ensuring that potentially out of date or costly manufacturing processes will be used and reducing the opportunity for speed or cost savings in bringing these new medicines to patients. For example, a biotherapeutic Neal R. Gross & Co., Inc. 202-234-4433
Page 170 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 produced in recombinantly modified Chinese hamster ovary cells grown in stir tank bioreactors may have post-translational glycosylation patterns that include galactosealpha-1,3-galactose or N-glycolylneuraminic acid residues and these themselves are not produced by humans cells and are not normally seen in human proteins and these are potentially antigenic to patients. Adherence to strict biochemical mimicry to fulfill the highly similar standard might be interpreted to require biosimilar to have identical glycosylation and perforce require the biosimilar to be made in CHO cells rather than by another modality that would provide identical safety and efficacy but at lower cost. Additionally, the strict standard would expose patients to allergic or neutralizing antibody responses which might not otherwise occur if more advanced manufacturing technologies, whether present or Neal R. Gross & Co., Inc. 202-234-4433
Page 171 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 future, could be employed. Our interest at iBio, Incorporated is production of protein therapeutics and vaccines in whole plants using a novel method of transient expression. The process is
easily scalable and could be semi-automated in a factory setting and modest pilot plant facilities can produce more than half a million vaccine doses per month. Extensive research and development of biotherapeutics using this system has shown similar bioactivity, efficacy and pharmacologic behavior to protein biotherapeutics produced in bacteria, yeast and animal cells. All types of existing biotherapeutics can be manufactured with this whole plant system and, indeed, we've produced some recombinant proteins which could not be produced by more traditional expression systems. Manufacture in plants does not Neal R. Gross & Co., Inc. 202-234-4433
Page 172 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 have the risk of endogenous or carryover viral contamination from the use of animal cells or substrates and the resulting proteins are easily characterized due to the homogeneity and reproducibility of post-translational glycosylation and other modifications. Of even greater value from a patient point of view, manufacture of biotherapeutics in whole plants prior to purification steps can result in a decrease in bulk drug material cost of approximately 80 to 90 percent when compared with more traditional expression systems, thereby potentially increasing patient access to these medicines. We feel that the term highly similar should emphasize safety and efficacy above all other considerations. Analytical
biochemistry analyses should show the same primary sequence as the reference molecule and matches purity and dispersity. The biosimilar
molecule should have no significant differences in pharmacokinetics, ADME or Neal R. Gross & Co., Inc. 202-234-4433
Page 173 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 questions. DR. BEHRMAN: Thank you for your toxicology when compared with the reference molecule. Effective characterization of all post-translational modifications of the primary sequence should be required, and where differences occur should be shown to have no significant effect on safety and efficacy as well as on PK, ADME and tox. Such an interpretation of highly similar would allow emerging and currently experimental technologies such as production in new animal or human cell lines, stem cells, engineered plant cells or whole plants to be considered for future biosimilar work and allow for progress to substantially reduce development time and manufacturing cost resulting in an increase in the number of patients receiving life-saving medicines at affordable prices. I'd be happy to answer any
Page 174 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Kozlowski. DR. KOZLOWSKI: So, to clarify, Questions from the panel? Dr.
the point you're making is that no matter what the manufacturing substrate, as long as the product meets the goalposts, was the term used before, and any impurities, you know, or potential contaminates are adequately controlled and characterized and there's good science behind everything, that source alone should not be a limitation. DR. RYAN: believe that. DR. KOZLOWSKI: follow-up question. DR. RYAN: Sure. I have another Is that the --
Yes, we strongly
DR. KOZLOWSKI: Which may touch upon one of the statements you're making about the cost of -- I mean, one general question I was asked as we make that point. Are the cost
of goods the major driver of the cost for these products? Neal R. Gross & Co., Inc. 202-234-4433
Page 175 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. RYAN: There are many drivers
for cost of these products, but anything that you can do to lessen the eventual out-the-door cost, we think should be a benefit to the patient. Also, benefit the health care system
which has to pay for those products. So cost of goods is one factor and this is the one factor that our technology addresses. DR. BEHRMAN: DR. JENKINS: Dr. Jenkins. So you're taking a
fairly different approach from what we've heard from others who have argued that the physicochemical characterization should be the base of the pyramid and one of the earlier presenters had the top of the, the apex of the pyramid was a fairly small segment for the clinical comparison. As I understand it, you're saying that the PK/PD, the pre-clinical studies and the clinical study should be the base of the pyramid, maybe inverted, and that the Neal R. Gross & Co., Inc. 202-234-4433
Page 176 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 physicochemical characterization should be more limited so that you don't have to absolutely duplicate the molecule. You want
to duplicate the effect of the molecule. DR. RYAN: In broader terms,
duplicating the effect of the molecule we feel to be most important. However, that's not to
say that we think physical and chemical characterization of the protein is a minor aspect of this. We think that the differences that exist through any manufacturing system, differences between a potential biosimilar and a reference product, those differences should be shown to have no clinical significance. DR. JENKINS: wanted to go. Well, that's where I
Because others have built a
pyramid from the physicochemical characterization up to argue for a limited clinical comparison. So I'm interested in your model. What would the clinical comparison look like? Neal R. Gross & Co., Inc. 202-234-4433
Page 177 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 How rigorous would it be? What margins? What size study?
Would it be a feasible study? Not being a company
DR. RYAN:
that conducts clinical trials or actually develops biologics, but actually holds technologies that are useful to development of biologics, I don't want to comment too extensively. However, my expectation as a scientist would be that on a case-by-case, molecule-by-molecule basis, you could anticipate different levels of requirements and interactions. In a case where a molecule is very simply manufactured with relatively few posttranslational modifications, it's easier to establish an identity at a chemical level. However, as the complexity of posttranslational modification such as heterogeneous glycoprotein additions are introduced as you go up in a scale of complexity and perhaps activity of a molecule, Neal R. Gross & Co., Inc. 202-234-4433
Page 178 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 those post-translational modifications may or may not have clinically significant or relevant activities. They'd be more necessary for proper protein folding. serum half-life. They may not affect
They may or may not affect Those should
on-rates or molecule receptor. be explored.
But, in fact, you know, speaking as a scientist, I believe the differences that do exist that have no clinical significance should not be the subject of, you know, very deep or prolonged discussion. If the molecule
itself behaves with the same safety and efficacy which overall are rules number 1 and number 2, every other rule you might make is to ensure those first two. DR. BEHRMAN: DR. KOZLOWSKI: Dr. Kozlowski. So, to follow up
on Dr. Jenkins' discussion of the approach, even if one uses an unusual source substrate for manufacturing, with genetic engineering, Neal R. Gross & Co., Inc. 202-234-4433
Page 179 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 you know, and we've heard examples talked about today, one can alter glycosylation potentially and change things. DR. RYAN: Absolutely. So, one could use
DR. KOZLOWSKI:
different source material and aim for the pyramid the way it was described earlier which is to try and make the closest material you can. I guess we heard a similar is reasonably So, is
achievable and then to work from that.
that an area that you're also discussing? DR. RYAN: We're not discussing it
specifically, but it's certainly within the realm of possibility and also of current activity. However, we feel that the fact that a production substrate or method is different should not a priori disqualify it from manufacturing a biosimilar. As long as
safety and efficacy are fulfilled, we think that should be allowed with appropriate documentation and characterization of the Neal R. Gross & Co., Inc. 202-234-4433
Page 180 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 product. DR. BEHRMAN: I thought you went a
little farther than that and said that, in fact, if there are modifications, if you will, the molecules that are not necessarily -- or can be shown not to be important to the safety and efficacy profile that there should be no need to make sure, if you will, one tinkers until that degree of similarity is achieved. DR. RYAN: Well, you should
understand what the differences are, and if they're inconsequential in terms of your clinical performance, I think we should say that should be good enough at this point. That doesn't rule out somebody aspiring to achieve absolute chemical identity. DR. BEHRMAN: DR. JENKINS: Any other questions? I just can't get
away from, in my mind, thinking that the approach you're describing would lead to a larger, more rigorous clinical program to Neal R. Gross & Co., Inc. 202-234-4433
Page 181 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 assure that the differences in the molecule aren't relevant. All the other paradigms I
think we've seen have been about making it the same as reasonably possible at the base so that as you get up to the -DR. RYAN: Right. -- top of the
DR. JENKINS:
pyramid you have do less and less to actually have an abbreviated program. concerned about your approach. DR. RYAN: I'm just Maybe --
I am not at all What
advocating an expanded clinical program. I am speaking to is directly about the technology that is used to manufacture a biosimilar.
With that understanding in hand of what that technology does, we feel it's up to the panel to then establish what they feel are appropriate criteria for the characterization and clinical testing of material made in a different expression system. And we speak only to the Neal R. Gross & Co., Inc. 202-234-4433
Page 182 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 name. close. DR. BEHRMAN: DR. TZIANABOS: Thank you. Very difficult Tzianabos. questions? technology and I'm not making any suggestions about structure, size or goals of clinical trials. Just to be clear. DR. BEHRMAN: Thanks. Any other
Thank you for your comments. Our next speaker is Arthur Am I close? DR. TZIANABOS: That was really
Honored FDA officials, industry
colleagues and other interested parties, good morning. My name is Arthur Tzianabos, Vice
President, Program Management at Shire Human Genetic Therapies. I'm standing in this
morning for Sue Bruhn, Head of Regulatory at our company. She was called away unfortunately, had an unavoidable conflict. I'm testifying today on behalf of Shire and its business unit, Shire Human Genetic Therapies. Neal R. Gross & Co., Inc. 202-234-4433
Page 183 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Shire Human Genetic Therapies has specific experience with all parts of the life cycle of therapeutic biologics which we feel positions us to provide relevant input on the implementation of biosimilars approval pathway. While Shire Human Genetic Therapies is focused on the development of therapeutic biologics for rare diseases, the standards for biosimilars and for interchangeability should be the same across all disease areas, we believe. Our thesis
centers on the overriding importance of ensuring patient safety with specific consideration of the unique safety challenges that are faced in the development of biologic products. The first question we will address is the following: What factors should the
agency consider in determining whether a proposed biological product can be, quote, "expected to produce the same clinical result Neal R. Gross & Co., Inc. 202-234-4433
Page 184 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 as the reference product in any given patient?" What makes biologic products unique is their complexity relative to smallmolecule chemical entities. Typically,
biologics are developed and manufactured from living organisms, including cell-based systems, that in themselves are a complex environment with potential for impact on product quality. The manufacturing process can impact key attributes of biologic products including stability, impurity, profile, size, shape, glycosylation or other posttranslational modifications. Differences in these key attributes may impact pharmacokinetics, pharmacodynamics, biodistribution and, importantly, immunogenicity. This can lead to
alterations in purity, potency, efficacy and safety, thereby impacting the benefit/risk profile of the product in patients. It is,
Page 185 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 therefore, essential that each product be independently evaluated. As a result of these wellcharacterized differences between biologics and small molecules, biologic innovator companies work to carefully identify and understand the complex relationship between process, product and risk/benefit profile during the development and manufacture of products with all subsequent product improvements, including those derived from alterations in manufacturing processes facing rigorous standards of comparability. These standards are appropriate in the context of the unique challenges that biologics create when used as therapeutics in the human body. They require a demonstration
of product comparability and its impact on safety and efficacy. It is important to patients that the same high comparability standards that apply to product improvements of innovative Neal R. Gross & Co., Inc. 202-234-4433
Page 186 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 biologics should minimally apply to biosimilar products developed using the 351(k) pathway and the scope of the data required in support of approval should reflect the magnitude of the differences seen in the protein product and their potential impact on the benefit/risk to patients. Any differences in product quality, safety, or efficacy should clearly be outlined in the approved product label. We suggest that biosimilars should undergo comparative clinical assessment at least as stringent as provided by biosimilar guidances published by other health authorities around the globe, including the World Health Organization guidelines on the evaluation of biotherapeutic products in the EMEA. Based on these guidelines, the clinical evidence needed to support interchangeability of a biosimilar product with a reference drug, which we believe should Neal R. Gross & Co., Inc. 202-234-4433
Page 187 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 be the innovator drug, should take into consideration the following factors. At least one clinical trial should be comparative in nature, head-to-head with the innovator drug. Clinical study or studies should be designed to demonstrate comparable safety and efficacy of the biosimilar in direct comparison to the innovator product. If any relevant differences between the biosimilar and the innovator product are detected, the reasons need to be explored and justified. If this is not
possible, the new product may not qualify as a biosimilar and a full drug application should be considered. In addition to ensuring patient safety, clinical trials should be conducted with established and well-recognized efficacy endpoints for the disease under investigation. The plan for acceptable clinical similarity with regard to efficacy should be proposed and Neal R. Gross & Co., Inc. 202-234-4433
Page 188 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 justified, ensuring that a sufficient number of patients are enrolled to demonstrate comparable efficacy. The studies should reflect the original patient population studied with the innovator drug in the same indication. The justification for the choice of the clinical study design such as noninferiority or equivalence design should also be considered. The design should ensure an
adequate study duration that allows the collection of not only the necessary clinical data, but also any long-term immunologic effects such as generation of neutralizing antibodies, anaphylactic responses or cellmediated immune responses. The biosimilar sponsor should provide a justification for each indication for which approval is sought. Efficacy in one
indication should not be extrapolated to efficacy in others, as the characteristics of a product have the potential to affect Neal R. Gross & Co., Inc. 202-234-4433
Page 189 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 efficacy and safety in different clinical settings. Because of the potential impact on patient safety, the comparative clinical immunogenicity of biosimilars to innovative products should be specifically addressed in patients. Many factors impact the An
immunogenicity of biologic products.
assessment strategy should be justified that can adequately characterize and quantify the immunogenic effects in patients. Antibodies which are generated should be fully characterized with a clear understanding of their relationship to and impact on all aspects of safety and efficacy assessed in the study. In particular, the
potential for neutralizing the effect or elicitation of anaphylaxis. If differences in immunogenic profiles are observed, further and more detailed characterizations should be required. Because of the complexity of factors related Neal R. Gross & Co., Inc. 202-234-4433
Page 190 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 to immunogenicity, each therapeutic indication presents a potentially different clinical environment for the therapeutic that prevents extrapolation from one patient to another. The second question we will address is the following. What factors should
the Agency consider in the evaluation of the potential risk related to alternating or switching between use of the proposed interchangeable biologic product and the reference product where among interchangeable biologic products? The safety of the patient should be the most important consideration with regard to interchangeability. Interchangeability, as defined in the legislation, allows two biological products to be switched for patients multiple times at the pharmacy level without consulting a physician provided there is no impact on safety or efficacy in patients. The data required to demonstrated Neal R. Gross & Co., Inc. 202-234-4433
Page 191 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 safety in the context of interchangeability is beyond that of market authorization and should require very high standards and careful study for biologics in particular because of the unique challenges associated with the potential for immunogenicity. To ensure patient safety for repeated switching, the sponsor of a biosimilar interchangeable product should be required to conduct clinical trials demonstrating the safety and efficacy of repeated switching between products. The potential risk associated with switching or alternating use between the proposed interchangeable biosimilar and the innovator product or among interchangeable biologic products will need to be addressed using adequately designed and well-executed crossover clinical trials. Particular consideration should be given to the increased risk for immunogenicity in the context of product switches as repeated Neal R. Gross & Co., Inc. 202-234-4433
Page 192 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 challenges in the background of existing patient antibodies has the potential to lead to serious hypersensitivity or anaphylactic responses if the two therapeutics have different antigenic profiles. The sponsor of the interchangeable biosimilar should provide justification for the clinical study design. For example, a
single crossover design would reflect one switch to a different product, whereas multiple crossover design would reflect alternating use of a product and be more aligned with the true interchangeability. The overall study of the duration will be primarily dependent on the number of cycles of switches needed to ensure no diminished efficacy. Justification for a
washout window, if necessary, and the length of the washout window should be provided. Where multiple indications exist for the innovator product, careful consideration should be given for Neal R. Gross & Co., Inc. 202-234-4433
Page 193 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 interchangeable safety extrapolation to other indications. So, in summary, the safety and efficacy of highly complex biologic products should be the focus of the approval process for biosimilar therapeutics to be approved via the 351(k) pathway for each product, disease state and labeled population. Clinical immunogenicity needs to be rigorously assessed to ensure the safety of patients. Interchangeability at the pharmacy
level should require a higher standard of proof than approval of the innovator product. The specific studies designed to address the unique challenges inherent in the manufacturing of biologics in living systems and the multifactorial impact that biologics can have on different patient populations. We believe the standards for biosimilars and for interchangeability should be the same across the disease areas. Thank you very much. Neal R. Gross & Co., Inc. 202-234-4433
Page 194 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 short. lunch. level. DR. KOZLOWSKI: I'll try and be comments. Kozlowski. DR. TZIANABOS: Getting towards DR. BEHRMAN: Thank you for your Dr.
So I'm sure that's impacting energy
You mention that obviously you need to
do immunogenicity studies on these products. So what if you had a product with a very low level of immunogenicity in the innovator, well below 1 percent, no evidence of adverse events from antibody formulation. Would you need
potentially a thousand-patient study to, you know, show that that level is the same? And then if you're doing a switching study for such a product, would you need to again have that same level of sensitivity for immunogenicity in the switching study? DR. TZIANABOS: So we're talking
about a hypothetical, obviously, to be clear, Neal R. Gross & Co., Inc. 202-234-4433
Page 195 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 experience. and then, you know, there's a big difference between doing immunogenicity studies in mice versus rats versus non-human primates versus humans. So, if you're saying that there -if you're demonstrating low immunogenicity in pre-clinical models, I absolutely still think that you need to do that kind of level in humans. So, are you saying humans? DR. KOZLOWSKI: No, the innovator
In other words, what you would
look in the label as terms of the percent of immunogenicity. DR. TZIANABOS: So we still think
that there are a lot of aspects outside of the immunogenicity, just antibodies that could be impacting potential safety for patients. These include cell-mediated responses, T cell responses, anaphylactic reactions. So, there
are a lot of other aspects aside from just antibody levels that need to be assess to Neal R. Gross & Co., Inc. 202-234-4433
Page 196 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 ensure patient safety. So we still believe that those kind of rigorous studies should be done. DR. KOZLOWSKI: To push the
hypothetical, say, in fact, the innovator product didn't have any of those adverse events associated with an immune response and if there was some anaphylaxis or something, you know, it was in the one in 50 or 100,000 where literally, you know, you couldn't design a study to compare that. DR. TZIANABOS: position is this. I think our
That if we -- what we'd
like to see is a standard that's similar to the innovator product. So in the scenario
that you're painting, if it's very low immunogenicity, then again you could apply that to the biosimilar. DR. BEHRMAN: Okay. Could I ask
you a couple of points of clarification because you gave us a lot of information rapidly? Neal R. Gross & Co., Inc. 202-234-4433
Page 197 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 position. DR. BEHRMAN: And if there were position. DR. BEHRMAN: And was the same That the Did you state or imply that the comparison for biosimilarity should only be to the innovator part? Only the innovator part
can serve as a reference product? DR. TZIANABOS: Yes, that's our
true for interchangeability?
comparison can only be with the innovator product? DR. TZIANABOS: Yes, that's our
more than one biosimilar then licensed, what do you see as the relationship of those products? DR. TZIANABOS: So, we see -- in
the terms of interchangeability is what you're referring to? DR. BEHRMAN: I guess both
biosimilarity and interchangeability. DR. TZIANABOS: Well, let me
Page 198 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 address interchangeability first. I think
there we see a higher bar because of the potential for multiple switches back and forth potentially between the innovator branded product and multiple biosimilars and so, what you see there, in our opinion, is a greater potential for immunogenic or anaphylactic response. So I think that is important to assess in a very, very rigorous way. In terms of biosimilarities, I think I stated the same position. I think we
need to see the same level of rigorous assessment of the biosimilar compared to the innovator product. DR. BEHRMAN: You're very kind. Other questions?
I think you get the award
for the name I most butcher so far today. Thank you for your time. DR. TZIANABOS: been an early morning. DR. BEHRMAN: Our last speaker Thank you. It's
Page 199 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Thank you. this morning is Joseph P. Miletich from Amgen. How am I doing? I guess I'm getting hungry. That was fine.
DR. MILETICH:
This is Joe Miletich. Dr. Behrman and members of the
panel, thank you for the opportunity to testify here today. My name is Dr. Joe Miletich. a physician and molecular biologist. I'm
Before
joining Amgen, I spent 24 years at Washington University in St. Louis treating patients and using the tools of molecular biology to try to understand human disease. Our message today is really simple: put patients first and sound policy will follow. Amgen does believe that biosimilars have a meaningful role to play in the health care system. However, as we've
heard multiple times, biosimilars unlike generic drugs are just simply not identical to the innovator biologic products. Neal R. Gross & Co., Inc. 202-234-4433
Page 200 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 to go blank. So, to keep patients first, we have to acknowledge what it is that we do not yet know and then set a reasoned path forward. My testimony today is intended not I'm sorry. Oh, sorry. We were
upside down or I was. Thank you.
Something was wrong.
My testimony today is intended to offer three recommendations. First, use well-
designed clinical trials to establish biosimilarity. Second, ensure that the product manufacturer and the lot number are known for each biological and by that I mean that they're traceable from an adverse event report and if possible, from other sources of useful data, to the lot, to the manufacturer and to the lot number. And finally, if interchangeability is deemed feasible, then by all means, consider both scientific and practical criteria for interchangeability. Neal R. Gross & Co., Inc. 202-234-4433
Page 201 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Alongside the Agency's Office of Biotechnology Products, we have learned a lot about the complexity of biologicals and their interactions with the human body and we believe that the biosimilar policy must reflect that knowledge. As we have heard, two biological products are unlikely to ever be identical when they're made inside different living cells that are nourished by raw materials from different sources and then are harvested, purified, formulated, packaged and shipped in different ways. So, the problem is that we have a relatively heterogeneous distribution of closely related molecules in a product. important that we characterize these, and Amgen uses all the latest technology to do the best job possible understanding what that variability in the molecules is. It's important as we go forward that we recognize increased characterization Neal R. Gross & Co., Inc. 202-234-4433 It's
Page 202 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 is vital. However, that's not the rateThe
limiting step right at the moment.
problem is that we don't know enough human biology. So we don't know what the
distribution of heterogeneity means in every patient, in every clinical setting, in every indication. So when we're trying to compare a biosimilar to the innovator product, we have two different distributions of closely related molecules and it's more complex the more complex the biological is that we're trying to make and we just can't figure out in a mass spec whether or not that makes a difference in the human body. It's important that we understand the differences and that we characterize them, but we don't know what they mean without clinical experience. We have to have clinical
evaluations and experience in order to address the questions. So, therefore, the first point. Neal R. Gross & Co., Inc. 202-234-4433
Page 203 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 We need to use clinical trials to establish the biosimilarity. In our 30-year history of
making biologics, Amgen has achieved remarkable breakthroughs. We've developed
complex proteins and we've supplied them to millions of patients. However, in the process, we have been humbled a few times by unexpected outcomes even in the face of encouraging analytical and pre-clinical data. As an example, we planned a major manufacturing change for Epogen. We didn't
see any differences analytically or in our non-clinical studies that we thought would have an impact. But, in a clinical study, we
found an increasing potency that did exceed our pre-specified endpoint. the process change. An even more important point than that is even with all the analytical tools available to us, I still can't explain to you what the real difference in the distribution Neal R. Gross & Co., Inc. 202-234-4433 So we cancelled
Page 204 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 of those molecules is that led to the increase in efficacy. I know it's there, but I still
can't explain it. We can also look to the biosimilar experience in Europe where 11 distinct products have been submitted for approval, some under multiple trade names. Clinical
data provided to the EMA had a significant impact on the regulatory review of at least six of these 11. was rejected. Three were withdrawn. One
One was restricted to IV
administration and one required a manufacturing change. Amgen has also learned about unintended interactions of a product with its container. We discovered new information
through voluntary reporting and we've relied on accurate traceability to conduct recalls, prompt recalls, when necessary. So, as we've heard from many other speakers, products must be distinguishable for correct attribution and reporting of adverse Neal R. Gross & Co., Inc. 202-234-4433
Page 205 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 PRCA. events and it's best if this is as easy as possible for patients and other health care providers. When there's only one manufacturer of a biological, you know who to call. When
there's more than one, you need to know who to call. For example, we've heard about So, at the time PRCA, this unfortunate,
dramatic increase in an uncommon but potentially life-threatening immune reaction against the biological and ultimately against the patient's own erythropoietin. At the time
that was detected, there were three ESA manufacturers in Europe. I think we could probably all agree that it was difficult and it took probably too long from a patient's point of view to figure that out. Now, there are six manufacturers distributing ESA products under at least 11 brand names. This has being addressed in the Neal R. Gross & Co., Inc. 202-234-4433
Page 206 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 EU, but it's being addressed retroactively. We need to get this right for patients from the start. I think next, since I see my yellow light, I think I should turn to interchangeability. Patients need the FDA, not individual states, payors or formulary committees to determine if a biosimilar may be interchangeable. Biosimilars that haven't
been determined to be interchangeable by the FDA should clearly be labeled that way and an interchangeability determination, if possible, would be very difficult to make and it requires significant time and experience to address both scientific and public health challenges. Guidance class by class is also going to be necessary to avoid confusion and unnecessary uncertainty in the regulatory pathway. We've heard about some of the Neal R. Gross & Co., Inc. 202-234-4433
Page 207 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 practical considerations that need to be considered. This includes differences in
approved indications and in use between the products, unintended switching and attribution of the adverse events after switching if it occurs. Safe interchangeability means all patients need to be assured that switching products will not cause harm or differences in their response. The potential for patients to receive their therapies from different pharmacies, hospitals, PBMs or more are all real world concerns. These challenges may not
preclude a scientific assessment, but they have to inform the clinical standards and design of studies. So, we want the FDA to be the body to determine if biosimilars are interchangeable for U.S. patients. I think
I'll actually conclude there since I see the red light. Thank you very much. Neal R. Gross & Co., Inc. 202-234-4433
Page 208 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. DR. BEHRMAN: Thank you for your Questions from
remarks and your timeliness. the panel? Dr. Jenkins.
Well, actually, we
should let Ms. Esposito go. MS. ESPOSITO: Thank you for your
My question relates to your
interchangeability discussion. If I heard you right, I thought you were advocating not permitting interchangeability determinations to occur at the time of first approval of the biosimilar. So, are you anticipating or envisioning a second stage of the approval process so that when the product is first approved as a biosimilar, it would only be biosimilarity and then a second submission would be required to establish interchangeability post-marketing? DR. MILETICH: It's very difficult
for me to think of an example where it would be prudent to approve interchangeability at the time of approval. I think post-marketing
experience and surveillance would definitely Neal R. Gross & Co., Inc. 202-234-4433
Page 209 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 be required because of the complexity of interchangeability for all the reasons that have been discussed. MS. ESPOSITO: And to follow up on
that, have you put any thought into or have any recommendations regarding either a length of time or number of patients exposed postapproval before enough data would be collected to establish interchangeability? DR. MILETICH: We've heard a
number of suggestions from a large number of speakers. I think this testimony, this oral
hearing has been extremely helpful in airing some of those. I think that it's impossible to do this by example. I think for every example I
can think of I can think of exceptions. That's why I think we need class-by-class guidance. So I think it's dangerous to put
out a model that we think would work for interchangeability for all biosimilars. I
think we need the guidances and that's the Neal R. Gross & Co., Inc. 202-234-4433
Page 210 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 next step, to work on those. DR. BEHRMAN: DR. JENKINS: Dr. Jenkins. I want to ask the
question I've asked others who have been innovators who have biosimilar competition around the world. So I'm interested in
knowing, has Amgen been able to identify safety, efficacy or immunogenicity problems with the biosimilars of your products that are approved in Europe, India, Asia, wherever in the world they may be approved? Can you point
to any places where there have been problems? DR. MILETICH: I wish I could
answer that question, but as I and other speakers already told you, I really don't have access to the information that you really need to do that. I'm not aware of problems, but if they haven't been reported or the surveillance programs aren't in place that we think might be the standard, it's impossible to know. DR. BEHRMAN: Other questions?
Page 211 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 MS. ESPOSITO: With respect to
your discussion about ensuring ease of identification of the source of the product by manufacturer and lot number, do you have any recommendations regarding whether that should be achieved by different non-proprietary names, a prefix or a suffix? We heard
yesterday some discussion about referring to the NDC number and trying to incorporate that somehow. Have you given any thought to how the identification should be achieved? DR. MILETICH: Yes, there were a I think
number of good suggestions made.
that, from the patient's perspective, having more information and more possible ways to trace any adverse event or even the epidemiology of the use of a product over time is beneficial. So I would certainly be in favor of a unique nonproprietary name. I would also
be in favor of a unique brand name and Neal R. Gross & Co., Inc. 202-234-4433
Page 212 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 certainly having the lot number information somehow in the system traceable to something that patients and other health caregivers can easily remember and report. DR. BEHRMAN: MS. MALONEY: Ms. Maloney. Just picking up on
that, we've had a lot of discussion on the naming, but I'm curious about what are the other issues with regard to, you know, failures for figuring out the adverse events? What other things are we missing? I've heard
some people talk about, for instance, more need for education. So are there any other
things you might point to? DR. MILETICH: I certainly believe
that there is room for improvement in education, in teaching people how they report adverse events and when they should report adverse events. Again, more data for everybody to understand about what the clinical experience is can only be helpful. Neal R. Gross & Co., Inc. 202-234-4433
Page 213 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 MS. MALONEY: And just to pick up
on that, I think Dr. Siegel talked about, for instance, you know, the electronic medical records there. So what's needed there as
we're doing more, you know, Sentinel and active surveillance? DR. MILETICH: Well, there are
very large databases, as you're well aware, and if we could connect the use of actual particular products to the clinical experience using those databases, again, I would think that would be beneficial. Our goal here is to
understand, really for the benefit of patients, how these products perform and provide them in the safest possible way. it would have to be beneficial if we could think of a way to do that as well. DR. BEHRMAN: DR. KOZLOWSKI: Go ahead. Just to follow up So
on the nomenclature in tracking, are there any risks associated with different nonproprietary names like accidentally receiving a medication Neal R. Gross & Co., Inc. 202-234-4433
Page 214 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 twice because patient didn't realize they're the same? DR. MILETICH: I suppose when a
question is asked in a theoretical sense like that, I guess there's always some risk. I
would expect it to be pretty small since the medicines we're talking about at this point are still pretty much injectable medicines and a lot of them are given in settings where there are health care providers in close contact if not in immediate contact. So, I think -- although I can't say there's not a theoretical risk, I think it would be somewhat small at this point. DR. BEHRMAN: Could I ask a point
of clarification about the interchangeability? You mentioned labeling. So you believe the
biosimilar should be labeled as not interchangeable with the innovator. Should
the innovator labeling carry any information? DR. MILETICH: Yes, I think if I'm
understanding your question correctly, on the Neal R. Gross & Co., Inc. 202-234-4433
Page 215 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 label, I think with the current labels that we have in the U.S. it's possible to include that information for both. If there's non-interchangeability, there shouldn't be interchangeability. Absolutely. DR. BEHRMAN: And then one
question about you gave the example where you had made a process change and to your surprise, there was this increase in potency. What made you choose to do a clinical study for that particular process change? If you could -DR. MILETICH: We just deemed that That was
in the best interest of patients. not mandated in any way. DR. KOZLOWSKI:
To follow up on
the process change, you mentioned you don't know the exact biochemical link. Does that
mean there were no differences or you just haven't figured out which differences, you know, mattered? Neal R. Gross & Co., Inc. 202-234-4433
Page 216 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. MILETICH: Depending on the
resolution with which you look, there are always differences. The problem is it's very difficult to know across a wide distribution of molecules exactly which ones might have had the impact. this problem. I'm sure you're well aware of It's just extremely difficult
to pinpoint and trace back. DR. BEHRMAN: Any other questions? Thank all the
Thank you for your comments. speakers for the morning. morning. It's now lunch.
It was a terrific
I just remind you
a la carte items are available for purchase. The restrooms are to the left and the right. Don't forget the trash receptacles in the hallways and in the back of the room. And please be back at five to 1:00. Thank you. (Whereupon, the above-entitled matter went off the record at 12:00 p.m. and resumed at 1:02 p.m.) Neal R. Gross & Co., Inc. 202-234-4433
Page 217 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. BEHRMAN: Welcome back. A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N 1:01 p.m. We're
resume with our afternoon session. Our first speaker will be Richard Kingham from Covington & Burling. MR. KINGHAM: Thanks very much. I'm a partner
My name is Richard Kingham.
with the law firm of Covington & Burling assigned to both the Washington and London offices of the firm. For the last ten years
I've been representing research-based manufacturers of biopharmaceutical products in connection with the development of legislative pathways and regulatory implementation for approval of biosimilar products. I was heavily involved in the legislative process and also in the comment and other processes relating to the development of the EU biosimilars regime. participated in the development of the biosimilars guidance in Canada. And also in I
Page 218 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 proceedings with WHO relating both the international nonproprietary names and to the biosimilar guidance and to the biosimilar guidance that they recently issued. I believe that the European and other non-U.S. experience is particularly relevant here today. Because we find
ourselves in the unusual situation of the United States and the FDA being somewhat behind other parts of the world. For 20 years
working in the EU I've often been in the reverse situation where I could say, "Well, we thought about that in America." But we hadn't
thought about all this yet, and the Europeans have. So, I'd like to talk about a couple of things. First, very briefly, what
the biosimilars outside the United States has been. And secondly, with particular reference
on the European Union where by far the deepest experience resides, how the procedures have been developed for actually establishing the Neal R. Gross & Co., Inc. 202-234-4433
Page 219 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 criteria, the site of the testing requirements, the issuance of guidance with respect to standards for demonstrating similarity. Secondly, the approach to postmarketing measures to detect rare but serious side effects. And finally, how Europe has dealt with the product interchange or substitution issue. Now, Europe has by far the deepest experience in this area. The discussion
actually began in earnest in January of 2001 when a comparability draft guidance was issued and the question arose whether it should address biosimilars under the heading of comparability as well as changes in the manufacturing process of existing products. Ultimately the decision was no that it was quite with issue and it needed to be addressed in its own body of legislation. That was done
in secondary legislation in the annex to Neal R. Gross & Co., Inc. 202-234-4433
Page 220 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 there. Directive 2183 that took effect in October of 2003. And at that point there was a pathway
in Europe. It was confirmed by primary legislation enacted by the European Parliament and Council taking effect in October of 2005. Since then, the European Union's European Medicines Agency and its Committee for Medicinal Products for Human Use have issued both general umbrella guidance for biosimilars, guidance specifically relating to a common DNA derive therapeutic proteins, other crosscutting advice such as guidance on immunogenicity determinations and product specific guidance for a number of sectors beginning with somatropin and human insulin, GCSF, alpha interferon, erthropoietin, low molecular weight heparin which the Europeans consider to be within their biosimilar regime, and of course now monoclonal antibodies guidance is under development, So, there's a lot of experience I'm going to talk about that in more Neal R. Gross & Co., Inc. 202-234-4433
Page 221 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 detail in a second. Meanwhile, the WHO has developed guidance who purpose is to assist the national authorities in countries around the world. Canada developed guidance for so called subsequent entry biologics, which is now final. Japan has finalized guidance. And
other jurisdictions such as South Africa, Singapore, South Korean, Saudi Arabia now a growing of others have developed guidance. The vast majority, however, have relied heavily on the experience in Europe. So, let's turn to European specific things. First, what's the process
for actually establishing the specific testing requirements for particular marketing authorization applications for biosimilar products? The first point that I would make is that the process has been open and transparent. There has been a system under
which where appropriate stakeholder meetings, Neal R. Gross & Co., Inc. 202-234-4433
Page 222 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 very much like this, have been held. They
were held at the beginning of the development of the process and summer before last when a major new departure was undertaken of considering monoclonal antibodies which we believe to present unique and difficult questions. The process is typically begun with the issuance of concept papers that simply identify the issues that should be addressed in guidance, without necessarily taking a position on how they should be addressed. There's then a comment period.
That's followed by the issuance on a draft guidance which lays out the CHMP's specific thoughts on what would be in a guidance with another period for comment. final guidance is issued. Now throughout that process 27 member state governments have the right to participate, as do multiple scientific working parties of the CHMP and the full CHMP itself. Neal R. Gross & Co., Inc. 202-234-4433 And finally,
Page 223 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Despite that, the process has been quite efficient. Guidances have been developed
within periods of 18 to 24 months, in most cases. Monoclonal antibodies are taking,
perhaps, a bit longer but they are a great deal more complex than, for example, somatropin ones. In the meantime, the possibility of obtaining scientific advice from the European Medicines Agency in dealings directly between sponsors and the agency has not been precluded. But it's been done in parallel
with the development of guidance in public, and no product has been approved to date until there was actually guidance in place that has gone through the public guidance development process. Now, it seems to me that this process offers a number of advantages. First
of all, the European Medicines Agency benefits from information that is available to all of the relevant stakeholders including the Neal R. Gross & Co., Inc. 202-234-4433
Page 224 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 information. The second point I think is public confidence in the system. The system is sponsors of the referenced products as well as academics, generic manufacturers, trade associations and so forth. And let me say if you look in the record, and you can do it on the web if you know where to look, you will find that the comments are quite sophisticated. been very substantial comments. They have They've not
been political in nature, but they've gotten right down to the scientific issues that have to be addressed. And I believe they've been
genuinely helpful to the CHMP in developing its final guidance. So the first point is full
developed openly, transparently and in public and there are documents to point to to show that the standards have been thought through. And finally, there's a roadmap for all concerned companies. Not just the big
Page 225 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 biosimilar manufacturers, but the smaller ones as well that may not otherwise be able to develop their own roadmaps. Let me move to post-marketing safety assessment. This is a big issue in
Europe because of the PRCA experience about which you've probably heard a great deal so far in this hearing, so I won't belabor it. But the fact is that that experience played out when a number of countries outside the U.S., including Canada and elsewhere but particularly in Europe, and as you may know it first came to light through the work of Professor Kasse de Waal in France. As a result of the PRCA experience a great deal of emphasis has been placed on the need to have procedures in place after marketing to find effects that could not be detected in reasonable pre-marketing programs. Now these include routine consideration of risk management plans, routine requirements for detailed pharmacovigilance, and possibly Neal R. Gross & Co., Inc. 202-234-4433
Page 226 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 other testing as well. But there's also been
a major focus on assuring that adverse events can actually be attributed to specific products. This is done, in part, by requiring
some form of distinctness in the name of virtually every product. The EU lacks the authority that FDA has by statute to demand a specific new name for a product if it chooses to do so, and must ordinarily follow the INN and the European pharmacopeia names. But it has de
facto achieved this result by either accepting applications with distinct nonproprietary names with a combination of company name and nonproprietary name or with a brand name. Finally, the European Union has proposed and is considering legislation that will require that every adverse event be traceable through the manufacturer's capabilities to the specific product with which it was associated. And finally, let me turn to Neal R. Gross & Co., Inc. 202-234-4433
Page 227 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 interchangeability. This is not the EU's job.
You've been given the job to consider this issue by Congress, but the European Medicines Agency does not have that job under the European Union legislative system. It has been the position, however, of the CHMP that these products are not generics in the ordinary sense, and the clear signal has been sent that the usual generic substitution arrangements are inappropriate. So far every member state government in the EU within the member states of the European Union that has considered this issue has decided that ordinary rules on substitution and interchange should not apply. So in conclusion, I think there's a great deal for FDA to learn. I'd like to point out to you that the next issue of the Food and Drug Law Journal will have two major articles that you may find interesting, one on the development of international standards and the other a very detailed history of the Neal R. Gross & Co., Inc. 202-234-4433
Page 228 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Esposito? MS. ESPOSITO: for your comments. Can you speak to generally your view of whether the EU process has been overall a positive one, and also any lessons learned in your view either positive or negative that the agency might consider in implementing our BPCI? MR. KINGHAM: Well, I think that Thank you so much comments. Questions from the panel? Ms. development of the BPCIA itself. Thanks very much. DR. BEHRMAN: Thank you for your
you will find that the vast majority of manufacturers and I think also academics and others who have watched the process are pretty satisfied with the quality of the process, with the way in which the interchanges have occurred and the quality of the guidance that's been developed. That doesn't mean
Page 229 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 everybody's happy with every provision of every guidance, but I think people are happy with the rights of participation and the degree to which attention has been paid. The process has also demonstrated that there are issues associated with some products relating to significantly increased efficacy in the case of one human insulin product, antibody formation in the case of other products and so forth which I do not believe could have been detected without fairly robust programs of pre-market testing. So it seems to have borne out the basic assumption that underlies the European system that fairly substantial comparative clinical trials are key to the process. DR. BEHRMAN: Other questions?
You mentioned that EU lacks the same authority over naming. MR. KINGHAM: DR. BEHRMAN: Yes. But that they have
set things up in a way that most of these Neal R. Gross & Co., Inc. 202-234-4433
Page 230 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 products have different nonproprietary names, is that correct? MR. KINGHAM: No. No. Actually,
it's very pragmatic and ad hoc, and it's something you don't have to do because you have explicit statutory authority under the federal Food, Drug and Cosmetic Act, which
applies to all drugs including biologics to establish legal names if you choose to do so. Of course, you could also work with USAN to ensure that these products get distinct names if that's what you want to do. But that's not how the European legislative system is designed, and normally the EU authorities must defer either to an established WHO INN, or to a name given in the European Pharmacopeia. What's worked out as a practical matter, but it's work out in practice through the cooperation of manufacturers, some products do have distinct nonproprietary names. The manufacturers actually went to the
WHO INN process and got new names, epoetin Neal R. Gross & Co., Inc. 202-234-4433
Page 231 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 zeta for example. Some products are being marketed, many, with brand names such as Omnitrope for a particular brand of somatropin. And others
are marketed where the nonproprietary name is coupled as part of the actual name of the product with the name of the source. For
example, epoetin alfa Hexal is one example of that. And I believe that if you look at all of the various European public assessment reports you'll find that to date one or another of those options has been chosen. That's not ideal, but it does increase the chances that an adverse event report will be connected with a particular product source. DR. BEHRMAN: Dr. Jenkins?
Could you speak a little bit more about pharmacovigilance? I thought you
implied that we might want to consider placing the burden on the biosimilar manufacturer to assure traceability, but basically European Neal R. Gross & Co., Inc. 202-234-4433
Page 232 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 experience I'm just curious if you have any other advice, whether they believe they have successfully harnessed what they need to to make sure that they're filing these products appropriately. MR. KINGHAM: I think the candid
answer is probably not, and that's one reason why legislation is going through the system now. The mandatory traceability provision
that I spoke about, which would apply only to biologics is still a work in progress. It would be an amendment to Article 102 of Directive 2183. It's not there yet. And how It's
it's going to be implemented is unclear.
simply a mandate from the European Union to the governments of the member states to make sure it gets done somehow. I'm not exactly
sure how it's going to be done. It seems to me the distinct names in one way or another are a much better way of assuring that kind of traceability than simply an order to go forth and make things Neal R. Gross & Co., Inc. 202-234-4433
Page 233 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 traceable. DR. BEHRMAN: A point Dr.
Kozlowski made earlier in the day about perhaps confusion among prescribers if there are several products with different names which were in fact essentially equivalent products, can you comment on that? MR. KINGHAM: Well, the first
thing is they're not really essentially equivalent, and that's the reason for having different names. The products almost certainly will have slightly different effects. And the
issue is similar to the one that you have now with switching from one manufacturer's source of recombinant DNA human insulin to another where you've re-established the dose and so forth. So it's a question of degree. But, I would echo the answer that a previous speaker made, which is that these are almost all products that are administered in circumstances where the chance of confusing the green pill and the blue pill and so forth Neal R. Gross & Co., Inc. 202-234-4433
Page 234 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 is not very likely to occur. DR. KOZLOWSKI: To comment or ask
you to clarify on your comments on interchangeability. state decisions? MR. KINGHAM: DR. KOZLOWSKI: Right. Have there been a So, it's been member
number of decisions to make things substitutable and related to Dr. Behrman's question, has there been any pharmacovigilance on those decisions? MR. KINGHAM: Okay. Well, first
of all, about half the member states have addressed the question as to whether the products should be treated as substitutable in the same way as ordinary generic drugs. Every
one of the member states of the EU that has addressed that issue has decided that they should not be. There may be some member states where formal determinations have not yet been made where practices may be going on that are Neal R. Gross & Co., Inc. 202-234-4433
Page 235 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 not even known. I have to admit there are
some member states that are, frankly, less sophisticated than others in terms of how they manage their pharmacy systems and so on. But the member states that have considered it have decided that substitution is not appropriate. Now, there isn't that much experience with biosimilars actually in the marketplace in Europe. The number of products
yet approved, despite the fact that the process begin in 2003, was relatively small and the market penetration is actually relatively small. So, there isn't some vast body of experience. The largest number of products in this category are in the developing countries around the world. And, of course, there
they've been admitted to market on conditions that are quite different from what I expect will be required here that they required in Europe and in systems where pharmacovigilance is very difficult to maintain. Neal R. Gross & Co., Inc. 202-234-4433
Page 236 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. KOZLOWSKI: So to follow-up,
have there been large formularies, you know at a national level that have switched and has there been any follow-up on those? MR. KINGHAM: There are tenders in And,
some countries, in Germany for example. yes, there have been. I'm not aware of
specific problems. The main problems I'm aware of with respect to products that at least might be called biosimilars are in developing countries. And there have been some
significant ones in Thailand and else with erythropietin products. DR. BEHRMAN: MS. MALONEY: Ms. Maloney? I'm just going back
to the legislation under consideration with regard to traceability. Have folks identified
the key hurdles in the area that need to be addressed? MR. KINGHAM: Well, obviously,
there's yet, although there are in theory electronic reporting systems for adverse Neal R. Gross & Co., Inc. 202-234-4433
Page 237 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 events in Europe and a variety of other systems have been put into place, they're imperfect as are systems in many other countries. And consequently a lot of data is
lost in just the background noise of the system so forth. My personal view is that until we get perfect electronic reporting which links every report to an manufacturer's product and so forth. It would be highly desirable if the
name of the product, the name that the physician would recognize from the prescription, the name that the pharmacist would recognize from dispensing were somehow distinctive. DR. BEHRMAN: One last question.
You noted there's been quite a lag between legislation and Europe and here. And but you
also noted there's been a very small market penetration, so a small experience to date. Can you comment on why you think that is? it the difficulty developing the compounds? Neal R. Gross & Co., Inc. 202-234-4433 Is
Page 238 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Ruckman. DR. BEHRMAN: Okay. I'm sorry. comments. Our next speaker Jeanne Novak. Will you be speaking, or all three of you? DR. RUCKMAN: I'm actually Judy Is it not an attractive route, or so forth? MR. KINGHAM: an unattractive route. I don't think it's It's clear that the
safety oriented requirements that the Europeans have developed make it a pretty substantial enterprise to develop these products. And the traditional generic type manufacturer will have to modify its business practices significantly in order to get into this business. DR. BEHRMAN: Thank you for your
Well, Judy Ruckman and Michael Strauss from CBR International. DR. RUCKMAN: Thank you. Thank And
you for the opportunity to speak today. as I just noted, I'm Judy Ruckman.
I'll be
Page 239 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 presenting on behalf of the co-authors of this presentation, Dr. Jeanne Novak and Mr. Michael Strauss. I'd like to first briefly introduce you to CBR International. We are a
biopharmaceutical development consulting firm located in Boulder, Colorado. For over ten
years we've assisted our clients on scientific and regulatory issues related to product development with an emphasis on biologic products. Due to the depths of our clients programs we are experienced in the scientific and clinical issues surrounding comparability and immunogenicity testing for biologic products relevant to today's discussions on biosimilar products. First, I'd like to start with a few overarching concepts for consideration. First, the concept of biosimilars includes the principle that biologic products manufactured by similar but non-identical manufacturing Neal R. Gross & Co., Inc. 202-234-4433
Page 240 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 processes may exhibit some minor differences in physical chemical attributes. These
differences may or may not have impacts on the biological activity of the molecule as measured by in vitro or in vivo biological assays, and further may or may not have significance for the efficacy and safety of the molecule in human patients. The focus
should be to identify the differences that are present and the clinical significance of these differences. The EMEA has been engaged in regulating biosimilar products for several years now and has established a worthy precedent to guide the FDA's approach to biosimilars regulation. In particular, the
CHMP has shown significant flexibility in its application of guidelines and has allowed scientific considerations to guide its decision making for individual products. We agree with EMEA's stepwise approach to biosimilar assessment building on Neal R. Gross & Co., Inc. 202-234-4433
Page 241 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 analytical and non-clinical data to justify comparative clinical trials, However, we
strongly recommend that a stepwise approach include flexibility for products or product classes where certain steps may not be necessary, or where steps may be reasonably performed concurrently rather than in succession. Flexibility may be particularly
needed for biosimilar products already approved outside the U.S. and for which extensive non-clinical and clinical data are already in hand. We concur with previous speakers that a harmonized approach permitting concurrent development for multiple jurisdictions is desirable. In responding to Question A1, we consider that quality non-clinical and clinical factors are all considerations for the determination of a product as highly similar. We recommend the Agency consider the
following with respect to biosimilar product Neal R. Gross & Co., Inc. 202-234-4433
Page 242 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 quality. It is widely agreed that a biosimilar product should share the primary amino acid sequence as the referenced product. and in general, secondary and tertiary structure as well as physical chemical characteristics such as pI should also be very similar between the biosimilar product and the referenced products unless it is known or can be demonstrated that any structural or physical chemical differences have no measurable impact on biological activity. Differences in post-translational processing such as differences in the profile, specific glycoforms is not a priori inconsistent with biosimilarity. It depends on whether the differences in the glycan profile impact the biological activity of the protein. We recommend that the focus of comparative physical testing should be on the critical quality attributes of the molecule and where appropriate, orthogonal methods should be used Neal R. Gross & Co., Inc. 202-234-4433
Page 243 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 to evaluate CQAs. We recommend that the Agency limit its requirements for any given product to a battery of assays that adequately characterize all key attributes of the molecule without excessive redundancy. FDA should consider that biosimilars are most likely reverse engineered, and as a consequence a biosimilar developer will not know what the design space is of the reference protein. We recommend
that FDA primarily judge the similarity of the two proteins by the convergence of their CQAs and not by comparison of release parameters or an unknown design space target. With regard to non-clinical studies, it is our view that these studies should be narrowly targeted since small differences that might be observed in animal studies will ultimately be followed up by human clinical comparisons and are likely to be discounted if the human data detect no Neal R. Gross & Co., Inc. 202-234-4433
Page 244 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 differences. We recommend that the primary focus of animal studies should be to ensure the safety of a product not previously tested in humans. A non-comparative toxicity study
may be adequate for this purpose. Further, where a relevant animal model exists, pharmacokinetic or pharmacodynamic comparisons might be used to lower the requirements for comparative clinical trials. For example, if no gross
differences in pharmacodynamic behavior are found in a well accepted animal model, then it might be appropriate to proceed directly to phase 3 comparative testing of a biosimilar product without the stepwise requirement to evaluate comparative human pharmacokinetics beforehand. However, where a clinical PK/PD
study is planned and a non-clinical PK/PD comparison does not add significantly to the overall assessment of biosimilarity, we would ask the Agency to consider whether such a Neal R. Gross & Co., Inc. 202-234-4433
Page 245 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 study was needed. We anticipate that clinical data will always be required for initial licensure of a biosimilar product. However, we
recommend that the scope of clinical development should be tailored to the product class. Specifically, for relatively simple
proteins where physicochemical and bioanalytical data provide a convincing demonstration that the product is similar to the referenced product, a comparative PK/PD study along with an adequate demonstration of safety may be sufficient for licensure. For
more complex proteins or products where small differences in structure or activity have been detected by sensitive analytical techniques, a comparative efficacy trial would be expected. Regarding studies to evaluate potential differences in a biosimilar product, the significance of any structural differences depends on whether the differences impact the Neal R. Gross & Co., Inc. 202-234-4433
Page 246 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 critical quality attributes of the product in question and therefore have a greater risk of altering the effectiveness of the biosimilar product in clinical use. For one protein the
degree of glycosylation may have no impact on biological activity or for another, the identity of the glyco forms may effect receptor binding affinity. CQAs, and
therefore the criteria for biosimilarity will differ from protein to protein or between product classes. Even if differences in a
known CQA are detected, a biosimilar product may perform comparably to the referenced product in clinical use. So supporting clinical or non-clinical data should be reviewed to assess patient risk. Regarding Question A4 concerning circumstances where non-clinical or clinical studies requirements may be reduced, we consider the non-clinical studies may not be needed in the circumstance where adequate preclinical or clinical safety data exists to Neal R. Gross & Co., Inc. 202-234-4433
Page 247 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 support clinical evaluation under a US IND. This scenario may arise when a product is already under investigation or has already been authorized for commercial distribution in a jurisdiction outside the U.S. In addition, as noted previously, we suggest that comparative non-clinical studies should be justified based on the utility of the data to limit the scope of clinical development. And if this
justification is lacking, the Agency should consider limiting requests for such studies. We expect clinical testing will be necessary for development of a biosimilar product. And we concur with the EMEA approach describing guidance to permit extrapolation
of comparative efficacy data from one indication to other indications where the mechanism of action and safety profile of the reference in biosimilar products are well known. In addition, we recommend that the Neal R. Gross & Co., Inc. 202-234-4433
Page 248 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Agency consider the acceptability of clinical studies preformed in other regulatory jurisdictions using an acceptable, non-U.S. source referenced product to limit inappropriate repetition of clinical studies. Finally, we suggest that the Agency consider scenarios where licensure may be appropriate on the basis of comparative PK/PD only where clinical efficacy data are available from other sources and unwanted immunogenicity risk is deemed to be low. Regarding Question B1, an interchangeable biosimilar product should be labeled for use in all of the indications and patient populations for which the referenced product is labeled. In the case that FDA chose to license a biosimilar product for only a subset of the indications appearing on the referenced product label, that biosimilar product would not meet this criterion for interchangeability. FDA should discuss with
Page 249 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 development. sponsors the data necessary to meet this criterion at an early stage of biosimilar product development. Regarding Question B2, the primary theoretical risk associated with switching between referenced product and a biosimilar product is unwanted immunogenicity. Clinical
data would be necessary to evaluate this potential risk. This could include cross over
studies, pre or post approval safety databases or pharmacovigilance. The preconditions for
achieving of similarity versus interchangeability should be agreed upon during prelicensing meetings with the Agency or during application review. Until interchangeability has been established, FDA may wish to consider labeling requirements to indicate that the risk of switching or alternating between products in the same class is unknown. Quickly with regard to guidance We recommend that the Agency Neal R. Gross & Co., Inc. 202-234-4433
Page 250 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Questions from panelists? Neal R. Gross & Co., Inc. 202-234-4433 Mr. focus its initial guidance development on overarching guidance for stepwise approach to biosimilar development. And in addition,
concrete guidance on expectations for comparative clinical safety and efficacy study design, and a regulatory guidance or information sheet specific for biosimilar products would be beneficial. We've noted
additional guidance recommendations for subsequent efforts. And finally in closing, I would like to comment that there may be classes of biosimilar products other than recombinant therapeutic proteins that may be appropriately regulated as biosimilars as the FDA gains experience with this regulatory paradigm. we list some of those examples here. And, again, thank you for the opportunity today. DR. BEHRMAN: Thank you for your And
Page 251 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 slide 16. Schwartz? MR. SCHWARTZ: Thank you.
Could you possibly go back to your I'm not sure that I understood
exactly what you were saying. It has to do with expectations for an interchangeable biosimilar product. DR. RUCKMAN: MR. SCHWARTZ: Yes. Which would be
deemed interchangeable if the biosimilar is labeled for us in all of the indications in patient populations for which the referenced product is labeled. on that, please? DR. RUCKMAN: Sure. This is our Could you just elaborate
interpretation of the language of the Act that labeled for use in any given patient suggests any given patient for any given indication. In other words, there isn't any subdivision here that any given patient within an indication is not in the language of the Act. So our interpretation is that to meet this Neal R. Gross & Co., Inc. 202-234-4433
Page 252 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 criterion for interchangeability the biosimilar product would have also need to have met all of the biosimilarity requirements dictated by the Agency for all of the indications in the referenced product label. DR. BEHRMAN: Can I follow-up. So
that if then the innovator gained a new indication, what do you see as happening to the biosimilar product? DR. RUCKMAN: considered that. Yes, we've
With this interpretation it
certainly it may be the case. But if the referenced product gains a new indication and there would be additional clinical data required for the biosimilar product to obtain that indication, it might lose its interchangeability status. Otherwise, it would be necessary for the Agency to come up with a mechanism to have interchangeability for a subset of the indications. DR. BEHRMAN: DR. KOZLOWSKI: Dr. Kozlowski? So to follow-up in
Page 253 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 that, so do you think that that covers any given patient that that's basically the explanation of that clause? DR. RUCKMAN: That's our
interpretation of the clause, yes. DR. KOZLOWSKI: In another area,
you mentioned the importance of critical quality attributes. And clearly, ideally if
you knew every critical quality attribute of a product, that's all you'd need to worry about. But there's a lot of uncertainty for
complex products in assigning criticality and you have a lot of uncertainty. So, do you have any sense of how a biosimilar manufacturer would go about establish critical quality attributes? DR. RUCKMAN: Critical quality
attributes should be defined in part, of course, by what is known about the referenced product and what is in the literature, and based on the information that the biosimilar developer themselves have developed Neal R. Gross & Co., Inc. 202-234-4433
Page 254 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 internally. Again, our view is that while these products are derived from very independent processes and the design space around each process is independent, as long as the product remains comparable within its design space, as long as there is appropriate overlap between the critical quality attributes, it should be sufficient. DR. BEHRMAN: Could I go back to How might you
do changeability for a moment? see that being implemented?
Do you see that
as a labeling issue that if a biosimilar is interchangeable, if labeling states that point and if it loses, the labeling change, or do you see another system? DR. RUCKMAN: I think we would see
it as a labeling issue that a product that had not achieved interchangeability would appropriately be labeled, that it was not interchangeable. And if that
interchangeability status was lost, that might Neal R. Gross & Co., Inc. 202-234-4433
Page 255 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Our next speakers are Bruce Babbit and Cecil Nick from PAREXEL, or just one. DR. BABBITT: Hi. On behalf of lead to a labeling revision. DR. BEHRMAN: Do you see any
information about interchangeability being in the innovative labeling? DR. RUCKMAN: That was brought up
previously, and it was an interesting question. It may be appropriate, yes. DR. BEHRMAN: Thank you for your
PAREXEL Consulting, part of PAREXEL International, a global biopharmaceutical services provider, we would like to thank the FDA for the opportunity to present our insights regarding the development of biosimilars. My name is Bruce Babbit, and I am accompanied today by my colleague Cecil Nick, who is our European biosimilar expert, and if needed today Cecil can address questions Neal R. Gross & Co., Inc. 202-234-4433
Page 256 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 related to the European experience with biosimilars. PAREXEL has participated in the development of many of the biologics approved by the FDA. In addition, to date our experts
based in Europe have been involved in supporting approximately 20 biosimilar development programs, including some of the products already approved in the EU. Based on these experiences we understand that there cannot be a one size fits all approach for the development and regulation for biosimilar products. For
example, we can envision somewhat different clinical trial requirements depending on the structural and functional complexity of the biologic, as well as the breadth of the approved indications. Patient safety is paramount, and for biosimilars safety can ultimately only be established through clinical trials followed by a post-marketing risk management program. Neal R. Gross & Co., Inc. 202-234-4433
Page 257 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 The more complex question is the extent to which comparative efficacy needs to be established through clinical trials. If the
preclinical and phase 1 programs already demonstrate biosimilarity, there may be no need to repeat the entire original clinical program performed for the referenced product. A key principle underlying our thinking for streamlining biosimilar development programs is to acknowledge that unlike when a new biological entity is first developed, much is already known about the structure, function, relationships, mechanism of action and safety and efficacy profile of the innovator product in specific patient populations. In addition, there has been a vast improvement in the scope and quality of physical chemical and biological methods used for characterization of therapeutic proteins. Such data will provide the most accurate indication of any structural or functional Neal R. Gross & Co., Inc. 202-234-4433
Page 258 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 differences between the product. Another key concept we would like to discuss is what we refer to as the totality of the data. By this we mean that the physical chemical and biologic characterization coupled with clinical pharmacological data already provide a solid basis for establishing biosimilarity. We consider it important to
balance the value and relevance of these data against the need for clinical safety and efficacy data, particularly where minor or modest differences between the biosimilar and referenced products are unlikely to translate into any meaningful differences in the clinic. This approach is somewhat similar to how the Agency has reviewed comparability testing data from developers of new biological entities following major changes in manufacturing. Now I'm going to transition to discuss three distinct areas of clinical development: One, extrapolation of Neal R. Gross & Co., Inc. 202-234-4433
Page 259 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 indications, two, use of surrogate endpoints, and three, use of non-inferiority trial design that we believe might provide opportunities on a case-by-case basis to streamline biosimilar development. Most biologics have been approved for multiple indications. Clinical trials on
new biologic entities were designed to demonstrate efficacy against placebo. However, placebo trials will no longer viable, at least for serious and life threatening diseases for which there exists effective therapies. Therefore, for following biologics
it is necessary to perform much larger, noninferiority or equivalence trials which are not always feasible. It is our position that as long as the mechanism of action if relatively well understood across indications, it should be possible to demonstrate comparable and safety and efficacy of biosimilar and referenced product in one adequately sensitive Neal R. Gross & Co., Inc. 202-234-4433
Page 260 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 indication, and then taking into account all prior analytical non-clinical and clinical comparability data, to conclude therapeutic equivalence for all indications. In other
words, extrapolate the results across multiple indications. By "adequately sensitive," we mean a patient population where differences between the biosimilar and referenced products if they exist, are most likely to be detected and generate a dataset with a relative low degree of variability. Even in cases where the target indications of how these diverse, for example as is the case with many approve monoclonal antibody products, extrapolation should be considered reasonable. Monoclonals can
theoretically exert multiple effect in vivo and the relative contributions of these effects might not be the same across indications. Nevertheless, if all relevant
biological effects are understood to be Neal R. Gross & Co., Inc. 202-234-4433
Page 261 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 involved in generating a therapeutic effect in the selected target population, then this should be an adequate indicator for general therapeutic equivalence. Selection of clinical trial endpoints represents another potential area for streamlining biosimilar development programs. For those innovative products where
there exists a strong and well defined pharmacodynamic effect, for example as with insulin and GCSF, PD markers may trump clinical endpoints in terms of precision and could be equally or more relevant. When using PD endpoints as surrogates for clinical endpoints, the PD effect needs to be dose sensitive and to correlate to the therapeutic effect. If this
correlations can be adequately demonstrated from literature, then we would consider a PD marker to be a potentially more sensitive measure of efficacy than a clinical endpoint. The use of surrogate clinical Neal R. Gross & Co., Inc. 202-234-4433
Page 262 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 endpoints can also play a key role in the development of biosimilars. For example, in
oncology overall survival is considered the gold standard, but this is often not a practical endpoint for non-inferiority trials. Moreover, demonstration of survival becomes extremely challenging as next line therapies become available to treat disease progression. Progression pre-survival is perhaps the next endpoint, but it can also take many years to demonstrate equivalence. Therefore, a more practical approach would be to use response rates as the primary endpoint and to include progression pre survival and where possible overall survival as secondary endpoints. There is
already regulatory precedence for this, for example, in the approval of liposomal doxorubicin versus doxorubicin. Finally, we would like to address the issue of whether to perform a noninferiority or equivalence trial for Neal R. Gross & Co., Inc. 202-234-4433
Page 263 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 demonstration of biosimilarity. Where a
protein exerts a direct physiological effect and there's a close association between dose and therapeutic effect, as is the case for products such as insulin and GCSF, EPO and somatropin, clearly supra-activity will be a safety concern and equivalence trials are likely essential. However, in the case of
monoclonal antibody products, clinical effect and inflammatory disease or oncology is generally measured in terms of the proportion of responders and not as a physiological effect. Under these circumstances it is our
view that it is more appropriate to perform non-inferiority trials since an increase in responders, in other words crossing the upper bounds of the selected equivalence margin, should not a priori be a reason to reject the product as biosimilar, especially given that safety would be monitored independently. In this case one would not claim superiority for the biosimilar and there would Neal R. Gross & Co., Inc. 202-234-4433
Page 264 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 be a need to provide a rationale for the improved efficacy relative to referenced product, one possibility being the result of reduced immunogenicity. In conclusion, patient safety is paramount and for biosimilars the safety profile can ultimately only be established through clinical trials followed by a postmarketing risk management program. It is our
view that certain biosimilar clinical development programs can be streamlined employing some combination of extrapolation of indications, use of surrogate endpoints and non-inferiority trial design. Thus, a single
equivalence or non-inferiority therapeutic trial in a sensitive patient population utilizing an appropriate and relevant endpoint should generally be sufficient to confirm biosimilarity even when indications are highly diverse provided that the mechanism of action is reasonably well understood. Finally, we believe that Neal R. Gross & Co., Inc. 202-234-4433
Page 265 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 biosimilarity should ultimately judged on the totality of the data taking into account the complex set of head-to-head studies referenced product. We consider that against
extensive in vitro physical, chemical and biological characterization followed by comparative PK/PD assessment in humans already provide strong evidence for biosimilarity, and therefore that safety and efficacy trials in patients are intended primarily as final confirmation of therapeutic equivalence. The extent of clinical data required will be driven by any differences detected through the physical, chemical and biological testing, the clinical relevance of any pharmacological data, the therapeutic relevance of the surrogate clinical endpoints and the complexity of the molecule. This
approach is somewhat analogous to how the Agency has reviewed comparability testing data submitted by developers of new biological entities in support of major changes in Neal R. Gross & Co., Inc. 202-234-4433
Page 266 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Jenkins? DR. JENKINS: As often happens in comments. Questions from the panel? Dr. attention. DR. BEHRMAN: Thank you for your manufacturing. Thank you for your time and
these meetings, we're getting advice that's pretty diametrically opposite from various speakers. So, an earlier speaker suggested
that oncology would be inappropriate to use the earlier endpoint such as response rate as the basis for a biosimilar determination. And
they were suggesting overall survival as the ultimate goal, and that should be the endpoint. You articulated reasons why those ultimate endpoints really aren't feasible. So, how should we reconcile those two very different viewpoints on what endpoints to use in the clinical trials? DR. BABBITT: I know that question
Page 267 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comes up and you get diametrically opposed responses. My view on it, having seen lots of these different programs come through PAREXEL, is that in this case it's again the totality of the data that's working in favor of using maybe a surrogate endpoint where there might be otherwise for a new biological entity considered some risk. So I think if you built up similarities with very extensive preclinical work, including in vitro work, including some non-clinical testing and then including at least one clinical trial, if more than one if you're developing a monoclonal and you've been both in the rheumatology arena as well as the oncology arena, I just think there's more evidence in it from a risk benefit standpoint, more support for taking the non-inferiority approach and using a surrogate endpoint of needing as a primary endpoint to use progression pre-survival or survival. Neal R. Gross & Co., Inc. 202-234-4433 I think
Page 268 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 it's a reasonable risk. DR. JENKINS: You mentioned in
your talk that in some cases the pharmacodynamic measure might be more sensitive and more useful. So, would you
consider response rate and oncology to be closer to a pharmacodynamic measure that's more sensitive than survival? Is that part of
the basis for why you look at it that way? DR. BABBITT: Only part. When I
was speaking about a pharmacodynamic PD endpoint, I was thinking actually more of the programs that are focused on the GCSF studies and biosimilars where I think there might be stronger evidence that that endpoint correlates with clinical outcome. And I'm aware that some programs including, I think, those that might have been approved in Europe have actually used the pharmacodynamic endpoint in the filgrastim programs as primary endpoint head-to-head against comparators to show biosimilarity, and then they were Neal R. Gross & Co., Inc. 202-234-4433
Page 269 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 followed or not depending on their program with a follow-up study in patients. So, I look at those somewhat differently, and I look at them as not having the scientific proof underneath. DR. JENKINS: One other follow-up
question, you seem to be inching fairly close to a bio-better standard where you suggested that the biosimilar might in some cases have better efficacy or lower immunogenicity, or better safety and that would still be okay. Can you comment on how you put that together with the statutory language of no clinical meaningful differences? You suggested they
wouldn't be able to make a superiority claim, but you also suggested that those products might still be approved as biosimilars? DR. BABBITT: Yes. And let me
state first that I've actually dealt at PAREXEL with several bio-better candidates in the last few years, so I'm trying to put this in the right perspective. Neal R. Gross & Co., Inc. 202-234-4433
Page 270 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 I guess the point I wanted to make there is that to have some degree of flexibility from the Agency standpoint that if you do see a difference in a controlled trial, a non-inferiority trial is in particular what mentioned in terms of the efficacy, that not to have that mean that you don't have a biosimilar any more if there's sort of data to support a potential understanding of why that difference existed. And all I can think of
off the top of my head is that it's possible if you had, as I said, a lower immunogenicity if it came not from lacking in epitope that their referenced product had, but from having a lower degree of aggregation in theory or a greater stability, or something that would not reflect a difference in structure between the molecules, but a difference in those parameters and could that lead to a difference in the efficacy if indeed it's know that there's an antibody response that inhibits efficacy. That's just one example, but I Neal R. Gross & Co., Inc. 202-234-4433
Page 271 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 guess I wanted to put it out there that the idea that will it necessarily be the case that you don't have a biosimilar and you're moving towards a bio-better if you are above the upper limit of the efficacy margin? DR. BEHRMAN: So let's say, it's
less immunogenetic, which is an advantage to a patient, you believe under 351(k) we have the authority to prove that and label it accordingly? DR. BABBITT: I think I would
guess that in most cases unless the sensitive patient population which you did the study had, unlike the B cell malignancies, a relative high degree of immunogenicity it would be actually hard for the developer of the biosimilar what I'm hypothesizing and to have it end up as a label. straightforward about that. DR. KOZLOWSKI: To follow-up on I mean, to be
this distinction between products that I guess you described as saturable versus those with Neal R. Gross & Co., Inc. 202-234-4433
Page 272 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 a dose response and having need to be treated differently. So, say efficacy is saturable in
some way by the product, how do you know that the safety effects are? In other words, there
may be some dose response for a safety issue that is different than efficacy, which might be saturable. DR. BABBITT: No. Then I think
that's why you need to run randomized controlled trials against comparator and even as a secondary endpoint to follow various -to have safety as a secondary endpoint for whatever period of time that you need to assess safety. DR. KOZLOWSKI: on the totality of the data. And your comment So we certainly
heard that description a number of times, and we've also heard examples of where we need to look at each aspect separately. Is there a
way of incorporating that totality of the data or prior knowledge to think about what the impact on clinical studies are? Because
Page 273 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 usually the impact is some big step function; what your endpoint is, you know what's an acceptable surrogate. And the quality of the data may very in terms of the level of characterization and the actual similarity. So, is there a model? And I think we heard a
discussion about maybe such models should be developed. But someway of translating
totality of the data from some step function in change of how you look at something to an approach, a way of thinking about this study? DR. BABBITT: Well, if I
understand your question, I guess what I would say is that all that the biosimilar developer do is do an extremely extensive in vitro and biological in vitro testing of the reference produce product versus the U.S. and typical European source reference product. And I would think that if differences are seen that are qualitative differences, which it might be worrisome you do or you don't have a function, I'm thinking Neal R. Gross & Co., Inc. 202-234-4433
Page 274 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Our next speakers or speaker are from Technology & Business Law Advisors, Robert Bakin and Bernard Rhee. MR. RHEE: Good afternoon. My look at it. of antibody products for example, versus quantitative differences and then versus small quantitative differences, I think along that spectrum maybe in terms of what you meant by a step function if I see qualitative or nonminor quantitative differences between any of the key parameters that you're measuring, I think I might then do more testing in the clinic. I might even do a little bit more
testing if it's relevant in animals. I mean, I guess that's the way I So, I think that the totality of
data to me means that it helps you either further streamline or not further streamline what you're doing next based on the data that you generate. DR. BEHRMAN: Thank you for your
Page 275 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 name is Bernard Rhee. I'm a patent attorney,
and I appear before with my colleague Robert Bakin. We're from the law firm of Technology & Business Law Advisors. The
majority of our work is for organizations in the pharmaceutical and medical device industries. We want to thank FDA, and specifically each member of the Panel for the opportunity to speak today. We're here to
speak on the issue of what factors should be considered when determining what a related entity is for the purposes of the exclusivity provision in the Patient Protection and Affordable Healthcare Act. MR. BAKIN: All right. So thank
you, Bernie. Thank you FDA Panel. So as Bernie alluded to, basically our primary goal here is to start a discussion of what actually a related business entity is, and who or who should not be eligible for Neal R. Gross & Co., Inc. 202-234-4433
Page 276 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 multiple 12 year extension periods. And the
question that we're asking essentially was from the Federal Register. pasted it up there. We copied it and
I will read it briefly.
That in light of the potential transfer of BLAs from one corporate entity to another and the complexities of corporate and business relationships, what factors should the Agency consider in determining the types of related entitles. And I have that in bold "That
because that's the language in the Act. may be ineligible for a period of 12 year exclusivity for a subsequent BLA.
And I guess the question is, the broad question we're asking is: Are there any
type of favorable evergreening clauses that are good for an admission? And so here's the Act. going to read it in its entirety. I'm not I'm sure But I
you're all somewhat familiar with it.
will touch on each subject individually. So the first section A, as Neal R. Gross & Co., Inc. 202-234-4433
Page 277 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 everybody knows, the intent here is to grant innovators 12 years of market exclusivity against follow-on biological applicants. The second section deals with the four year, the other exclusivity period, follow-on biologic applicants from even submitting the application, similar to the paragraph for ANDAs, which is small molecule generics. And then the third paragraph is kind of where it gets messy and confusing. This is where the anti-evergreen clauses are kind of buried in there. And as you can see,
it's kind of large, so I'll just go through it in parts. The first part is essentially to deny additional exclusivity for any company filing non-innovative drugs, a supplemental BLA. The second part, kind of shaded out the superfluous stuff and if you just focus on the bold, essentially starts off the Neal R. Gross & Co., Inc. 202-234-4433
Page 278 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 same but then you get the same sponsor language and this other structural language that confuses things a bit. here is, again, similar. And the intent
To prevent evergreen Any related
by a single related entity.
entity that files multiple applications for a new indication market dosage strength will not be rewarded with an additional exclusivity period. But the problem here is that there's,
we'll call it the first evergreening loophole, where if the same sponsor or any related entity makes basically any structural, then additional exclusivity is theoretically possible. Now the second part, capital II, again starts off the same. Same sponsor or
other related entity and it brings in the structural language. And the intent here is,
again, to deny additional exclusivity to a single company or related entity files multiple applications for quote/unquote, we'll call then non-innovator biologics. Neal R. Gross & Co., Inc. 202-234-4433
Page 279 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 here. Again, now there's another problem Evergreening loophole, we'll call it
number 2, again is basically any structural change will likely presuppose a change in safety and/or potency. And so the same
sponsor any other related entity makes structural changes, then it's possible to get another 12 year exclusivity period. And so just to review what we've gone through here so far in the last couple of days, it sounds like, is that some follow=on biologics are going to be biosimilar, not necessarily interchangeable with a notable exception of this recent ANDA, FDA approval of ANDA for Lovenox, which is -- technically it's a small molecule, I guess, but it's somewhat of a pseudo-biologic that may signal the interchangeability are at least possible. Most follow-on biologics, even biologics with minor changes will represent distinct biological drugs. We have number 3, which we're Neal R. Gross & Co., Inc. 202-234-4433
Page 280 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 calling it the structural loophole. obvious evergreening loophole. And then the fourth one is the related entity loophole. I think we missed the boat on the legislation part, but this kind of points us in the direction of what we were thinking, or at least our thought process going. So you It's an
can just focus on the red bold part of number 2 where you would limit, again this is just limiting who gets the extra 12 year exclusivity. And we're thinking along the
lines of limiting through any subsequent application for biosimilar interchangeable product filed by the same sponsor or any current entity under the financial control of the same sponsor, the same manufacturer and the same licensure, or any predecessor in interest. And literally, there's nothing here that would prevent an innovator from filing a subsequent application. They just
Page 281 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 would not get the extra 12 year exclusivity. So, I'll end with that. And leave
you off with the related entity loophole that Bernie is going to talk about. MR. RHEE: Thank you, Rob.
We know that in some situations a related entity is not eligible for the 12 year exclusivity period. questions. One question is what happens when a different sponsor or a different manufacturer, a licensee, a successor in interest or other unrelated entity files an application and that entity is subsequently acquired or the marketing rights or license by the referenced product sponsor? Another question is: What are the This raises some
boundaries of other related entity? We think it would be most helpful to define what an unrelated entity is. Our
proposal is the following generally accepted legal concepts and contract language that are Neal R. Gross & Co., Inc. 202-234-4433
Page 282 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 commonly used in the industry. An unrelated
entity would be an entity that does directly or indirectly control, is not controlled by, or is not under common control with another entity. For the purposes of this law an
entity shall be regarded as in control of another entity if: A. It owns directly or indirectly
more than 50 percent of the voting stop or other ownership interest of the other entity, or; B. It poses directly or
indirectly the power to: (i) Direct the management policies of the other entitles or; (ii) Elect or appoint more than 50 percent of the members of the governing body of the other entity. There are two scenarios which can be used to highlight some of the complexity surrounding the issue of related and unrelated entitles. Scenario 1 is a classic situation Neal R. Gross & Co., Inc. 202-234-4433
Page 283 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 where you have in January of 2011, hypothetically, Company A filed a BLA for a monoclonal antibody product 1A. 2015 the BLA is approved. In January
The 12 year
exclusivity period is granted. And the exclusivity period extends to January 2027. Sales are great, it becomes a blockbuster product and then the light bulb goes off in Company A's head and says all right, let's do this again. So, in January of
2017 Company A files a second BLA for monoclonal antibody product 1B. In January
2021 the BLA is approved and they get a second exclusivity period which extends to January 2033. Now, scenario 2 is similar to scenario 1, however in scenario 2 a second company comes into the picture. It starts off
the same where in January 2011 Company A files a BLA for monoclonal antibody product 1A. January 2015 the BLA is approved. their 12 year exclusivity period. They get Sales are In
Page 284 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 great, exclusivity period will extend to January 2027. Now in this hypothetical on January 2017 Company B has been working on a similar product for a monoclonal antibody product 1B. And in January 2017 Company B On January 2021 the BLA is
files their BLA.
approved, a second exclusivity period is granted and extends to the same date, January 2023. Now there can be three related situations in this scenario. The first here
is that Company A buys Company B one month after Company B's BLA filing, or at any point in time Company A licenses Company B's monoclonal antibody product 1B, or at some point before the second BLA filing Company A
establishes an unrelated entity or maybe multiple unrelated entities to develop monoclonal antibody product 1B and file the BLA. And that established unrelated Neal R. Gross & Co., Inc. 202-234-4433
Page 285 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 entity can take many forms. That could be a
situation where Company A takes a minority ownership interest in Company B, it could be a situation where Company A funds a specific development project within Company B. It could be some type of other complex business relationship. Actually, you can see on the bottom there the equation where conceptually you have Company A with their technology underneath it, Company B with their technology underneath it and it comes the collective Company AB entity with the collective technology. And the exclusivity period will
extend to January 2023, which is basically one exclusivity period piggybacking on the other exclusivity period. In all three of these situation we propose maintaining the first and second 12 year exclusivity period. We believe that
theoretically additional 12 year exclusivity periods will hurt innovation and will act as Neal R. Gross & Co., Inc. 202-234-4433
Page 286 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 a barrier to entry for drugs. However, we
believe in reality additional 12 year exclusivity periods will actually encourage innovation and result more drugs entering the marketplace. Some of the benefits of multiple 12 year exclusivity period were set forth on our final slide here. One benefit is patient safety. More products coming to the marketplace, patients will have more choices so there's greater safety for the public. This technology is complicated and unpredictable. So what is safe for one
patient may not be safe for another. Point 2 is better drug products. We create incentive for all companies to develop and commercialize bio-betters. Point 3 is collaboration among the drug companies. An example is creating an
incentive for large reference drug companies to help unrelated entities to develop bioNeal R. Gross & Co., Inc. 202-234-4433
Page 287 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. In terms of, it looks like you're proposing perhaps the adoption of regulatory guidance or regulatory definition of related entity, if something along the lines of the language that you proposed in terms of common control or succession in interest was adopted by the Agency, do you think that is pro or anti evergreening and it would be consistent with the statutory intent? Neal R. Gross & Co., Inc. 202-234-4433 comments. Questions from the Panel? MS. ESPOSITO: Thank you for your betters. And our final point here is fairness to all drug companies. There's no
loss of rightly gained exclusivity rights during intellectual property licensing, business acquisitions, mergers or similar other transactions. Thank you. DR. BEHRMAN: Thank you for your
Page 288 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 MR. RHEE: To be honest with you,
our agenda if we can say we have an agenda is really to bring clarity to everybody. I think
it benefits everybody for follow-on biologic companies, innovator companies and everybody in between. We think that without clarity it's going to create a lot of problems. There are
going to be companies trying to maneuver left and right to get into the marketplace. And
it's going to create a lot of; a lot of people wont' do anything. We think with clarity, whether this proposed language or any language, we think it will benefit everybody. We really don't think it's a pro big company or pro small company or pro innovator or pro followon biologic company. But we do feel strongly
that there should be some clarity with regard to this because the majority of the people that talk today and yesterday talked about the scientific issues. We think once we take a
Page 289 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 step pass that, there are very, very real business issues and we need to deal with those issues now to keep technology innovation going. DR. KOZLOWSKI: Do you think some
of your concerns about this will depend on how we interpret or how it's interpreted that a structural change that impacts safety, purity and potency is interpreted? MR. BAKIN: Yes. I mean, to be
honest with you, the whole structural issue I find very confusing. that means. I don't really know what
Any changes is going to change
the structure, so by definition any change is going to be a new rug. answered your question. DR. KOZLOWSKI: Again, depending I'm not sure I
on how you define the change in safety, purity and potency, that creates a very different standard for what could be evergreened and what couldn't. So, I think there is a sort of a scientific component to interpreting this Neal R. Gross & Co., Inc. 202-234-4433
Page 290 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 too that may deal with some of your concerns. MR. RHEE: Yes. Our position is
that at this moment in time with the technology that we have today basically any structural change will be a change in efficacy, potency and safety. our position. That's really
That's not say, I mean
hopefully down the road it's not going to be like that. DR. BEHRMAN: I just have one
question, which is yesterday we heard from a number of speakers that the 12 year period of exclusivity had drawbacks from the point of view of patient safety, innovation, perhaps encouraging unnecessary or unethical duplicative testing. And your last slide is
entitled Benefits of Multiple 2-4 Year Exclusivity Periods. on that? It sounds like from what you just said you're here primarily to help provide clarity, yet you seem to be, in fact, taking Neal R. Gross & Co., Inc. 202-234-4433 Do you have any comments
Page 291 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 a position somewhat opposite from what we heard yesterday. MR. RHEE: Yes. There's some irony
here where it's analogous to maybe a patent situation where on the surface having patent rights one argument is that it blocks innovation, blocks drugs from coming to the marketplace. But in reality I think we'll
agree that there's a strong incentive there to bring products to the marketplace and to be innovative. That's analogous to this slide where multiple 12 year exclusivity periods will actually in reality bring more drug products to the marketplace, encourage collaboration among drug companies and ultimately, hopefully, result in greater patient safety. I think we all wished that we all lived in a world where drugs were 100 percent safe, 100 percent effective and a 100 percent free. But there are just certain economic Neal R. Gross & Co., Inc. 202-234-4433
Page 292 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. MR. RHEE: Thank you. Our next speaker is realities that don't make it such a place. DR. BEHRMAN: Thank you for your
DR. BEHRMAN:
Mary Gustafson from Plasma Protein Therapeutics Association. MS. GUSTAFSON: I would like to
thank the organizers of the Part 15 Hearing for providing the opportunity to comment on FDA's implementation of this milestone legislation. PPTA is an international trade and standard setting organization. We represent
the collectives of source plasma, which is a human plasma that is used in the manufacture of plasma drug therapies. And we represent the manufacturers of plasma drug therapies and their recombinant analog products, which are referred to as plasma protein therapies collectively. Plasma protein therapies are used Neal R. Gross & Co., Inc. 202-234-4433
Page 293 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 in the treatment of a number of rare diseases. These diseases are often genetic, chronic, life threatening conditions. They require
patients to receive regular infusions or injections of plasma protein therapies for the rest of their lives. Some of these conditions are hemophilia A and B, and other clotting factor deficiencies primary immune deficiency disorders and alpha 1-antitrypsin deficiency. PPTA appreciates FDA's efforts to create a forum to obtain input on specific issues and challenges associated with implementation of the Biologics, Price Competition and Innovation Act. We do not
doubt that FDA, specifically the Center for Biologics, Evaluation and Research that reviews our products, recognizes the uniqueness of plasma protein therapies and their vital role for patients with a number of rare diseases. We welcome the opportunity to discuss our therapies in this public forum, and my comments will be limited to the effect Neal R. Gross & Co., Inc. 202-234-4433
Page 294 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 of the law on our therapies. As has been mentioned previously, the consideration of biosimilars has not unique to the U.S. FDA. market globally. PPTA member companies
On a practical level
harmonization between U.S. and EU requirements will prevent the necessity of different clinical development plans in the U.S. and EU. It helps that we also consider that both the European Medicine Agency and the World Health Organization to have adopted the right approach. And PPTA supports an FDA
approach similar to EMEA and WHO for plasma drugs and recombinant analog therapies. Both positions are addressed in published guidelines. It is important to note that the BPCI Act does not allow the Agency to be as far-reaching as either the EMEA or the WHO with respect to recombinant proteins. Subsection 351(k)(8)(a) allows guidance to be developed that is either general or specific. Neal R. Gross & Co., Inc. 202-234-4433
Page 295 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 For recombinant proteins that are analogs to native plasma drug proteins, PPTA support specific FDA guidance with strict criteria for approval of an abbreviated BLA. For plasma drugs therapies the EMEA states in its guidance that, and I quote, in view of complex and variable physiochemicals, biological and functional characteristics it will not be acceptable to submit reduced clinical dossier when claiming similarity to referenced medicinal product. Applications for such similar products will certainly dissatisfy safety and efficacy requirements for new product. New subsection 351(k)(8)(e)(i) of the PHS Act allows FDA to indicate in a guidance document that the science and experience with respect to a product or a product class, not including recombinant proteins, does not allow approval of an application for a license as provided under this subsection for such product or product Neal R. Gross & Co., Inc. 202-234-4433
Page 296 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 class. PPTA supports the development of such guidance documents for plasma derived therapies. While much is known about these For these
proteins, much is not known.
products the process truly defines the product. Similarly, small differences in
manufacturing methodologies can result in unexpected differences in the plasma drug product. In the short amount of time allotted for the presentation, we have chosen to focus on the general aspects and harmonization as just noted, and the topics of biosimilarity and interchangeability as they relate to plasma protein therapies. The first question asked what scientific and technical factors should be the agency consider. As just stated, while much
is known there are potentially relevant scientific and technical factors in plasma protein therapies that are numerous and are Neal R. Gross & Co., Inc. 202-234-4433
Page 297 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 not known. Testing alone cannot guarantee
that the biosimilar is highly similar to the relevant product. What scientific and technical factors should the agency consider in determining the appropriate analytical studies and other studies to assess differences between the proposed biosimilar product and the referenced product? For plasma protein therapies, the agency must consider that these therapies are used to treat small patient population on a continuing life long basis. At present it is
impractical, if not impossible, to identify all the differences between the proposed biosimilar product and the referenced product as the products are process dependent. Also, it would be impossible anticipate how much product difference may effect the outcomes and adverse event profiles in patients with different patient characteristics. Neal R. Gross & Co., Inc. 202-234-4433 to
Page 298 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 That range of structural differences between a proposal biosimilar product and the referenced product is consistent with the term highly similar, we would contend for plasma protein therapies that no range of structural differences is consistent with standard, highly similar, or acceptable in a 351(k) application. Small
differences in manufacturing methods and the fractionation of purification, stabilization and viral inactivation can produce structural differences. Such structural differences, for
example, heterogeneity and the chemical structure of the molecule or antibody content and structure and/or impurities can interact with particular patient characteristics in ways that are clinically meaningful, but impossible detect, measure or recognize without efficacy and safety data for human clinical studies. In terms of clinical studies, while we support the need for studies, it must Neal R. Gross & Co., Inc. 202-234-4433
Page 299 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 be recognized that the patient populations that receive plasma protein therapies are small, novel approaches as are currently employed by the reviewers in CBER must be considered and are supported by PPTA. As part of novel approaches to studies for therapies that treat small patient populations there are some circumstances that the Agency should consider in determining the necessity of certain animal and human studies. These circumstances include whether the product is manufactured by a similar process, and if the product has a similar analytical profile, and if the referenced product has a history, a long history of safety and efficacy. In terms of interchangeability, what factors should the Agency consider? Since we know that small differences in manufacturing can result in significant differences in products, we do not believe that plasma protein therapies are Neal R. Gross & Co., Inc. 202-234-4433
Page 300 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 interchangeable with respect to the product classes. The interactions of these changes
with patient characteristics are numerous and highly variable. What factors should the Agency consider in evaluating the potential risk related to alternating or switching? While
plasma protein therapies generally have a good adverse event profile, we know that real but serious adverse events can occur. The adverse
events often result from interaction between product and patient characteristics. Some
events are the formation of inhibitors caused by immunogenicity, particularly in patients receiving clotting factors. The differences in the manufacturing methods of immune globulins can result in different adverse event profiles in patients due to excipients and/or contaminates in the product. Also thrombosis is a rare but
serious adverse event in patients with certain characteristics. Neal R. Gross & Co., Inc. 202-234-4433
Page 301 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Questions from the Panel? No. The Federal Register notice asked for comments in other areas. As the time allotted today is short, we cannot cover all the areas today, but we will address them in written comments to the docket. PPTA thanks FDA for holding this public hearing. And I will end now.
Thank you. DR. BEHRMAN: Thank you for
Thank you for your comments. MS. GUSTAFSON: DR. BEHRMAN: Thank you. Our next speaker is
from the European Generic Medicines Association. And instead of butchering your
name, I will ask you to introduce yourself. DR. WINDISCH: So my name is Jeorg
Windisch, and I represent the European Generic Medicines Association. I would like to thank FDA for the opportunity to share our thoughts on the new Neal R. Gross & Co., Inc. 202-234-4433
Page 302 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 pathway in the U.S. today. EGA represent all license holders of biosimilars in the European Union with one exception, and that is a company that has licensed this project from one of our members. So there's enormous experience we can draw from, up to 15 years without our companies and much longer even for biologics in general as some of our members also work on biologics. EGA members have pioneered biosimilars in Europe, but also in Japan, Canada, Australia and if one may count growth hormone as an FD&C Act product which is not formally a biosimilar to a degree also in the U.S. Biosimilars are in fact gaining significant market share in these markets, and they have been used safely without any safety and potency issues for more than four years now. Now going into the topics raised by FDA, starting out with the biosimilarity. Neal R. Gross & Co., Inc. 202-234-4433
Page 303 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 We believe that a degree of similarity is key, and it is in fact the basis for a number of things. It's the basis to justify abbreviated It is the It And
non-clinical and clinical programs.
basis to extrapolate between indications. is the basis to allow interchangeability. I'm not saying the basis doesn't mean that
that is all that we have to do, but it's the basis. And it is also, and that's not
unimportant, the basis to gain acceptance by health care providers and by patients. While we acknowledge that there is still some debate about the terminology, we are convinced that the scientific principles that underlie the demonstration of biosimilarity and that underlie the demonstration of comparability of a product pre and post manufacturing change are the same. And provocatively speaking it is not
the process that is being injected into a patient, it is the product. And that product
carries certain product attributes, which can Neal R. Gross & Co., Inc. 202-234-4433
Page 304 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 be critical or not critical and these similarities or differences are what matters and what needs to be evaluated very closely. Now, today we do have the technology in place to get very close to the original product. And defining the original product is actually the first thing one needs to do. Defining the target range, we've heard
that several times before, actually comes from buying the original product over a number of years, multiple batches and also from different geographies, and then defining the variability both from batch-to-batch and also historically. And if we buy from different
geographies, that also gives us a lot of information about the reference products from different geographies and how they differ or how they are the same. And then we've already heard about the interactive process that we have to go through to get our product as close as possible to the original product. And today Neal R. Gross & Co., Inc. 202-234-4433
Page 305 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the science is in place to actually get this accomplished. Now what does it mean? How close does one have to close to get or how close is close enough or what factors need to be taken into account to access differences? First of all, the differences should be very minor. And the nature of all
the differences should be fully elucidated analytically, and then the individual differences should be assessed based on existing knowledge and also based on specifically conducted investigations. One needs to look at the extent of the difference, how much is there and how different is it. The information from the
literature, and there's a lot that can be found, the presence and products other than the referenced product, and that is fortunately also included in the statute and can be very helpful. And then the
characterization of these products in Neal R. Gross & Co., Inc. 202-234-4433
Page 306 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 bioassays, immunologic assays and if necessary, also animal studies. And in most cases the above studies should clarify the relevance of these differences. That doesn't
that then one doesn't have to do a clinical study. We do not think there's any general range or rule of which differences would still be consistent with the standard of highly biosimilar. We believe that FDA has
years and years of experience in this area and should be given the discretion to make that decision on a case-by-case basis. Now when it comes to pharmacovigilance, we think there's no need to reinvent the wheel. The U.S. already has a
functioning REMS system in place, and this system will work just fine for biosimilars as well. We think that it would be very beneficial to have a close collaboration between FDA and EMEA when it comes to Neal R. Gross & Co., Inc. 202-234-4433
Page 307 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 pharmacovigilance, but also when it comes to biosimilars in general. With respect to naming, we don't believe that different non-proprietary names prefixes or suffixes will be necessary since we can already clearly identify biologics today based on the product name, the manufacturer, the NBC number and a lot number. Now coming again to what we call global development, which is the use of reported data or the use of data generated against a foreign reference product. And when
we talk about foreign reference product, then we only talk about reference products coming from highly regulated markets such as the EU. And we know that while these products are often the same, legally they are different products. And if we do not introduce some
flexibility here, this would mandate the performance of separate full development programs for each country. unnecessary. And this is
It's also unethical because it Neal R. Gross & Co., Inc. 202-234-4433
Page 308 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 leads to the duplication of animal and human studies. And it would also be uneconomical. And I think if we keep in mind what the BPCI Act actually has in mind as it's main objective, that's the affordability, and that is access to patients, then we shouldn't lose track of this. Now, if we have clear demonstration that the reference products are coming from different regions are physically the same or if we can show a very high level of comparability, then we do not think it should be required to duplicate preclinical or clinical studies for each country or region. Now there may be cases where, for example, there are slight differences in formulation. And, of course, those need to be looked at specifically again. A rigor physical, chemical and functional comparison needs to be demonstrated. But in those cases,
it may also be necessary to provide more proof in the form of comparative animal studies or Neal R. Gross & Co., Inc. 202-234-4433
Page 309 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Jenkins? DR. JENKINS: The question I've comments. Questions from the Panel? Dr. rigorous clinical phase 1 PK/PD studies. And in summary, EGA welcomes the establishment of a pathway in the U.S. and the opportunity to work with FDA. Biosimilars
have been used for many years already safely in the EU. The science and the technology to
develop these products exists already today. And global development must be allowed in my view, if we want to achieve the objectives of the BPCI Act, that being affordability and patient access. Thank you. DR. BEHRMAN: Thank you for your
asked of the innovators yesterday and today who have biosimilars to their innovative products marked in other countries is whether they've been able to identify any problems with those biosimilars. And I don't think
Page 310 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 anyone has said they've identified any problems. You said the same, that there have
been no problems in Europe without four years in marketing. Have there been any challenges in Europe from the innovators claiming that the biosimilars that have been approved or less effective, less safe, more immunogenetic, or have they been pretty well accepted by the public as well as the innovator companies? DR. WINDISCH: The acceptance, I
think, correlates very strongly with knowledge and education. So, initially when we talk to
people, we often see a reaction oh well, we're not sure about this. And then when you
explain how these products are developed and how they're brought close to the original product and how extensive the development program is for these products, then their reaction typically changes totally. But we still do see quite a significant need for education in Europe as well. But of course, as Neal R. Gross & Co., Inc. 202-234-4433
Page 311 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 knowledge. DR. JENKINS: DR. BEHRMAN: DR. MARCHAND: for your presentation. I'd like to refer to your slide 7, and your second bullet point there you indicate that given that the U.S. already has Neal R. Gross & Co., Inc. 202-234-4433 Okay. Dr. Marchand? Thank you very much these products are becoming more common and as they've been around for a longer period of time, they are gaining a lot more acceptance now. And as to the originators, I'll let them comment. But, of course, they're
doing their job as we are doing ours. DR. JENKINS: little further: Just to probe it a
Have the innovators
challenged the biosimilar approvals in Europe? Have they tried any legal challenges to say these products are not equally safe or effective or -DR. WINDISCH: Not to my
Page 312 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 a REMS system, for example, you would recommend that there would be no need for a separate system for biosimilars. And if we
reflect on some of the elements to assure safe use under REMS programs, in some instances there's some significant post-marketing studies that might be required. So, are you
also advocating a position for biosimilar you would recommend a similar type of a postmarketing study that would be required? DR. WINDISCH: I think that will
very much depend on the product. And also now in Europe for certain products we do have such programs in place post-approval, in the form of post-approval safety studies. I think that will be necessary for some products and not be necessary for others. And where it is
necessary, of course it would be ideal if it could be harmonized between the different countries and regions. DR. BEHRMAN: DR. KOZLOWSKI: Dr. Kozlowski? Sir, you discussed
Page 313 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 use of ex-U.S. manufactured material or foreign material in the clinical trials in place of U.S. material. So, you talk about
structural, functional comparisons and then potentially a bridging study. DR. WINDISCH: DR. KOZLOWSKI: Right. Correct.
So you feel that
in some cases even a bridging study would not be necessary? DR. WINDISCH: I think that if
there is evidence that the product is really physically the same, coming out of the same factory and if we can also show that analytically that would not be the case. And if I could just to the power of the analytics. We've been following these
products for more than ten years now. And we can tell batch from batch. So, you know,
products coming out of one facility we can tell when a new batch comes to the market. So, it is possible to show a high degree of comparability here. Neal R. Gross & Co., Inc. 202-234-4433
Page 314 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. KOZLOWSKI: I think though we
can show this high degree of structural similarity for a biosimilar versus an innovator, we still worry about uncertainty. So the question is are you adding a second layer of uncertainty if you're entirely relying on the structural similarity? And then sort of as a follow-up for that you have a lot of experience with these products in the EU, but the EU doesn't use non-EU approved references, not that I'm aware of. And so there is anywhere where there is experience about using reference standards that are not marketed within the approving country? DR. WINDISCH: The whole effort of So
biosimilars, of course, started in Europe. most companies actually did use EU source products. And, yes, it is correct that the
same discussion actually currently is going on with EU regulators and lawmakers. I think
Page 315 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 what we would really appreciate here is a dialogue between European and American regulators, how this conundrum can be solved. I think it can only be solved in a joint effort. DR. BEHRMAN: I have one question Again,
about your last bullet on the slide.
thinking about Centennial and our efforts to make use of data or what's secondary use and similar efforts in Europe. How easily
traceable are these products if they don't have a different name, well in our country of claims databases? DR. WINDISCH: I think the key
thing is to establish the systems that capture all of the information to make them traceable. I agree that today improvements may be needed and the systems may be imperfect, but if that can be fixed, that is possible. I also think that it is inconsistent with the whole concept of biosimilarity and interchangeability to start Neal R. Gross & Co., Inc. 202-234-4433
Page 316 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 off with non-proprietary names. I think that
that would actually make the administration of, for example, interchangeability very different. And we've already seen cases in
Europe, and we think that's unfortunate, and also Australia where either companies have gone ahead and voluntarily selected different names or where different names have been allocated. So the products leading to a
situation are one in the same product may have different non-proprietary names in different countries around the world. We think that
that might actually cause more confusion. DR. BEHRMAN: your comments. We've reached our break time. We'll take a 15 minute break and then we'll resume at a quarter to 3:00. Thank you. (Whereupon, the above-entitled matter went off the record at 2:34 p.m. and resumed at 2:48 p.m.) Neal R. Gross & Co., Inc. 202-234-4433 Okay. Thank you for
Page 317 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. BEHRMAN: Okay. Our next Oh, good.
speaker will be Marie Vodicka. From PhRMA. Welcome. DR. VODICKA:
Good afternoon.
mean Marie Vodicka, Associate Vice President of Scientific and Regulatory Affairs at the Pharmaceutical Research and Manufacturers of America or PhRMA. training. PhRMA represents the country's leading pharmaceutical research and biotechnology companies which are devoted to inventing medicines that allow patients to live longer, healthier and more productive lives. We thank FDA for the opportunity to provide PhRMA's views. Given the brief time allotted, my comments will address some of the key issues raised by the FDA in the Federal Register notice. PhRMA plans to submit to the And I am a biologist by
docket more detailed answers. We hope this will be the first of Neal R. Gross & Co., Inc. 202-234-4433
Page 318 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 many opportunities for public comment and dialogue as FDA establishes policies in the form of regulation and guidance for the implementation of a biosimilar pathway. First, I will present a set of key principles that should guide FDA's implementation of the new approval pathway for biosimilars, later I will provide PhRMA's views on several specific items identified in the FDA's hearing notice. The FDA should be guided by the following principles as it implements the pathway passed by Congress. Ensure patient
access to safe and effective biosimilars, create a science-based pathway through an open transparent process and encourage innovation and enable additional competition. In the interest of transparency, predictability, sound science and the public health the PhRMA stresses the importance for FDA to issue implementing guidances and regulation. Regulations and guidance would Neal R. Gross & Co., Inc. 202-234-4433
Page 319 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 provide certainty and transparency to sponsors in order to help them design effective development strategies to meet FDA regulatory expectations and help ensure consistency amongst and between biosimilars and referenced product. We urge FDA to look to the European Medicines Agency processes that enabled safe and effective biosimilars to reach European patients. As FDA implements a biosimilar pathway in the U.S., PhRMA urges the FDA especially to consider how it implements the following topics addressed in the Federal Register notice: Biosimilarity,
interchangeability, pharmacovigilance, naming and labeling and exclusivity. In the interest of patient safety FDA should require that companies seeking to demonstrate biosimilarity to an existing licensed biologic should use a stepwise process requiring high quality, well designed Neal R. Gross & Co., Inc. 202-234-4433
Page 320 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comparative studies beginning with molecular evaluation and ending in safety and efficacy trials in patients. BPCIA requires a biosimilar to use a biologic project licensed in the U.S. under a full application as a reference product for a showing of biosimilarity. Data generated
using the biosimilar and the U.S. licensed referenced product should be sufficient to support the biosimilar product's claims and for FDA evaluation and licensing of the biosimilar product. Demonstration of the likely similarity is a prerequisite for using the abbreviated preclinical and clinical pathway for biosimilars. Analytical methods to
demonstrate molecular similarities should be orthogonal and sensitive enough to detect relevant differences if they exist. Structure that can be controlled, such as amino acid sequence, should be conversed between the biosimilar and the Neal R. Gross & Co., Inc. 202-234-4433
Page 321 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 referenced biologic, and any other structural features such as post-translational modifications including glycosylation should be conserved if they are known to be essential for function. Given that it is difficult to link differences in molecular structure to function and clinical outcomes, comparative clinical trials for safety and efficacy and relevant patient populations should be required for biosimilars including an immunogenicity assessment. For safe and effective medicines for patients clinical data with the biosimilar should be required for each indication. Allowing approval of indications without clinical data would be waiving the clinical data requirement under the statute. should only be done if justified scientifically. FDA should at a minimum This
consider the following factors before deciding to waive the clinical requirement for any Neal R. Gross & Co., Inc. 202-234-4433
Page 322 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 indication: Molecular mechanism of action; Diseased mechanism of action, and; Diseased state of the patients. Congress intended the scientific and regulatory standard for interchangeable biologics to be above and beyond that for biosimilars. Given current science we do not
think it would be safe for patients if FDA were to approve interchangeable biologics now. Unlike a generic drug, which is the same as the reference drug, a biosimilar will be similar to and not the same as the reference biologic. There's currently no scientific
regulatory or medical consensus on how the statutory requirement, the same clinical effect in any given patient, would be demonstrated. However, the statute authorizes FDA to make such determination and we therefore suggest that FDA consider additional factors, including those outlined below, when considering how to implement the statutory Neal R. Gross & Co., Inc. 202-234-4433
Page 323 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 approval; The many potential interchangeability relationships with multiple biosimilar products, interchangeable products and the referenced products in class; The potential for increased immunogenicity from switching between Neal R. Gross & Co., Inc. 202-234-4433 provisions on interchangeability. Only FDA should make interchangeability decisions. In making an
interchangeability determination, FDA should require clinical data for all indications of the referenced product. Because once it is on
the market it will be used interchangeably for all indications by physicians and pharmacists. Beyond the issues of what evidence should be required for approval of an interchangeable biologic, FDA should consider the potential impact of the following on public health and safety of interchangeable biologics in the market: Divergence of products post-
Page 324 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 products, and; Especially the implications this would have for pharmacovigilance including determining whether an adverse event was caused by a single products or by switching between one or more products. Pharmacovigilance for biologics will be especially challenging in an environment in which patients may receive multiple similar products that are not the same and may or may not be distinguishable by name. FDA should apply post-marketing
commitments to biosimilars using the same scientific criteria as for any new products, using what is currently known about the product class and individual product. In order to assure that patients who take biosimilar medicines are protected to the same extent as those taking a license referenced biologic, any REMS for a biosimilar should be at least as rigorous as for the referenced product. Neal R. Gross & Co., Inc. 202-234-4433
Page 325 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 In the interest of patient safety to help ensure clear prescribing and dispensing and for pharmacovigilance purposes each biologic product should have a unique non-proprietary name. In the interests of
transparency and patient safety each biosimilar and interchangeable biologic should have it's own labeling which clearly states relevant regulatory information such that the product is a biosimilar to a specific referenced product, the approved indications and whether the product is deemed interchangeable. For each indication the biosimilar labeling should state whether there are supporting data for the biosimilar or only for the referenced product. Moreover, if FDA has
not determined that a biosimilar is interchangeable, then labeling should state this to help prevent substitution without an interchangeability determination by FDA. Congress thought to balance the Neal R. Gross & Co., Inc. 202-234-4433
Page 326 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 desire for increased competition with the need to preserve incentives for R&D investment to develop tomorrow's new treatments and cures. In determining which products are eligible for the 12 year data production period, refer to as the exclusivity period in the Federal Register notice, FDA should adhere to the wording of the statute. Any difference in
structure of the product accompanied by data demonstrating differences in safety, purity or potency from a previous product warrant a product receiving its own 12 year exclusivity period. We know that notwithstanding the phrasing of the question in the Federal Register notice, this is not a second period. Under the statute the original biological product receives a 12 year exclusivity period and a next generation product that meets the criteria receives a separate and independent period. After the data exclusivity period
ends for the first generation product, an Neal R. Gross & Co., Inc. 202-234-4433
Page 327 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Questions from the panel? Neal R. Gross & Co., Inc. 202-234-4433 No. questions. DR. BEHRMAN: Thank you for your approved biosimilar of that product could enter the market. Qualifying structural differences in a subsequent product would include, but are not limited to: Differences in amino acid
sequence and post-translational modifications such as peglylation. FDA should apply the
provisions to encourage, not discourage, innovation that expands treatment options for patients. In conclusion, as the discussion over the past two days has demonstrated, the science and complexities of biologics are many. These complexities underscore the need
for the FDA to engage in ongoing dialogue through an open and transparent process with key stakeholders. And I'm happy to take your
Page 328 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Thank you for your comments. Our next speaker is Rasmus Rojkjaer. He's correct me. Pharmaceutical Association. DR. ROJKJAER: Not even close, I'm afraid. Well anyway, good afternoon and thank you for the opportunity to provide Generic Pharmaceutical Association's view on the Biologics, Price Competition and Innovation Act of 2009. My name is Rasmus Rojkjaer, again. In real life I'm head of R&D for Biologics for Mylan, the biggest global generics company headquartered in the U.S. and one of the GPhA member companies. GPhA represent more than 100 generic manufacturers and distributors, and their products is usually nearly two billion prescriptions every year. The GPhA mandate to improve the lives of consumers by providing timely access Neal R. Gross & Co., Inc. 202-234-4433 Yes. Rojkjaer. From Generic
Page 329 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 to safe and effective, yet affordable pharmaceuticals. With health care costs
rising to unsustainable levels, nowhere will the GPhA mandate be more important that the area of biologic medicines. In the eyes of the GPhA the Biologics, Price Competition and Innovation Act was a cautious first step. However, it
will take much more to create price competition for the more than $30 billion worth of biologics scheduled to expire their date of exclusivity on or before 2018. Fortunately, the FDA has the scientific expertise and experience of approving complex biologic products and the GPhA members is blazing a trail towards of approval of high quality biogeneric medicines at prices that's within the grasp of the American patients. Collectively we think that we have the tool to make this work, just as a quarter of a century ago for small molecules under the Hatch-Waxman Act. Neal R. Gross & Co., Inc. 202-234-4433
Page 330 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 So, biogenerics has the key to lowering pharmaceutical costs over the next several decades while increasing patient access. Yet as we see the new pathway is full
of land mines that will hamper the true intention of the law, namely bringing low cost high quality biogenerics to the American public. FDA's immediate support for this new
pathway is crucial, and this includes the Agency's timely advice to sponsors allowing a reduced biosimilarity data burden, always preserving the safety, purity and potency of all FDA licensed biologics. So, I'm here today to discuss ways to achieve this. Due to the time constraints,
we have focused in on four of the issues raised in the FDA notice. Namely:
biosimilarity, naming, interchangeability and the use of referenced products. I've also show the cover and approach to user fees at the end. So the first one, biosimilarity. Neal R. Gross & Co., Inc. 202-234-4433
Page 331 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 I think to some extent it has been covered extensively. I think it's worthwhile to say
at the end, though, that this is the cornerstone of the new pathway, and that we feel that it's possible that the FDA already has extensive experience here. The FDA has
been evaluating products for biosimilarity for years. Anytime a brand new biologic
manufacturer has changed his manufacturing process, added new facilities, substituted an ingredient or changed the cell line, the FDA has used the same time honored data driven scientific standard: these changes. As the FDA is well aware, comparability between biologic products is defined as highly similar quality attributes. Rarely are clinical studies required. work in developing its approach to comparability lead to the creation and the international comparability standard, the ICH Q5E now in use all over the world. And really FDA's Comparability to analyze
Page 332 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 the basis for the already approved European biosimilars. So we think that the ultimate goal of the comparability exercise is to ensure that the safety, purity and potency of the biologic are the same before and after this manufacturing change, and this same approach can and should be applied to biogenerics. Again, step one, as we heard many times today, is to compare physical chemical attributes and truly promoting between the potential biogeneric medicine and the reference product. For this a series of overlapping analytical tests should be employed. The science necessary for this
sophisticated analytical comparability exercise is already in use for multiple biologics today. The second step is to conduct long standing studies, compare functions using appropriate animal or tissue modeling necessary. The aim of these studies is to Neal R. Gross & Co., Inc. 202-234-4433
Page 333 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 verify comparability. Finally, step 3, chemical testing for biogenerics should not be required to the same extent as for new active substances given that the patient response to a biogeneric will be vastly more predictable. Thus, biogeneric
sponsors using state of the art and analytical validation tools that are confirmed that the proposed product is highly similar to the referenced product should be subjected to clinical study requirements only to the same degree as expected for the originator products making manufacturing changes. Accordingly, any clinical -- must be need based and data driven taking into account the degree of similarity demonstrated earlier in developments. If the biogeneric
has been demonstrated to be highly similar to the referenced product, the established safety approach and potency profile of the referenced product can be relied upon without mandating unnecessary duplicative testing. Neal R. Gross & Co., Inc. 202-234-4433
Page 334 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Naming. In our view, one of the most unfortunate features of the abbreviated biogenerics pathway study does not dictate that biogeneric has the same name as the referenced product. them the same name. Both the EU and WHO gives This process to us is
sensible the actual degree has been shown to be highly similar. It's the GPhA's position
that biogenerics should be given the same generic name as the referenced product, otherwise a finding of interchangeability or biosimilarity for that matter will come for a review among health care providers diminishing meaningful opportunities for market access. Interchangeability. Confidence in
the FDA and the Agency's determination in interchangeability is what drives generic competition. It is the reason why generic
drugs has generated savings in excess of $800 billion U.S. dollars over the last decade. The way that FDA deals with this topic interchangeability will be directly Neal R. Gross & Co., Inc. 202-234-4433
Page 335 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 responsible for the market dynamics generated for biogeneric pathway. Thus, FDA must be
exceedingly cautious in elevating the interchangeability status to a level that is unattainable. The standard imposed for their
own products is the correct standard for generics also, otherwise products that have been driven monopoly pricing for the last 25 years often costing tens of thousands of dollars for a single patient will burden patients and payers for the next 25 years also. Finally, use of data on foreign reference products. One of the most immediate
ways for FDA to be proactive is to permit biogeneric applicants to use the work they have already done to establish biosimilarity against referenced products marketed in all the highly regulated markets in support of their application in the United States. All the first high approval agencies such as Canada, Japan as well, has Neal R. Gross & Co., Inc. 202-234-4433
Page 336 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 supported this scientific sound way of thinking. Permitting the use of testing --
that are highly similar to U.S. referenced product will maximum the availability of high quality, safe and effective biogenerics by minimizing unnecessary and unethical questionable studies. This is essentially the
case where the foreign referenced product is the same the U.S. referenced product in all ways except the label. More generally, we encourage the FDA to take the leadership role in developing a framework for appropriate use of foreign referenced product data that recognizes genuine science while at the same time preserving FDA's authority on the ultimate question of safety and efficacy. Lastly, on the user fees. The
GPhA look forward to working with the FDA to create a user fee program for biogenerics to emphasize safety, access and transparency. This program should also include a program Neal R. Gross & Co., Inc. 202-234-4433
Page 337 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. Questions from the panel? Neal R. Gross & Co., Inc. 202-234-4433 Dr. metrics to help expedite the availability of biogeneric medicines and user fees should not be used to create a barrier to entry for biogenerics. A proactive and safety driven
approach will expedite the availability of competitively priced biogenerics while at the same time ensuring the FDA is able to appropriately manage their development and manufacturing. Then when the patient is faced
with a choice brand or biogeneric, they will rest assured that the product is safe and effective according to FDA standards. So, at the end, we would like to thank the FDA for its time and interest and GPhA hopes that this public hearing is the start of a dialogue between the FDA, stakeholders on these important issues. I'll be glad to at least try to answer any questions you might have. DR. BEHRMAN: Thank you for your
Page 338 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Kozlowski? DR. KOZLOWSKI: We've heard from
prior speakers that in a development of biosimilars in Europe there were examples where the clinical studies were important, that they yielded information that changed the development path. So, I guess I want your
view on the importance of the clinical development part of the O program and how that would reflect on what the Agency should think about? DR. ROJKJAER: No. I think that
there is no doubt that in some cases clinical programs is -- I think our point here is that it should be evaluated on a case-by-case basis. That this extensive program of
biosimilars should be leveraged toward clinical trials. Not sort of a package
solution that everybody has to do the same thing, but in every single what makes sense. So, I'm very much aware of the experience from Europe, and I think clinical Neal R. Gross & Co., Inc. 202-234-4433
Page 339 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. DR. ROJKJAER: DR. BEHRMAN: Sara Radcliffe from BIO. MS. RADCLIFFE: Good afternoon and Thank you. Our next speaker is the Panel? All right. Thank you for your trials has its role to play. But forcing the industry to fit into a one fits all kind of approach I think will seriously keep the development of these biogeneric compounds back. DR. BEHRMAN: Other questions from
thank you for the opportunity to present today. I am Sara Radcliffe, Executive Vice
President for Health at the Biotechnology Industry Organization, BIO. BIO supported the passage of legislation to enable FDA to approve biosimilars so that patients living with unmet medical needs with have expanded access to safe and effective medical therapies at lower Neal R. Gross & Co., Inc. 202-234-4433
Page 340 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 cost. I will address only four broad topics this afternoon, but we have appended 21 slides to our presentation that provide more information and we look forward to submitting written comments to the docket. My testimony
today is grounded by the specific hands-on experience of bio-member companies. Experience that is crucial to understanding biological products. First, I would like to address biosimilarity. The demonstration of
biosimilarity should begin with the side-byside analytical comparison of the biosimilar against the reference product. This
comparison should be made with regard to the active protein molecule as well as the formulated drug product. While analytical techniques are increasingly capable of discerning differences between biologics, at present, they have limited predictive value with respect to Neal R. Gross & Co., Inc. 202-234-4433
Page 341 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 establishing that no clinically meaningful differences exist. Therefore, comparative
non-clinical and clinical studies should also be performed. Clinical data should be provided for all indications for which the biosimilar applicant seeks approval except in cases where extrapolation can be scientifically justified and where the mechanism of action is not only known, but well understood. Extrapolation of data among indications must be handled extraordinarily carefully because it is well known that products behave quite differently when used to treat different disease states and patient populations. In particular, immunogenicity should be assessed in clinical studies. The
present limitations of analytical and nonclinical testing are particularly apparently when predicting immunogenicity is concerned and especially across indications. Neal R. Gross & Co., Inc. 202-234-4433
Page 342 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Second, I'd like to address interchangeability. The standard for
interchangeability in the law states in part that an interchangeable product can be expected to produce the same clinical result as the reference product in any given patient. This is an appropriately high standard directed toward protecting patient safety. We believe this standard requires that there be no divergence in safety or efficacy profiles when an interchangeable product is substituted or alternated by any individual in any relevant patient population. We think that FDA guidance will be needed for each product type to establish acceptable confidence intervals for analysis. Further, for interchangeable biosimilars, we urge that efficacy and safety be studied in clinical trials for each indication. If an interchangeable biosimilar
is approved, it is likely to be used interchangeably for all indications by Neal R. Gross & Co., Inc. 202-234-4433
Page 343 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 pharmacists and physicians. There must be
assured that patients would not be deprived of therapeutic actions as a result of alternating or switching. For example, the patients would develop a reaction that would render use of the reference product ineffective or unsafe. Moving to my third topic, patient safety and pharmacovigilance. Current systems
for naming and labeling generic medicines were not designed to address biosimilars which are not identical with the innovative product. To
avoid inappropriate assumptions about product sameness and interchangeability, facilitate clinical vigilance and traceability and protect patient safety, each biologic should have a distinct international non-proprietary name, INN. Ideally a standardized naming system would be developed and utilized globally. For example, a distinct INN could
consist of the same stem name as the innovator Neal R. Gross & Co., Inc. 202-234-4433
Page 344 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 plus a unique suffix. We are aware that some suggest national drug codes. NDC numbers and lot
numbers could be used in place of unique nonproprietary name. However, while lot numbers
are always provided by the manufacturer, experience has shown that they are not always recorded by the end user. In addition,
neither NDC codes nor lot numbers are very useful to patients and prescribers and they are not used globally. Finally, I'd like to address several issues related to maintaining incentives for innovation. First, use of the
351(a) versus the 351(k) pathway where submitted BLA meets the statutory definition of a biosimilar. FDA should not accept such applications under Subsection A. To do so
would result in the biosimilar applicant receiving the benefits of the new pathway without having to bear the concomitant Neal R. Gross & Co., Inc. 202-234-4433
Page 345 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 burdens. For example, waiting for the expiry
of exclusivity or complying with other provisions designed to protect innovator rights. Protection of innovator rights to notice and comment to biosimilar applications. Biomembers believe that FDA has an important role in the implementation of the Act's patent resolution and information exchange process. For example, we ask FDA to obtain binding assurance from the Subsection (k) applicant that the applicant has or will provide the reference product's sponsor with sufficient notice and information to allow the resolution process to begin. Otherwise, innovators will
not be able to exercise their rights as set forth in the statute. Additionally, we ask that FDA clarify other procedures necessary to insure that the careful statutory balance of innovator and biosimilar rights is preserved. FDA reliance on reference BLA and Neal R. Gross & Co., Inc. 202-234-4433
Page 346 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 protection of confidential information. In
the Hatch-Waxman context, FDA does not review or rely upon information or data contained in the reference NDA. Rather the Agency relies
upon its previous finding of safety and effectiveness. Likewise, in the biosimilars
context, the statute makes clear that the Agency may rely only on the information submitted by the Subsection (k) applicant. Therefore, we ask the FDA to make clear implementing regulations. That when
evaluating a Subsection (k) application, reviews are not permitted to rely upon proprietary or confidential information and data contained in the reference product BLA. Significant product modifications. We believe it is important for FDA to make several clarifications regarding the proper interpretation of the statute exclusivityrelated provisions. following. First, FDA's Federal Register Neal R. Gross & Co., Inc. 202-234-4433 Three of these are the
Page 347 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 notice states that the date of first licensure does not apply to approval of a supplement or subsequent BLA meeting certain criteria for the same product. We note that the proper
interpretation of this provision is that a subsequent BLA or supplement that falls within the statutory criteria in Subsection(k)(7)(c) is protected by the remaining period of exclusivity that applies to the first license BLA. Second, the notice states that in certain circumstances a subsequent BLA may be eligible for a second 12-year period of exclusivity. This is inaccurate and the only
product has been modified structurally so that it is different from the reference product in terms of safety, purity or potency can obtain a 12-year period of exclusivity. In such a
case, the exclusivity period attaching to the original product is not extended in anyway. We suggest that relevant modifications to structure include but are not Neal R. Gross & Co., Inc. 202-234-4433
Page 348 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 limited to changes in amino acid sequence, critical post-translational features of the active ingredient or biological components that result in a product with a change in safety, purity or potency as compared to the reference product. Third, we ask that FDA prepare, publish and periodically update a list of approved biologics identifying first licensure dates and establishing associated dispute resolution process. Also, we ask that FDA
establish a process by which a company can obtain advanced determination of whether first licensure restrictions would limit exclusivity for proposed R&D targets. Finally, I'd like to say a word about user fees. BIO recognized that
application for approval of biosimilar products will raise novel and complex questions of science and law. We ask FDA to insure that workload associated with these new applications does Neal R. Gross & Co., Inc. 202-234-4433
Page 349 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. not harm the Agency's ability to efficiently review new drugs and biologics. We also note that under PDUFA 4 innovator user fees were extended to support post-market safety evaluation by FDA. Biosimilar user fees should also support postmarket safety evaluation. Again, thank you for the opportunity to present today and I'd be happy to take your questions. DR. BEHRMAN: Mr. Schwartz. MR. SCHWARTZ: your comments. Can we go back to slide number 7 for a moment please? I was hoping you could Yes, thank you for Thank you for your
elaborate on the first bullet point and whether you think that the statute actually requires that the products go under the 351(k) pathway or whether you are urging that the Agency use discretion which you might believe is in the statute to require that the product Neal R. Gross & Co., Inc. 202-234-4433
Page 350 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 go through the 351(k) pathway. MS. RADCLIFFE: We believe that
the statute is not clear in its language. However, in constructing the statute, Congress went through a very careful process of balancing innovator and biosimilar rights and, therefore, we think it can be understood from the statute that it would not make sense for FDA to establish a process wherein the biosimilar applicants were able to evade the rights that are extended to the innovator manufacturer. DR. BEHRMAN: DR. KOZLOWSKI: Dr. Kozlowski. To follow up on
that, we've heard today a variety of different clinical programs described. Some of which were actually much larger than it would take to approve an innovator product. So, I think it's an interesting challenge if one has to be (k) and that (k) pathway is actually rather larger in terms of effort and resources than an innovator Neal R. Gross & Co., Inc. 202-234-4433
Page 351 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 product. MS. RADCLIFFE: I think we should One is
separate two different things. biosimilarity and the other is interchangeability.
Clearly, the purpose of the statute is to permit an abbreviation in the data that would be necessary to submit to get a biosimilar application onto the market. amount of abbreviation in that data package will depend very heavily on what data the biosimilar applicant is able to bring forward from analytical and non-clinical testing. think that that would be very different for different products. And that is one reason why touching on a product that I was -- I'm sorry. Touching on a topic that I wasn't able to bring up this morning, we think it would be very useful for the Agency to provide product specific guidance. In the realm of Neal R. Gross & Co., Inc. 202-234-4433 We The
Page 352 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 that? MS. RADCLIFFE: I think that for interchangeability, I think it does become much more complicated. Our company has not
said that interchangeability is impossible. That being said, I think it is widely understood that the size of the clinical trials that would be necessary to show interchangeability for many if not all complex biologics would be very big and that that exercise at this point in time seems to be infeasible. DR. KOZLOWSKI: One of the earlier
speakers, I think from Amgen, had mentioned the possibility of post-market data being useful in establishing interchangeability. Does BIO have a perspective on
every product, for every applicant who submits an application to FDA, it is clear that the clinical -- that the data package including most importantly the clinical data does not remove all risk. It is always the case that
Page 353 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 other way. Neal R. Gross & Co., Inc. 202-234-4433 there is some risks that remain to be addressed by pharmacovigilance and adverse collection post-market. That being said, it is incumbent upon us to provide as much information as possible in our application to FDA because to do otherwise is necessarily to expose the general population to some risk and, therefore, I think it is possible to address some risk post-market. But, certainly the intent and the default should be to try and get that information into the application prior to marketing. DR. KOZLOWSKI: I think actually
the thought was almost a two-stage process where that would be pre-market for the interchangeability determination. post-market for the biosimilarity. to clarify what the question was. MS. RADCLIFFE: Okay. Yes. The It would be At least
Page 354 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. KOZLOWSKI: Oh, right. So,
post-market for biosimilarity, pre-market for interchangeability. MS. RADCLIFFE: understand -DR. KOZLOWSKI: MS. RADCLIFFE: So, that -I think I Yes. Now, that I
understand what you're saying. DR. KOZLOWSKI: So -- well, no,
what I meant is that the post-market data would effectively become pre-market before an interchangeability determination and I have one last question. You mentioned -If I could just
MS. RADCLIFFE: address that though.
Yes, I do understand
your question better now and if, in fact, it is that perhaps a determination of interchangeability would not be possible at the time of marketing and that it would be better to gain some market experience before that exercise was undertaken, yes, I think that view is shared by the majority of our Neal R. Gross & Co., Inc. 202-234-4433
Page 355 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 on naming. names. comment. company. DR. KOZLOWSKI: And then one last
You mentioned active ingredients.
So, obviously obtaining purified active ingredients can be a challenge depending on the nature of the product formulation. So, does BIO have any plans to help make such material available? MS. RADCLIFFE: You know, we
cannot make promises of that kind on behalf of our company. I did hear a number of
presenters earlier today talk about the ways in which they would undertake the biosimilarity exercise. They obtain product
over a number of years from different geographic locations and that is the way they approach that. DR. BEHRMAN: I have one question
So, you're in favor of unique
We heard over the course of the two
days a number of speakers who suggested that, in fact, such an approach might be burdensome Neal R. Gross & Co., Inc. 202-234-4433
Page 356 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 concerns? MS. RADCLIFFE: It has been BIO's to patients and to prescribers, that it might be confusing, that it could lead inadvertently to a patient being prescribed what are essentially highly similar or identical medications at the same time. Do you have any comments on those
long-standing position that international nonproprietary names are essential. There is
really no other system that permits -- that could be extended internationally to allow pharmacovigilance and tracking. It is also important as I very briefly said in my testimony to avert inappropriate assumptions about interchangeability. The alternatives that have been discussed, NDC codes and lot numbers and so forth, I think are not really recognized by patients or physicians and, therefore, don't provide wise alternatives to a unique nonNeal R. Gross & Co., Inc. 202-234-4433
Page 357 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. proprietary name. DR. BEHRMAN: Ms. Esposito. MS. ESPOSITO: Thank you for your Other questions?
With respect to the comment that
you made about FDA being permitted to rely only on publicly available information about the reference product, can you elaborate a little bit more on that in terms of how you and your member companies view FDA's ability to approve a biosimilar based on certain knowledge that it already has of an approved reference product and how you would distinguish between what the Agency knows from, you know, having dealt with the company over the years versus what is actually publicly available in terms of clinical and non-clinical data? MS. RADCLIFFE: As in the Hatch-
Waxman context, we think it is inappropriate for reviewers to rely on proprietary information and data contained in an Neal R. Gross & Co., Inc. 202-234-4433
Page 358 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 question. application. We understand that there are circumstances in which reviewers do look at another application in order to determine, for example, whether the two products are similar, whether they are identical and so forth and various characteristics. We understand that.
Nevertheless, it is different conceptually for the reviewer to be relying on information in the application that is, in fact, a proprietary property of the innovator. MS. ESPOSITO: One follow-up
When you talk about the
acknowledgment that the reviewer would, by definition, kind of need to look -- to make similarity determinations, need to look at the comparator product -MS. RADCLIFFE: MS. ESPOSITO: Yes. When you're
referring to confidential proprietary information, are you focused more on the clinical and non-clinical data rather than the Neal R. Gross & Co., Inc. 202-234-4433
Page 359 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 minutes. comments. We've now reach the open public comment period. The first commenter is Dr. CMC or are you speaking of both and if both, then how can you make the comparison? MS. RADCLIFFE: I am speaking
about any trade secret or proprietary information that is contained in the application whether it is the CMC information, the pre-clinical information or the clinical information. To the extent that that is the
proprietary information of the innovator, it cannot be relied upon for -- that information as opposed to the finding of safety and efficacy cannot be relied upon for the approval of the biosimilar application just as it cannot be relied upon for the approval of a generic application. DR. BEHRMAN: Thank you for your
Lehrman from Lehrman Consulting. Please limit your comments to five Thank you. Neal R. Gross & Co., Inc. 202-234-4433
Page 360 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Okay. DR. LEHRMAN: Good afternoon.
So, since I believe you're not familiar
with me, I'll give you a brief induction. My name is Dr. Russ Lehrman. I've
been a pharmaceutical sciences consultant with over 25 years of experience supporting pharmaceutical and biotech companies in the development of large and small molecular therapeutics. That means that I've been a
director and senior director of analytical R&D formulation, R&D late stage API refinement prior to development. I greatly appreciate this opportunity to speak to the Committee on the topic of biological product definitions and will describe one specific situation that I hope will help clarify the way that the Agency characterizes chemically synthesized polypeptides. This is a point that's been raised during the course of the two days, but I don't think anybody has really focused in on that Neal R. Gross & Co., Inc. 202-234-4433
Page 361 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 and that's why I'm speaking. The FDA defines biologics as proteins otherwise known as polypeptides that are produced by biological media. Earlier
comments at this hearing have clearly highlighted the heterogeneity that can arise in proteins that are generated by fermentation. In contrast, peptides that are chemically synthesized using a process that adds one amino acid at a time from one end of the molecule and proceeds in an orderly fashion to the other end in a highlycontrolled, high-yield process that produces following purification obviously a very purified material. For this reason, peptides are typically regulated much as small molecules are not as biologics, but please consider the case of glatiramer acetate, an amino acid copolymer also known as Copaxone. This peptide is one of the primary Neal R. Gross & Co., Inc. 202-234-4433
Page 362 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 treatments for multiple sclerosis. that I'm sure you're aware of. Glatiramer is produced by a process in which four amino acids modified to readily form peptide bonds are mixed together and generate a gamish of peptides that contain peptide chains that both differ in length and in the ordering of the four component amino acids. The length of the chains and the order of the amino acids is highly dependent on reaction conditions, amino acid ratios and other factors too numerous to name in the time I have. This polypeptide cannot be chemically characterized in the same detail, in anywhere close to the same detail as other synthetic peptides and is absolutely defined by the process. No question about that. Something
In addition, a recent publication has clearly shown that altering the length and composition of this peptide mixture -- the Neal R. Gross & Co., Inc. 202-234-4433
Page 363 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 peptide mixture that constitutes this drug can result in increased safety risk and for technical details, I refer members of the Committee to published reports and if you would like references from me to help you in that end, I'll be happy to do that. For these reasons, the glatiramer needs to be classified as a biologic agent and any follow-on products based on this drug should be reviewed as biosimilars not as small molecules, not as generics and should, therefore, be chemically characterized as well as current technologies permit and clinically using clinically-driven endpoints such as relapse remission. In addition, any new peptide product candidate utilizing synthetic approaches such as the one used in the manufacture of glatiramer will clearly be a distinct chemical entity. They cannot match
it and should be given a distinct nonproprietary name. Neal R. Gross & Co., Inc. 202-234-4433
Page 364 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 afternoon. comments. panel? No. And more broadly, I fully expect that there will be additional peptide therapeutic drug candidates that will be reviewed by the Agency in years to come and that are manufactured using alternate technologies that generate heterogeneous mixtures or that include distinct chemical features that will require that they be classified as biologics. I thank you very much for your time and attention and I'll welcome questions. DR. BEHRMAN: Thank you for your
Are there any questions from the Thank you. DR. LEHRMAN: DR. BEHRMAN: Thank you. The next presenter
is Eric Katz from Katz and Company and again, please limit your remarks to five minutes. Thank you. MR. KATZ: Thank you. Good
My name is Eric Katz and I'm here
on behalf of decision.org which is the Neal R. Gross & Co., Inc. 202-234-4433
Page 365 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 American Center for Patient Decision Marking, a nonprofit group that helps connect to the health care they need. I'm attending today with just one brief comment, I hope brief, on the issue of accepting non-U.S. data in regulating and approving biosimilars. I'll start out by saying that this is part of a larger context that includes patients in this because just a very small degree of variation in the amount of data that you might take from a non-U.S. source product or a non-U.S. based clinical trial could have an amazing difference in terms of the cost of development, the speed of development and then ultimately even the number of products that patients might be able to access. I know this goes into the context of a larger discussion of international harmonization. I myself was the delegate of
the Surgeon General back to the first pair of ICH conferences back in the dinosaur age and Neal R. Gross & Co., Inc. 202-234-4433
Page 366 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 I think that one of the lessons from those early chapters was that different kinds of international drug regulation can stem from different kinds of international policy concerns and so, you don't need to take a one size fits all kind of model to the question of whether data from other nations would be fully accepted, fully rejected or something in between. I will fast forward here to three specific points in that then. end of the day. The first is that non-U.S. data whether from a clinical trial or in vitro studies or even in the inspection of manufacturing plants when it comes from a nonU.S. source innovator product should and must be acceptable essentially when these come from states in the ICH space. Exceptions to that ought to be rare and keep in mind that it's the patients who are paying with their cost in copays and Neal R. Gross & Co., Inc. 202-234-4433 I know it's the
Page 367 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 with the unavailability of more cost-effective products. The second piece, this same sort of faith in credit in the clinical trials should be given to the other aspects of the submission whether it be, as I said, the inspection of the manufacturing facility or the animal testing or the other aspects that lead into the dossier, the approval and even into the post-marketing surveillance. The third point is that in this area vague guidelines could cause a lot of damage. So, that as clear as you folks can be
as early on in the process will have an impact on whether or not companies keep or drop opportunities and the kind of patient availability that there might be a few years down the road. In sort of looking at the signals that might be coming out of the agency recently in looking, for example, at a citizen's petition on Lovenox, we see that Neal R. Gross & Co., Inc. 202-234-4433
Page 368 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. panel? Okay. Before we conclude I wanted there are very clear guidelines on what needs to be met or doesn't need to be met in the small molecule area that might be applicable in a large molecule area including the extent to which the data will need to be reproduced or whether it can be sort of incorporated by reference in a U.S. FDA submission. It's the end of the day. I'll
just close by saying that there's such a large pipeline out there. There are patients who
are hurting under just the copays alone and under the lack of availability of treatment options and we're hoping that you'll keep in mind that the patient has an equal place at the table here along with the regulators, the scientists and the industry. Thank you. DR. BEHRMAN: Thank you for your
Are there any questions from the
to ask the panel if there are any speakers Neal R. Gross & Co., Inc. 202-234-4433
Page 369 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 they would like to recall and, in fact, I already have a note. Could the three speakers from the last panel please either come up one by one or come up together and Ms. Esposito has two questions for each of you. MS. ESPOSITO: And just to clarify
so it helps you determine whether you all want to stand up, I thought since we had all three organizations from a bio and GPA here today, I'd like to ask two questions of each of you. One is with respect to guidance documents that the Agency might issue, do you have any input regarding priorities and what would be most useful to your member companies? And then the second is whether you have any input on biosimilar user fees and if you do, to share at a high level what you think about levels and structure of user fees for biosimilars. DR. VODICKA: So, on the first
question about guidances, we think that it Neal R. Gross & Co., Inc. 202-234-4433
Page 370 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Europe. would be helpful for the Agency to issue an overall guidance that kind of lays out the structure of the pathway and kind of what's expected generally. You could follow the model in You don't have to follow it exactly,
but that's one model that seemed to be pretty successful. They had an overview general
guidance and then more specific guidances on CMC and pre-clinical and clinical and then finally product class specific guidances. You know, notwithstanding -- not letting the lack of guidance get in the way of approval, at the same time, a lack of clarity that may be provided and that may exist in the absence of guidance may be just as stifling as, you know, waiting for guidance to come out to clarify. With regard to user's fees, that's something that our members are still discussing and I'm not prepared to talk about today, but we will address it in our docket Neal R. Gross & Co., Inc. 202-234-4433
Page 371 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. DR. ROJKJAER: Yes, generally on
the first question, we are I guess against those from two points of view. We feel that
each of the product's applicants should be looked at on a case-by-case basis. That there
are so many differences between these products that those kinds of ready-made guidances kind of hold some development back in terms of time and also effort. On the user fee, I touched upon that a little bit. It's in our paper and a
more expanded version of that will be in the docket at the end of the year for you all. Your review. MS. RADCLIFFE: In terms of
guidance, our members are not really to provide conclusions about specific topics that would be helpful to address first. I agree
with what Marie Vodicka has said about starting out by providing broader guidance and then moving on to specific product areas as Neal R. Gross & Co., Inc. 202-234-4433
Page 372 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 was done in the European Union. I would say we recognize that there is no requirement for guidance prior to approval of biosimilars and that requests for guidance should not be used to obstruct the approval of biosimilars. That being said, we think there are many reasons why issuing guidance would be very helpful. It will improve the It will allow
transparency of the process.
our members innovative companies to provide their input on the standard that would be necessary in specific product areas as well as the general public and we think that will, in fact, facilitate the entrance of biosimilar products to the market. With respect to users fees, in addition to the two points I made in my presentation regarding the fact that biosimilar user fees -- biosimilar workload should not negatively affect the review of new products and that we think user fees should be Neal R. Gross & Co., Inc. 202-234-4433
Page 373 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 speakers? directed toward post-market safety evaluation as they are for PDUFA products. We will also make some more extensive comments in our written submission to the docket about the best ways for a user fee program to function including technical discussions with regulated industry including a regular sunset so that the characteristics of the program can be revisited and so forth. But, we'll be laying that out in more detail in our written submission. DR. BEHRMAN: Okay. On behalf of the FDA panel, I would like to thank the speakers for their presentations and all in the audience whether in person or by webcast for your attention to the issues discussed today in the meeting. I would also like to thank the staff in the CDER's Office of Medical Policy for supporting the meeting and in particular Sandy Benton for a really superb and flawless Neal R. Gross & Co., Inc. 202-234-4433 Are there any other
Page 374 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Neal R. Gross & Co., Inc. 202-234-4433 seriously. organization of this meeting. The public hearing was extremely productive and informative. We will carefully
consider all comments both from the hearing and from the docket as we move forward in our implementation of the BPCI Act. Please remember the docket will stay open until December 31st and we strongly encourage all interested parties to submit comments. As I mentioned, we take these very This will not be obviously your
last opportunity to present your views to the agency, but it is a particularly critical time period. So, please take advantage of that and
please see the Federal Register notice for details. Today's meeting is concluded. Thank you for your participation. (Whereupon, the hearing was concluded at 3:42 p.m.)
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A AB 285:13 abbreviated 7:1 89:15 92:17 94:10 97:13 98:5 149:4 157:1 164:4 181:9 295:4 303:3 320:15 334:2 abbreviation 351:7 351:10 ability 27:22 33:13 41:5 87:1 104:14 151:7,10 349:1 357:10 able 12:6 20:11,14 26:18 52:10 53:5 55:15 63:22 96:10 102:5 104:22 107:16 112:5 135:13 144:3 152:13 154:14 160:2 210:7 225:2 269:15 309:21 337:7 345:16 350:10 351:12,18 365:17 above-entitled 108:17 216:20 316:20 absence 71:12 370:16 absent 130:10 absolute 180:16 absolutely 46:5 107:15 120:19 176:3 179:4 195:7 215:6 362:18 abstract 135:12 academics 224:2 228:17 accelerated 127:5 133:21 accept 35:13 142:5 344:18 acceptability 248:1 acceptable 13:3 26:22 27:3 61:13 71:11 74:12 75:10 75:16 126:9 131:21 132:18 139:6 153:17 187:21 248:3 273:3 295:9 298:8 342:16 366:18 acceptance 149:19 158:7 303:10 310:11 311:3 accepted 126:22 127:3 244:13 281:21 310:9 366:8 accepting 226:12 365:6 access 13:11,18,19 34:5,22 43:19 67:16 68:10 76:13 79:5 83:18 88:14 88:18,21 89:10 104:8,12 105:10 165:4,19 168:14 172:14 210:16 305:6 308:6 309:11 318:14 328:22 330:4 334:14 336:21 339:21 365:17 accessed 10:16 accidentally 213:22 accommodating 165:18 accompanied 255:20 326:9 accomplished 305:2 account 7:6 55:12 56:17,21 158:14 260:1 265:2 305:6 333:16 accumulate 105:13 105:15 accurate 204:18 257:21 acetate 32:10 361:20 achievable 13:6,8 138:13 139:8 179:10 achieve 90:20 91:2 91:8 92:1 93:20 94:1,5 102:13,14 106:12 158:22 180:16 309:9 330:15 achieved 94:6,9 133:22 138:15 180:9 203:3 211:6 211:12 226:12 254:19 achieving 249:12 acid 71:20 170:6 242:4 320:21 327:5 348:1 361:11,20 362:12 acids 362:4,9,11 acknowledge 112:11 119:9 200:2 257:10 303:12 acknowledgment 358:14 acquired 281:15 acquisitions 287:6 ACR 59:7 act 6:19,20,21,22 7:7 8:6 34:15 36:5 75:1,6 77:1 230:7 251:16,21 275:16 276:11,18 285:22 293:14 294:18 295:16 302:13 308:4 309:10 328:11 329:8,22 374:6 action 17:8,10 18:14 25:4 26:1 72:16 87:2 113:16 124:22 125:5,9,12 129:14 148:18 165:17 247:19 257:14 259:18 264:20 322:2,3 341:9 actions 54:2 125:1 125:18 129:21 130:16 343:3 activation 125:10 active 118:15,19,22 213:6 333:4 340:17 348:3 355:3,4 actively 141:10 activities 141:19 163:20 164:3 178:3 activity 40:13 54:8 56:19 59:11,12,18 65:4 85:7 111:22 127:10 145:17 177:22 179:15 240:4 242:12,18 245:15 246:6 actual 43:21 85:20 99:2 112:12 119:15 136:8 213:9 231:6 273:5 334:7 Act's 345:8 acute 59:10 ad 230:4 ADCC 125:11 130:9 add 14:20 54:5 145:4 244:20 added 161:13 331:10 adding 314:5 addition 141:6 152:17 187:17 247:6,22 250:3 256:5 257:17 344:8 362:20 363:16 372:18 additional 10:3,21 17:5 18:1 33:16 39:19 92:3 97:22 130:21 140:2 146:16 150:16 152:18 250:9 252:14 277:17 278:8,13,19 285:21 286:2 318:17 322:20 364:2 Additionally 38:1 170:18 345:18 additions 177:20 address 12:18 25:21 88:4,18 98:6 105:5 124:17 131:1,2 144:8 150:14 159:20 160:2,4 166:4 183:18 190:6 193:14 198:1 202:20 206:16 219:16 255:22 262:20 301:4 317:18 340:2,11 342:1 343:11 344:12 353:9 354:15 370:22 371:19 addressed 88:16 157:7 189:6 191:17 205:22 206:1 219:20 222:11,13 224:11 234:14,18 236:19 294:15 319:14 353:2 addresses 175:9 addressing 12:1 87:22 adds 361:11 adequacy 159:16 adequate 37:14 47:8 55:1 72:19 124:5 135:8 145:21 148:9 188:11 244:6 245:12 246:21 261:3 adequately 126:2 174:8 189:10 191:18 243:4
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259:22 260:7 261:18 adhere 326:7 Adherence 170:10 adjustment 161:17 ADME 172:22 173:8 administered 54:6 233:20 administration 1:4 1:13 115:9 168:2 204:12 316:2 administrative 10:8,12 admission 98:16 276:17 admit 235:1 admitted 235:18 adopted 287:19 294:11 adopting 76:21 adoption 287:15 advance 32:6 46:1 104:17 109:22 advanced 45:16 170:21 348:13 advancement 70:17 advancements 37:2 advances 144:11 advancing 41:12 advantage 271:7 374:15 advantages 223:19 adverse 19:18 20:3 20:7 83:5 115:14 120:4 162:10 163:9 194:12 196:6 200:15 204:22 207:5 211:17 212:10,18 212:19 226:2,18 231:15 236:22 297:20 300:9,10 300:10,18,21 324:4 353:2 adversely 128:20 advice 220:12 223:9 232:2 266:9 330:10 Advisors 4:5 274:20 275:5 advocate 85:20 86:2 advocating 40:20 80:15,18 181:12 208:9 312:8 Affairs 317:6 affect 38:13 44:10 178:5,6 188:22 372:21 affinity 246:8 affordability 13:11 31:13 69:6 308:5 309:10 affordable 6:19 140:22 165:4 173:19 275:16 329:1 afraid 328:6 Africa 221:8 afternoon 6:5 217:4 274:22 317:4 328:7 339:13 340:3 360:1 364:21 age 365:22 agencies 69:9 78:20 110:10 335:22 agency 27:10 29:2 35:18 36:15 37:1 43:6 45:19 122:15 135:19 141:7,20 142:3 147:13 148:4 152:14 183:20 190:7 220:7 223:10,11 223:20 227:4 228:13 241:21 243:2 244:22 247:11 248:1,7 249:14,22 252:4 252:18 258:16 265:20 270:3 276:9 287:20 294:10,18 296:19 297:5,11 299:9,18 300:5 319:8 338:10 346:4,8 349:21 351:20 357:14 360:17 364:4 367:20 369:13 370:1 374:14 Agency's 6:17 7:8,9 8:1 35:11 36:4 201:1 330:10 334:16 349:1 agenda 9:13,13,16 10:20 12:4 288:2 288:2 agent 130:12 363:8 aggregates 161:5 aggregation 270:15 aggressive 70:9 ago 329:21 agree 43:6 96:3 205:17 240:21 291:9 315:17 371:19 agreed 242:2 249:13 ahead 213:18 316:7 aim 179:6 332:22 airing 209:13 al 34:4 alfa 68:4 231:8 align 142:12 aligned 192:13 allergic 170:19 allocated 316:9 allot 11:13 allotted 10:21 11:2 12:6 296:12 301:3 317:18 allow 21:8 30:16 35:18 36:5 37:1 51:18 52:9 55:17 97:15 113:1 116:16 132:16 140:9 144:13 148:20 149:14 165:19 173:10,15 294:18 295:20 303:6 317:13 345:14 356:12 372:10 allowance 114:11 allowed 10:1 62:22 116:19 131:17 179:21 240:18 309:8 allowing 15:13 130:19 321:16 330:10 allows 10:3 55:20 145:16 188:11 190:17 294:21 295:16 alluded 24:10 123:15 275:19 ally 142:7 Alongside 201:1 alpha 220:16 293:9 alpha-1,3-galact... 34:2 170:5 alter 179:2 alterations 184:20 185:12 altering 35:1 246:3 362:21 alternate 364:5 alternated 342:12 alternating 54:18 63:1 190:8 191:14 192:12 249:19 300:7 343:3 alternative 132:3 137:22 alternatives 356:18 356:22 alters 107:14 amazing 69:18 365:14 amendment 232:12 amends 6:21 America 68:3 218:13 317:8 American 315:2 329:18 330:7 365:1 Amgen 3:23 199:1 199:10,17 201:18 203:3 204:14 210:7 352:12 amino 71:20 242:4 320:21 327:5 348:1 361:11,20 362:4,8,11,12 amount 15:11 27:5 38:22 296:11 351:10 365:11 analog 292:19 294:14 analogous 40:4 265:19 291:4,12 analogs 295:1 analyses 118:14 172:18 analysis 59:22 60:11,13,19 112:1 112:6 117:14 342:16 analytic 13:2 analytical 32:5,21 33:17 36:13 39:18 44:7 48:5,21 70:18 90:13 92:2 93:1,22 96:14,18 97:14,15 99:2 101:5 112:4 160:7 160:20,21 161:3 161:11 163:18,19 164:2 169:7 172:17 203:10,20 241:1 245:16 260:2 297:6 299:13 320:16 332:14,16 333:7 340:14,19 341:19 351:13 360:10 analytically 203:13 305:10 313:14 analytics 90:18 110:16 112:21
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313:16 analyze 331:13 analyzed 117:11,19 anaphylactic 188:15 192:3 195:20 198:7 anaphylaxis 189:18 196:8 ancillary 65:9 ANDA 279:14,15 ANDAs 277:8 and/or 38:3 42:7 279:5 298:15 300:19 animal 34:21 48:22 73:1,3,15 74:2 141:5 145:5,10 171:15 172:2 173:12 243:19 244:3,7,13 299:10 306:2 308:1,22 332:21 367:8 animals 85:5 145:4 274:10 ankylosing 88:22 annex 219:22 announcements 5:15 Anshuman 2:4 3:9 66:20 67:1 answer 43:10 101:8 122:21 131:2 173:20 210:14 232:7 233:18 337:19 answered 289:16 answering 163:19 answers 15:22 317:21 anti 287:21 antibodies 14:22 15:3 18:10 29:10 29:13 107:22 108:1 124:22 125:19 128:16 137:3 188:15 189:12 192:2 195:17 220:19 222:5 223:4 antibody 56:1 61:20 83:4 107:1 108:2 170:20 194:13 195:22 229:9 260:16 263:9 270:21 274:1 283:3,12,20 284:5,16,20 298:14 anticipate 99:10 109:21 177:12 245:2 297:19 anticipates 62:7 anticipating 208:12 antigenic 170:9 192:5 Antigens 34:2 anti-evergreen 277:12 anti-TNF 89:4 anybody 360:22 Anytime 331:8 anyway 328:7 347:20 apart 30:2,3,5 apex 175:16 API 104:9 106:2,9 164:1 360:11 apoptosis 125:10 apparently 134:19 341:20 appear 40:19 275:2 appearing 248:19 appended 340:3 applicable 22:21 90:9 368:3 applicant 341:7 344:20 345:11,12 346:9 351:12 352:18 applicants 277:3,6 335:16 350:10 371:5 application 35:6 143:21 163:21 187:15 240:18 249:15 277:7 280:14,22 281:14 295:21 298:8 320:6 335:20 346:12 348:18 351:9 352:19 353:6,13 358:1,4 358:10 359:6,13 359:15 applications 35:14 90:7 221:17 226:13 278:6,21 295:12 344:19 345:6 348:22 applied 13:16 33:20 41:15 46:8 89:18 133:5 144:1 144:2 161:18 332:8 applies 50:10 90:7 230:8 347:9 apply 9:20 32:8 44:7 50:6 54:2 66:3 87:4 89:12 89:13 134:12 185:22 186:1 196:17 227:15 232:10 324:12 327:7 347:2 applying 33:16 appoint 282:16 appreciate 109:2 166:2 315:1 360:13 appreciates 293:10 approach 33:4 40:1 45:1 49:21 71:4 91:7 94:12,21 95:6,13 96:13 101:6 107:8 110:2 136:7 142:17 143:7 164:22 175:12 178:20 180:21 181:10 219:5 240:15,22 241:3,14 247:15 250:2 256:12 258:15 262:13 265:19 267:20 273:11 294:12,13 330:21 331:19 332:7 333:20 337:5 339:3 355:17,22 approaches 35:6 35:15 147:8,14 299:3,6 363:18 appropriate 20:4 25:7 34:19 37:7 39:20 51:14 107:5 145:6,13 146:6,17 147:6,12,17,19 148:2,12 153:7 154:2,5,8 167:3 179:21 181:19 185:14 221:22 235:6 242:22 244:14 248:8 254:7 255:7 263:14 264:17 297:6 332:21 336:13 appropriately 13:17 27:21 41:14 144:21 232:5 250:14 254:20 337:8 342:7 approval 1:6 5:7 7:1 23:4 35:20 36:2,9,17 39:13 50:13 52:22 65:20 68:8 70:1 71:2 72:2,7 75:9 76:22 77:12 82:6 90:1 99:8 109:3 113:20 116:13,17 117:10 118:17 123:19 127:5 130:21 133:17,21,22 143:12 145:1 149:17 156:22 162:7,9 165:14 166:19 183:5 186:4 188:19 193:5,13 204:6 208:11,13,21 209:8 217:16 249:10 262:18 279:14 295:4,20 318:7 321:16 323:10,16 329:16 335:21 341:7 347:2 348:18 359:13,14 367:9 370:14 372:4,6 approvals 21:16 22:20 66:12 311:10 approve 23:14 87:6 132:18,20 165:21 208:20 260:15 322:10 339:19 350:18 357:11 approved 21:21 22:3 23:2,5 24:1,7 24:12,19,20 46:22 48:16 49:15 65:17 66:8 74:11 111:5 114:7,14 129:1 134:5,19 135:1 139:9,20 152:10 161:8 162:12,18 186:10 193:6 207:3 208:14 210:10,11 223:14 235:10 241:10 256:4,9,18 259:6 268:18 269:17 283:4,13,21 284:8 310:7 314:11 325:11 327:1 332:1 342:21 348:9 357:12 approving 149:7 314:14 329:14 365:7 approximately 10:17 172:11 256:7 Arabia 221:9
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arbiter 49:9 arbitrary 57:19 147:22 165:12 area 18:11 28:4,19 101:2 162:14 179:11 219:12 236:18 253:6 261:6 306:11 329:5 367:12 368:3,4 areas 18:12 102:9 140:20 183:12 193:21 258:21 301:2,4 371:22 372:13 arena 267:16,17 arguably 42:6 argue 176:19 argued 175:13 arguing 41:18 argument 291:6 arguments 48:19 arisen 24:22 134:22 arm 70:3 78:13 81:8 106:20 arms 57:18 58:10 65:3 arose 219:15 arrangements 227:10 arrive 18:17 arrow 93:17 art 333:7 arthritis 59:1 129:19 138:7 Arthur 2:10 3:22 182:6,14 Article 232:12 articles 79:17 227:20 articulated 39:9 266:17 Asia 68:2 210:10 aside 195:21 asides 153:2 asked 12:19 14:2 60:4 73:1 74:10 79:8 134:16 139:12 174:20 210:4 214:4 296:17 301:1 309:18 asking 276:2,15 asks 71:10 aspect 96:22 176:10 272:19 aspects 22:13 89:8 124:17 156:4 189:15 195:16,21 296:13 367:5,8 aspiring 180:16 assay 83:4,6,10,13 83:15 164:18 assays 75:13 125:17 145:22 240:6 243:4 306:1 assert 17:9 assess 38:2 94:22 166:20,22 195:22 198:10 246:16 272:14 297:7 assessed 129:12 146:18 147:18 148:13 153:10 189:16 193:10 305:11 341:18 assessment 55:5 64:3 110:8 186:12 189:9 198:14 207:15 225:5 231:11 240:22 244:21 265:7 321:12 assigned 95:17 217:10 assigning 253:12 assist 28:16 221:3 assisted 239:8 Associate 5:10 8:21 9:6,8 317:5 associated 93:10,15 191:5,13 196:7 213:21 226:21 229:6 249:5 293:12 348:10,22 association 4:8,9 4:13 263:3 292:7 301:16,20 328:4 associations 224:3 Association's 328:9 assume 63:7 93:10 assumed 54:12 60:13 assumes 45:3 assuming 10:3 71:1 119:19 assumption 229:14 assumptions 53:13 343:13 356:16 assurance 32:18 39:17 118:9 345:11 assurances 149:5 assure 122:15 181:1 231:22 312:4 324:17 assured 207:8 337:11 343:2 assuring 28:16 37:5 226:2 232:21 attaching 347:19 attendees 5:4,18 attending 365:4 attention 30:6 61:22 125:8 132:6 229:4 266:3 364:11 373:17 attorney 275:1 attractive 238:1 attribute 253:9 attributed 226:3 attributes 21:4 36:14 39:2 40:11 45:18 72:1 90:21 91:11 92:10,15 94:14 96:18 97:11 98:2,4 100:5,13 102:6,11 111:18 112:12,14 114:6 184:12,17 240:2 242:21 243:5 246:1 253:8,16,18 254:9 303:22 331:17 332:11 attribution 19:7,18 204:22 207:4 AUC 160:21 audience 373:16 audio 5:17 Australia 302:12 316:6 authorities 96:3 147:4 186:15 221:4 230:14 authority 226:7 229:19 230:6 271:9 336:16 authorization 124:8 191:2 221:17 authorized 247:4 authorizes 322:18 automatic 76:8 124:11 availability 168:8 336:4 337:1,5 367:17 368:12 available 8:3 10:4 43:3 58:15 105:2 105:14 142:9 154:22 203:21 216:15 223:21 248:10 262:8 355:8 357:7,17 Avenue 1:14 avert 356:15 avoid 26:6 27:1 206:19 343:13 avoidable 13:22 avoided 19:20 27:6 27:7 34:22 130:3 avoids 165:12 award 198:17 aware 24:5,21 88:20 210:18 213:8 216:7 236:7 236:8 268:17 314:12 331:15 338:21 344:2 362:2 awareness 121:14 121:15 A's 283:9 A-F-T-E-R-N-O-... 217:1 a.m 1:12 5:2,20 108:16,18 A1 241:17 A3 71:10 A4 73:1 246:17 B B 30:9,10,14 58:7,8 87:11 128:12,15 135:18 271:14 282:12 284:4,6,13 285:3,5,11 293:7 Babbit 4:4 255:10 255:19 BABBITT 2:14 255:12 266:22 268:10 269:18 271:11 272:8 273:12 back 6:7 11:10 54:18 56:11 77:11 117:7 122:13 138:22 198:3 216:9,18,19 217:3 236:15 251:3 254:10 339:5 349:15 365:21,22 371:9 background 192:1 237:5 backyard 69:16 bacteria 171:14 bad 29:12 Bakin 2:15 4:6 274:21 275:3,17 289:10 balance 43:2 108:4 119:14 258:9 325:22 345:20
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gamish 362:6 gathered 73:19 GCPs 75:17 GCSF 68:1,12,15 76:14 95:14 220:16 261:11 263:5 268:13 Genentech 123:7 123:10 general 16:2 22:5 22:14 29:4 154:19 156:8 157:20 174:19 220:9 242:5 261:3 294:22 296:13 302:8 306:8 307:2 353:8 365:21 370:8 372:14 generally 30:16 33:7 41:3 66:7 129:11 228:9 263:11 264:18 281:21 300:8 336:11 370:4 371:2 generate 105:15,22 112:2,5 165:7 260:11 274:16 362:6 364:6 generated 154:14 189:12 307:11 320:7 334:19 335:1 361:7 generating 261:1 generation 55:13 109:15 188:14 326:19,22 generic 4:9,13 32:9 49:17 89:22 156:18 199:21 224:2 227:9 234:16 238:7 301:15,19 322:11 328:3,9,18 334:10 334:17,18 343:10 359:15 generics 13:7 227:8 277:9 328:14 335:7 363:11 genetic 3:21 178:22 182:16,22 183:1,7 293:2 geno 146:12 genuine 336:15 genuinely 224:12 geographic 355:16 geographies 304:12 304:15,17 Germany 236:6 getting 48:7 194:4 199:2 266:9 give 15:3 23:6 96:4 102:14 106:12 164:14 360:3 given 10:20 12:4 18:1 25:15 27:12 31:5 42:19 119:1 126:12 132:20 184:1 191:21 192:22 211:11 214:9 227:2 230:16 243:3 251:17,18,18,20 253:2 263:19 306:12 311:22 317:17 321:6 322:8,17 333:4 334:9 342:6 363:21 367:5 gives 59:4 140:3 304:15 334:5 giving 67:5 123:11 164:11 glad 337:18 glatiramer 32:10 361:20 362:3 363:7,19 global 52:19 53:2 67:9 96:12 140:21 141:2,8 142:3 149:14 255:14 307:10 309:8 328:14 globally 294:5 343:21 344:11 globe 186:15 globulins 300:17 GLPs 75:17 glycan 242:17 glyco 246:7 glycoforms 84:6,10 85:2,6 242:15 glycoprotein 33:9 177:20 glycosignature 71:21 glycosylation 33:6 163:5 170:4,13 172:6 179:2 184:14 246:5 321:3 GMPs 75:17 go 9:17 26:18 28:11 54:17 57:4 59:17 60:12 72:22 77:11 78:8 120:22 138:22 148:7 166:10 176:17 177:21 200:5 201:21 208:4 213:18 232:22 251:3 253:15 254:10 277:14 304:20 349:15,19 350:1 goal 33:2 71:14 77:1 131:13 136:4 213:12 266:16 275:20 332:3 goalpost 92:16,21 93:20 goalposts 100:2 174:6 goals 35:7 161:13 182:2 goes 11:1 58:4 61:14 283:9 365:18 going 29:18 55:2 56:10 58:7 85:4 86:17 94:18 102:7 105:16 107:9 108:14 118:7,9 121:11 133:14 148:7 153:22 155:21 156:1 157:2,5 206:19 220:22 232:8,14 232:18 234:22 236:15 258:20 276:19 279:12 280:8 281:4 288:8 288:9,11 289:4,13 289:15 290:8 302:21 314:21 gold 262:4 good 5:3 22:15 31:22 52:17 61:5 66:21 89:2 105:4 108:21 114:16 140:15 143:21 174:9 180:14 182:13 211:14 274:22 276:17 300:8 317:2,4 328:7 339:13 360:1 364:20 goods 174:21 175:7 gotten 78:5 224:9 governing 282:17 government 227:11 governments 222:20 232:16 GPA 369:10 GPhA 32:4 328:15 328:17,21 329:4,6 329:15 336:19 337:15 GPhA's 334:8 grant 277:1 granted 283:5 284:9 graph 70:12 75:19 93:11,17 graphical 164:12 graphs 166:11 grasp 329:18 great 44:2 107:7 223:5 225:7,16 227:17 283:7 284:1 greater 32:18 48:14 118:9 129:10 137:11 172:7 198:6 246:2 270:16 286:12 291:17 greatly 21:3 360:13 green 233:22 gross 244:11 ground 9:18 grounded 340:7 group 87:18 365:2 groups 47:12 155:18 growing 34:6 221:10 grown 170:2 growth 302:12 growths 97:4 guarantee 297:1 guaranteed 74:17 guess 5:19 45:22 46:4 50:14 51:6 51:12 52:3 78:2 80:11 101:20 107:2 150:10 151:12 179:9 197:20 199:2 214:5 270:1 271:1 271:12,21 273:13 274:11 276:14 279:16 338:7 371:3 guidance 7:20 20:21 21:6 27:10 27:16,21 28:2,2,6 29:2,15 39:9,14 53:14 61:5 141:7 141:12,13,17,22 144:22 155:16 161:18 206:18 209:19 217:22 218:3,4 219:2,14 220:9,10,12,14,20
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happen 18:14 53:9 58:13 69:8 happened 29:8 happening 252:8 happens 46:16 266:8 281:10 happy 43:10 166:4 173:20 229:1,2 327:18 349:9 363:6 hard 15:13 131:7 271:16 harm 207:9 349:1 harmonization 141:9 149:13 154:13 294:6 296:14 365:20 harmonize 151:1 harmonized 241:14 312:19 harnessed 232:3 harvested 201:11 Hatch 357:19 Hatch-Waxman 34:17 69:17 329:21 346:2 head 60:6 124:1 182:17 270:11 283:9 328:13 heading 219:16 headquartered 328:15 heads 58:22 H head-to 123:22 half 55:14 59:19 head-to-head 14:20 171:8 234:13 127:18 131:9 half-life 56:3 139:2 187:4 265:3 147:16 178:6 268:21 hallways 6:2,8 health 1:1 6:22 9:1 216:18 9:3 62:9 67:9,19 hamper 330:5 70:20 75:5,19,22 Hampshire 1:14 76:5,7 77:2,4 hamster 34:1 170:2 88:14 89:2 168:16 hand 11:11 55:22 175:5 186:14,16 181:16 241:12 199:19 205:2 handled 341:12 206:16 212:3 hands-on 340:7 214:10 294:11 221:3,5,7,10 222:11,15,16,18 223:13,15,16 224:13 228:21 229:2 247:16 249:21 250:1,2,4 250:6,9 287:16 294:21 295:3,6,17 296:3 318:3,22 342:14 351:21 369:12 370:2,9,13 370:16,17 371:17 371:21 372:3,5,8 guidances 36:1 61:5 147:3 168:4 168:18,22 186:14 209:22 223:2 318:21 369:22 370:9,11 371:8 guide 240:15,19 318:6 guided 318:11 guideline 123:13 139:13 162:1 guidelines 61:17,19 75:4 76:22 155:14 155:18 161:19 186:16,19 240:18 294:16 367:12 368:1 Gustafson 2:18 4:8 292:6,8 301:13 303:11 318:20 323:13 329:2 334:13 339:16 365:3 healthcare 165:3 275:16 healthier 317:14 healthy 69:11 hear 355:11 heard 21:15 22:18 47:11 65:13 117:12 121:3,6 175:13 179:1,9 199:20 201:7 204:20 205:8 206:22 208:8 209:10 211:7 212:11 225:7 272:17,18 273:6 290:11 291:2 304:8,19 332:9 338:2 350:15 355:20 hearing 1:6 5:5,6 5:13 6:14,15 7:6,8 10:18 11:8,15 12:3,10,16 21:19 140:17 156:5 168:3 209:13 225:8 292:9 301:7 318:10 337:15 361:5 374:2,4,20 hearings 10:5 heavily 217:17 221:12 351:11 Heidi 1:21 8:22 held 222:1,2 help 21:3 36:15 125:17 145:22 165:4 286:22 290:21 319:2,4 325:2,20 337:1 355:8 360:17 363:5 helpful 52:12 97:5 162:2 209:13 212:22 224:12 281:19 305:21 370:1 371:19 372:9 helps 274:13 294:9 365:2 369:8 hemitrope 163:1 hemophilia 293:7 heparin 220:17 heterogeneity 202:5 298:13 361:6 heterogeneous 177:20 201:15 364:6 Hexal 231:8 HHS 1:1 Hi 8:11 255:12 high 33:17 34:6 62:20 75:12 84:13 86:6,7 89:12,14 90:5 92:2 99:17 110:4,6 130:14 135:3,21 137:5 140:4 185:21 191:3 271:15 308:11 313:21 314:2 319:22 329:16 330:7 335:21 336:4 342:7 369:18 higher 24:17 46:10 98:19 99:6,8,12 99:19 110:20 153:1 193:12 198:2 highest-quality 165:20 highlight 282:20 highlighted 361:6 highly 13:12,13 17:16 47:14 53:19 70:10 71:20 73:12 74:4 90:20 91:9 91:17 93:20 102:8 124:13 138:11 157:10 169:5,8 170:11 172:15 173:9 193:4 237:10 241:20 264:19 297:2 298:4,7 300:4 306:10 307:15 331:17 333:9,18 334:8 335:19 336:3 356:4 361:13 362:11 high-yield 361:14 historical 79:16 80:13 historically 33:3 80:8 304:14 history 73:14 149:7 155:11 203:2 227:22 299:15,15 hoc 230:4 Hodgkin's 70:10 Hoffman-La 3:14 123:6 hold 31:6 371:9 holders 302:2 holding 12:16 168:2 301:6 holds 177:5 homogeneity 172:4 honest 288:1 289:11 honestly 167:16 honored 182:12 331:12 hope 42:9 43:6 53:5 63:20 152:6 317:22 360:17 365:5 hopefully 290:8 291:17 hopes 337:15 hoping 349:16 368:13 hormone 302:13 hospitals 207:13 host 71:19 hot 153:3 housekeeping 5:15 huge 102:7
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human 1:1 3:21 15:5 34:21 73:14 141:5 157:15 170:8 173:12 182:15,21 183:1,7 185:17 199:13 201:4 202:3,15 220:8,15 229:8 233:15 240:8 243:21,22 244:17 292:16 298:19 299:10 308:1 humans 170:7 195:4,9,10 244:5 265:7 humbled 203:8 Humira 59:3,21 65:20 hundreds 69:20 hungry 199:2 hurdle 72:4 hurdles 236:18 hurt 285:22 hurting 368:11 hypersensitivity 192:3 hypothesizing 271:17 hypothetical 194:22 196:5 284:3 hypothetically 283:2 I iBio 3:19 167:21 171:2 ICH 39:9 113:21 141:10,17,18 142:7 149:13 154:12,16,20 161:19,22 162:2 331:21 365:22 366:19 ICH-type 148:21 idea 29:12 119:18 271:2 ideal 231:14 312:18 ideally 253:8 343:19 identical 71:19,19 78:10 90:6 106:6 156:14 170:13,16 199:21 201:8 343:12 356:4 358:6 identification 160:17 211:3,12 identified 24:6 124:11 236:17 310:1 318:9 identifiers 115:20 122:2,4 identify 185:6 210:7 222:10 240:9 297:14 307:6 309:21 identifying 127:20 134:21 348:9 identity 33:5 177:17 180:17 246:7 ignore 29:18 ii 278:15 282:16 illustrate 160:15 illustrated 100:11 immediate 214:11 330:8 335:14 immune 128:22 129:22 130:7 188:16 196:7 205:11 293:8 300:17 immune-related 83:5 immunocompetent 25:18 immunogenetic 271:7 310:8 immunogenic 38:7 70:14 189:11,19 198:7 immunogenicity 14:14,18,21 15:17 19:1 22:2 24:8 25:19 38:2 54:9 59:11 73:21 76:17 83:2 95:3,9,10 96:6,8 106:18 107:4,11,12,14,17 115:2 124:7 129:1 129:6 146:9 148:15 166:16,18 166:20 167:1 184:19 189:5,8 190:1 191:6,21 193:9 194:9,11,19 195:2,6,14,17 196:17 210:8 220:13 239:15 248:11 249:7 264:4 269:10 270:12 271:15 300:14 321:11 323:22 341:17,21 immunogenicity's 95:5 immunoglobulins 124:13,15 immunologic 188:13 306:1 immunology 42:21 128:7 immunosuppress... 18:6 25:17 impact 57:9 68:10 85:2 107:19 111:1 113:1 128:7 142:21 168:14 184:9,12,17 185:18 186:6 189:3,7,15 190:20 193:17 203:15 204:9 216:7 242:12,18 245:22 246:5 272:22 273:1 323:12 367:14 impacted 94:18 95:10 128:20 impacting 184:21 194:5 195:18 impacts 240:3 289:8 impair 19:6 imperfect 237:3 315:18 implement 27:22 35:21 43:8 85:21 322:22 implementation 6:17 7:7,10 16:22 20:5 36:5 69:17 183:5 217:15 292:11 293:13 318:4,7 345:8 374:6 implemented 37:11 40:21 232:14 254:12 implementing 22:15 34:12 228:14 318:21 346:11 implements 318:12 319:11,13 implications 104:14 127:18 129:5 324:2 implied 126:13 231:20 imply 25:11 51:22 197:1 importance 45:4 183:13 253:7 318:20 338:8 important 12:16 14:18,21 15:6 16:7,10 21:1 30:21,22 35:17 38:21 113:19 115:5,18 165:20 176:7 180:6 185:20 190:14 198:9 201:17,21 202:16 203:19 258:8 294:17 329:4 337:17 338:5 345:7 346:17 356:14 importantly 42:17 184:19 352:21 imposed 335:5 impossible 40:19 41:1,7 80:22 156:13 209:15 210:21 297:14,18 298:18 352:3 impractical 37:21 297:14 improve 32:22 328:21 372:9 improved 13:19 90:14 264:2 improvement 161:3,10,11 212:16 257:18 improvements 185:11,22 315:17 impurities 161:5 161:14 163:2 174:7 298:15 impurity 184:13 inaccurate 347:14 inactivation 298:11 inactive 53:21 157:12 inadvertent 19:21 115:21 121:12 inadvertently 356:2 inappropriate 51:5 153:7 227:10 248:5 266:12 343:13 356:16 357:20 incentive 286:17,21 291:9 incentives 326:2 344:14 inching 269:7 incidence 24:17 include 58:20 109:12,16 114:21 170:4 195:19
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215:2 225:20 241:4 249:9 262:14 299:11 327:4 336:22 347:22 364:7 included 20:3 21:16 148:15 305:20 includes 110:14 111:15 207:2 239:20 330:9 365:9 including 10:12 48:20 65:10 88:8 89:10 90:21 96:21 109:8 116:15,20 124:8 149:9 162:9 184:7,13 185:11 186:15 223:22 225:11 230:8 256:8 267:12,12 267:13 268:17 295:19 321:3,11 322:21 324:3 352:20 368:4 373:6,7 income 69:2 incompletely 125:6 inconsequential 180:12 inconsistent 242:16 315:21 incorporate 211:9 incorporated 171:2 368:6 incorporating 64:3 272:20 increase 13:10 19:1 54:8 59:18 76:9 165:3 173:17 204:1 205:10 215:10 231:14 263:15 increased 32:15 35:2 68:15 79:5 126:10 191:21 201:22 229:7 323:21 326:1 363:2 increasing 172:14 203:16 330:3 increasingly 20:8 34:6 340:20 increment 30:19 incumbent 353:4 IND 72:2 247:1 independent 254:4 254:5 326:20 independently 185:2 263:20 India 68:5,12,16,20 69:1,13 70:2 76:14 77:13 78:1 78:15,16,17,19 79:1 80:20 82:6 82:16 135:6 210:10 indicate 249:18 295:16 311:22 indicated 27:9 Indicating 163:10 indication 17:5,6 17:18,19 18:10,11 25:16 74:3 78:6 113:12 115:9 116:12,21 119:19 119:20,20 120:2,8 120:9,14 126:16 129:9 188:6,18,20 190:1 202:7 247:18 251:18,21 252:8,13,16 257:22 260:1 278:7 321:15 322:1 325:14 342:20 indications 17:4 24:21 25:5,9 37:22 56:3 61:2 111:6 113:13,15 114:8 116:19,22 124:4 126:14 128:1,20 129:16 138:1,2,7 139:20 148:17 149:17 153:16 165:16 192:20 193:2 207:3 247:18 248:14,19 251:11 252:5,20 256:18 259:1,7,19 260:4 260:6,14,21 264:13,19 303:5 321:16 323:5,8 325:11 341:6,12 341:22 342:22 indicator 261:3 indicators 148:3 indirectly 23:19 282:3,8,13 indisputable 68:21 indistinguishable 70:20 individual 22:13 66:11 115:15 206:8 240:20 305:10 324:16 342:13 individualized 136:7 individually 276:21 individuals 69:2 induction 360:3 industrial 110:10 industries 45:21 275:8 industry 4:14 27:11 32:22 33:3 41:4 165:11 182:12 282:1 339:2,17 368:16 373:7 ineffective 343:7 ineligible 276:12 infeasible 119:5 352:10 inferior 152:22 inferiority 37:19 96:2 118:1 188:9 259:15 262:22 inflammation 59:7 inflammatory 128:8 263:10 influence 169:1 influenced 44:14 influences 57:2 inform 8:1 36:15 207:16 informal 9:19 information 7:5,14 19:17 20:10 28:15 37:15 47:9 64:1,9 105:3 135:9,14 136:19 159:1 166:22 196:21 204:16 210:16 211:16 212:1 214:20 215:3 223:21 224:15 250:7 253:21 255:3 304:16 305:16 315:16 325:9 338:6 340:5 345:9,14 346:1,3 346:8,14 353:5,13 357:7,22 358:10 358:21 359:5,6,7 359:8,9,10 informative 38:5 374:3 informed 92:9 infusions 293:4 ingredient 331:11 348:3 ingredients 355:3,5 inherent 111:14 193:15 inhibitors 300:13 inhibits 270:21 initial 38:9 93:12 114:15 117:10 168:22 245:3 250:1 initially 310:13 injectable 214:8 injected 303:20 injections 293:5 INN 226:10 230:15 230:22 343:18,21 innovation 32:20 41:5 88:13 285:22 286:4 289:3 290:14 291:7 293:14 318:16 327:9 328:11 329:7 344:14 Innovations 6:20 innovative 20:12 41:13 109:11 110:3,9 123:22 134:4,13 142:6 144:1 185:22 189:5 255:4 261:8 291:11 309:19 343:12 372:11 innovator 14:9 15:2 21:2 24:18 48:15 65:17 83:11 104:8,11,20 114:1 120:1 129:8 132:2 132:19 133:6,11 134:18 138:13 142:14 143:15 146:15 150:10,18 151:3,20 152:20 158:12 159:11,21 161:7 167:14 185:5 187:1,5,9 187:11 188:6 191:16 192:21 193:13 194:11 195:11 196:5,15 197:3,3,9 198:4 198:15 199:22 202:9 214:19,20 252:7 257:15 280:21 288:5,17 310:10 314:4 343:22 345:3,5,21 349:4 350:6,11,18 350:22 358:11 359:9 366:17 innovators 40:17 45:20 150:13 210:5 277:2
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94:13 95:3 100:14 106:2 141:6 154:1 154:4 367:19,21 looks 287:14 loophole 278:10 279:2 280:1,2,4 281:3 lose 252:16 308:7 loses 254:15 loss 54:8 287:4 lost 237:5 254:22 lot 20:2 39:3 47:11 61:14 93:5 154:12 155:13 158:14,19 195:16,21 196:21 200:13,17,18 201:2 211:4 212:1 212:7 214:9 220:21 237:4 253:11,13 288:8 288:11,11 304:15 305:17 307:8 311:3 314:9 344:3 344:5,9 356:19 367:12 lots 112:2 115:15 143:14 267:3 lot-to 158:18 lot-to-lot 39:1 44:19 Louis 199:11 love 149:12 Lovenox 279:15 367:22 low 119:9 140:6 194:10 195:6 196:16 220:16 248:11 260:11 330:6 lower 59:19 86:7 99:11,20 119:10 170:17 244:10 269:10 270:12,15 339:22 lowering 330:2 lower-cost 88:15 lunch 6:10 11:14 194:5 216:14 lymphocytes 128:14 lymphoma 70:10 135:18,18 138:8 M MabThera 78:10 78:16 magnitude 129:10 186:4 main 44:6 52:8 98:22 236:8 308:5 maintain 235:22 maintaining 285:19 344:13 major 14:8,12 74:17,17 84:14,15 86:12,13 107:19 111:1 160:9 161:2 174:21 203:11 222:4 226:2 227:19 258:18 265:22 majority 11:22 74:18 221:11 228:16 275:6 288:20 354:22 making 28:7 38:10 38:14 84:3 90:3 157:17 158:10 174:4,18 181:3 182:1 203:3 240:20 323:3 333:13 malignancies 271:14 Maloney 1:21 8:20 8:20 102:18,19 120:21,22 212:5,6 213:1 236:14,15 manage 116:2 235:4 337:8 managed 13:18 27:4 management 9:8 124:8 150:21 152:12 182:15 225:21 256:22 264:9 282:14 mandate 36:1 78:20 97:12 232:15 307:19 328:21 329:4 mandated 215:16 mandating 333:21 mandatory 232:9 maneuver 288:9 manifest 38:8 manner 148:20 manufacture 171:22 172:8 181:14 185:9 292:16 363:19 manufactured 30:3 97:2 171:17 177:15 184:6 239:21 299:12 313:1 364:5 manufacturer 14:11 39:17 43:15 43:22 46:12 88:9 103:12 168:7 200:13,17 205:4 211:4 231:21 238:8 253:15 280:17 281:12 307:8 331:9 344:6 350:12 manufacturers 21:5 28:17 74:19 115:13 205:15,20 217:13 224:2 225:1 228:17 230:19,21 292:18 317:7 328:18 manufacturer's 159:6 226:19 233:14 237:9 manufactures 21:18 manufacturing 14:8 45:17,22 56:22 61:9 90:3 91:16,19 93:10,15 97:4 100:16 101:9 102:22 105:11 110:15,16 111:19 112:15 143:22 144:5 149:11 169:15,18 170:22 173:16 174:5 176:12 178:22 179:19 184:11 185:12 193:16 203:12 204:13 219:18 239:22 258:19 266:1 296:8 298:9 299:20 300:17 303:18 331:9 332:7 333:13 337:9 366:16 367:7 mapping 160:17 Marchand 1:21 8:22,22 85:9,10 311:17,18 margin 30:17 51:17,18 59:15 96:2 118:1 263:17 271:5 marginable 138:14 marginal 73:16 margins 118:12 126:8,13 140:5 147:20 177:2 Marie 2:20 4:12 317:2,5 371:20 Mark 1:22 2:4 3:11 9:5 87:15 marked 309:20 marker 261:20 markers 85:7 128:9 148:1 261:11 market 19:10 31:10 34:9 46:17 48:8 67:10,15 68:14 69:19 74:17 76:8 92:8 100:6 100:19 101:17 103:6 151:11,21 159:2 162:13 163:8 167:9 191:2 235:12,18 237:19 277:2 278:7 294:5 302:17 313:20 323:7,14 327:2 334:14 335:1 349:7 351:9 354:20 372:16 marketable 23:19 marketed 15:14 23:16,17 68:2 73:18 82:7 231:2 231:5 314:14 335:18 marketing 151:2 152:5 219:6 221:16 225:18 264:9 281:15 310:4 312:10 353:14 354:19 marketplace 34:14 69:12 74:22 235:9 286:5,10 288:10 291:8,10,15 markets 21:17 67:17,20 68:7 302:17 307:15 335:19 Marking 365:1 Mary 2:18 4:8 292:6 Maryland 1:14 maspec 160:17 mass 202:13 master 91:18 match 363:20 matched 160:20 matches 172:20 material 172:11 179:6,8 181:20 313:1,2,3 355:8 361:16 materials 149:20 201:10
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matter 12:17 25:13 108:17 174:4 216:21 230:18 316:21 334:12 mattered 215:22 matters 28:12 304:2 maximum 336:4 McCAMISH 2:4 3:11 87:15,17 98:22 99:21 100:3 100:10 102:1 103:8 105:4 107:6 111:11 Meador 34:3 mean 25:10 49:9 78:22 87:6 143:2 151:17,19 156:7 166:15 174:19 200:14 202:18 215:20 228:22 258:4 260:7 270:7 271:18 274:11 289:10 290:7 303:7 305:3 317:5 meaning 30:9 103:9 meaningful 14:7 16:5,6,20 19:17 26:17 47:20 53:22 71:12 72:21 199:18 258:14 269:14 298:17 334:14 341:1 meaningfully 118:18 119:3 means 53:18 56:8 161:4 168:6 200:20 202:5 207:7 274:13 289:13 360:9 meant 54:13 152:15 274:4 354:10 measurable 13:9 242:12 measure 15:6 16:7 59:7 65:3 80:11 85:1 261:21 268:4 268:7 298:18 measured 15:10 16:13,14 127:11 128:3 240:5 263:11 measures 16:11,15 65:9,10 219:6 measuring 274:7 mechanism 17:7,10 25:4 26:1 54:1,2 113:15 120:17 125:18 148:18 149:18 165:17 247:19 252:19 257:13 259:18 264:20 322:2,3 341:9 mechanisms 72:15 120:6 129:21 130:9 mechanistic 157:16 media 10:7,9 361:4 mediated 188:16 mediations 69:7 medical 5:11 20:9 32:1 89:9 213:3 275:7 322:15 339:21,22 373:20 medication 213:22 medications 18:7 35:1 67:17 128:21 356:5 medicinal 220:8 295:11 medicine 294:10 332:12 medicines 4:9 169:20 172:14 173:18 214:7,8 220:7 223:10,20 227:3 301:15,20 317:13 319:8 321:13 324:18 329:5,17 337:2 343:10 meet 26:16 89:9 124:6 144:4 159:4 159:8 248:21 249:1 251:22 319:3 meeting 9:19 10:14 52:21 57:9 347:3 373:18,21 374:1 374:18 meetings 221:22 249:14 266:9 meets 174:6 326:19 344:16 Mehta 2:5 3:13 108:20,21,22 117:20 119:6 120:7,19 121:10 122:8,19 member 222:20 227:11,12 232:16 234:4,13,17,20 235:2,5 275:10 294:4 328:16 357:10 369:15 members 1:17 8:10 9:22 10:22 199:5 282:17 302:5,9,10 329:15 363:3 370:20 371:17 372:11 mention 51:1 85:15 194:8 mentioned 25:4 26:3 43:17 63:14 84:2 105:7 107:10 118:13 125:7 153:12 156:18 214:17 215:18 229:18 253:7 268:2 270:6 294:2 352:12 354:13 355:3 374:11 mentioning 156:12 Merck 3:12 109:1,5 109:17 118:11 155:20 Merck's 117:17 mergers 287:6 message 199:14 messy 277:11 met 42:8 252:3 368:2,2 method 169:15 171:4 179:17 methodologies 296:8 methodology 143:9 methods 32:5,8,21 33:6,17 145:14 160:19 242:22 257:19 298:9 300:17 320:16 metrics 337:1 mice 195:2 Michael 2:5 3:14 123:3,9 238:18 239:2 micro 111:16 Middle 68:3 migrate 26:21 milestone 292:11 Miletich 2:11 3:23 199:1,3,4,8 208:18 209:10 210:13 211:13 212:15 213:7 214:3,21 215:14 216:1 million 108:6,9 171:9 millions 203:6 mimicry 169:10 170:11 mind 35:3 104:14 110:13 112:14 114:4,9 119:15 180:20 308:3,4 366:21 368:14 mineral 154:2 mines 330:5 minimal 56:4 57:22 157:15 minimally 186:1 minimizing 336:6 minimum 162:3 321:20 ministrations 56:7 minor 53:20 72:3 84:17 85:2,6 86:17 157:11 163:10 176:9 240:1 258:11 274:6 279:20 305:8 minority 285:2 minute 164:10 316:17 minutes 10:21 359:22 364:18 misread 121:22 missed 280:5 missing 212:11 mitigate 115:21 mitigating 66:3 mixed 362:5 mixture 362:22 363:1 mixtures 364:7 mobile 5:16 modality 170:15 mode 124:21,22 125:5,9,12 130:11 130:16 model 49:16 50:4,8 50:9,16 58:22 59:2 64:15 74:2,6 176:21 209:20 244:8,13 273:6 366:6 370:5,7 modeling 62:18 64:10 332:21 models 145:5,7,10 195:7 273:7 modes 129:14,20 modest 18:14 171:7 258:12 modification 177:19 modifications 72:4 72:10 84:7 90:22 91:2 137:8 169:12
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172:6 173:4 177:16 178:1 180:4 184:15 321:3 327:6 346:16 347:22 modified 151:7 170:1 347:15 362:4 modify 91:1 106:11 238:8 molecular 146:4 149:2 199:9,12 220:17 320:1,17 321:7 322:2 360:8 molecule 18:9,15 172:19,21 173:2 176:3,4,6 177:14 177:22 178:7,13 181:1 184:5 240:4 240:8 242:21 243:5 265:18 277:8 279:16 298:14 340:17 361:12 368:3,4 molecules 49:19 74:4 124:14 131:5 157:22 180:5 185:5 201:16,20 202:11 204:1 216:6 270:18 329:21 361:18 363:11 molecule-by-mol... 177:11 moment 153:3 202:2 254:11 290:3 349:16 Momenta 3:5 31:21 32:1,3 90:2 monitored 107:21 263:20 monitoring 30:6 121:2 162:8,8 monoclonal 55:22 61:19 124:22 125:19 220:19 222:5 223:4 260:15 263:9 267:15 283:3,12 283:20 284:5,16 284:20 monoclonals 124:15 125:2,8 260:17 monopolies 69:5 monopoly 76:2 77:3 335:8 month 171:9 284:13 months 223:3 moot 133:18 morning 5:3 6:4 31:22 52:17 61:17 64:2 66:21 108:21 140:15 182:14,17 198:21 199:1 216:12,13 351:19 mouse 74:6 move 43:7 69:21 225:4 374:5 moves 42:10 moving 74:9 89:10 96:5,11 99:17 108:4 143:9 271:3 343:8 371:22 MRI 154:5 multifactorial 193:17 multiple 18:8 95:15 95:20 112:1 143:14 148:17 190:18 192:11,20 198:3,5 199:20 204:7 222:21 241:15 259:7 260:5,18 276:1 278:6,21 284:19 286:6 290:17 291:13 304:11 323:18 324:10 332:17 362:1 multiplicity 60:19 mutually 70:22 Mylan 328:14 native 295:2 111:4 121:3 125:7 natural 160:16,16 126:13 135:20 nature 30:15 33:22 139:22 146:18 36:16 66:13 147:8,17,19 110:14 116:3 148:10,12 152:7 N 187:4 224:9 305:8 154:21 156:20 n 85:14 355:6 160:3 161:14 name 19:15 52:18 NBC 307:8 180:8 187:12 67:1 108:21 121:4 NCE 50:20 51:18 191:17 194:8,13 121:11 122:7,11 NDA 346:4 194:18 195:8,22 123:9 182:12,14 NDC 121:7,16 198:13 203:1 198:18 199:8 211:9 344:3,9 205:6 206:2,7 211:21,22 217:8 356:19 207:1,8 209:18,22 226:5,9,14,15,15 NDCs 20:2 210:16 212:13 230:16 231:5,6,7 near 20:18 225:17 232:3 237:11,11,13 nearly 328:19 236:18 252:2 255:19 275:1 necessarily 26:14 253:10 257:6 301:17,18 307:7 50:18 51:14 137:6 258:10 264:1 315:12 324:12 137:9 153:1 180:5 272:1,9,13,18 325:5 328:12 222:11 271:2 289:2 298:22 334:4,6,10 343:18 279:13 353:7 305:5 306:15 343:22 344:5 necessary 17:10 308:17 310:21 357:1 360:4 18:17 73:2 87:2 312:2 326:1 362:13 363:22 98:1,9 99:7 113:8 327:14 333:15 364:21 128:4 130:9 358:15,16 365:3 names 121:18 143:10,18 146:3 366:5 368:2,5 122:6,10 204:7 149:5 163:20 needed 14:9,14 205:22 211:7 164:3 178:4 15:11 25:20 35:19 213:22 218:2 188:12 192:18 48:15 166:14 226:11,14 230:1,9 204:19 206:19 186:20 192:16 230:11,21,22 241:6 247:14 213:4 219:20 231:3 232:19 249:1,8 252:18 241:9 245:1 233:5,11 307:4 259:14 306:2 246:21 255:22 316:1,8,8,11 307:5 308:21 315:17 342:15 355:20 356:10 312:16,17,18 needing 267:21 naming 19:21,22 313:9 332:15,22 needs 25:14 31:5 121:2 212:8 345:19 351:8 49:4 56:16 61:6 229:19 307:3 352:6 372:13 89:9 119:13 319:16 330:18 necessity 294:7 131:18 136:9 334:1 343:10,19 299:10 143:19 144:1 355:19 need 15:22 17:13 146:7 147:13 narrow 94:7 140:5 20:6 25:12 28:17 148:19 149:22 narrowly 243:18 34:18 36:22 43:4 153:9 193:9 257:2 Nasr's 45:13 53:14 54:22 55:7 261:16 304:3,7 national 221:3 55:8,12 56:4 57:5 305:14 308:20 236:3 344:3 59:16 61:10,12 339:21 363:8 nations 366:7 63:10 72:4 88:15 368:1 M.B.A 2:4 M.D 1:18,19,20 2:2 2:2,3,4,5,11,21 M.P.H 1:18
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negative 228:13 negatively 372:21 neither 13:8 38:4 344:9 net 125:4 130:15 neutralizing 106:22 107:4 108:1 170:20 188:14 189:17 never 89:3 Nevertheless 143:3 260:21 358:8 new 1:14 8:17 17:19 18:4,11 19:18 31:11,12 35:6,14 72:14 81:12 84:12 90:4 91:18,19 93:14 100:21 104:4 118:16 124:19 137:2,2 141:14 142:12 143:7 146:3 149:2 156:20 169:20 173:12 187:14 204:16 222:4 226:8 230:22 252:7,13 257:11 258:17 259:8 265:21 267:8 278:7 289:15 295:14,15 301:22 313:20 318:7 324:14 326:3 330:4,8 331:4,8 331:10 333:4 344:21 348:22 349:2 363:16 372:21 Nick 255:11,20 Nikhil 2:5 3:13 108:20,22 NK 130:9 noise 237:5 nomenclature 213:20 non 37:18 56:21 61:8 70:9 73:22 96:1 117:22 142:5 144:8 188:8 259:14 262:21 274:5 341:19 344:4 356:9,22 363:21 366:16 noncomparative 80:15 nonpolitical 131:3 nonprofit 365:2 nonproprietary 122:4,6 211:21 213:21 218:2 226:13,15 230:1 230:20 231:5 nonvalidated 127:6 non-clinical 39:19 41:22 124:1 143:9 144:15,20 145:9 145:12,19 147:1 203:14 241:1,11 241:18 243:16 244:19 246:15,18 246:20 247:7 260:2 267:13 303:4 341:3 351:13 357:18 358:22 non-clinical/clini... 149:4 non-comparative 244:5 non-EU 314:11 non-human 195:3 non-identical 239:22 non-inferiority 48:12 51:3,13,16 60:8 95:6,12 113:9 117:14 118:14 126:8 131:14 259:2 262:5 263:15 264:14,15 267:19 270:5 non-innovated 156:20 non-innovative 277:18 non-innovator 278:22 non-interchange... 215:4 non-proprietary 211:6 307:4 316:1 316:11 325:5 343:17 non-U.S 23:2 88:2 96:10,15 115:6 142:5 149:20 154:15,17 218:6 248:3 365:6,12,13 366:13 normally 170:7 230:14 notable 279:13 notably 113:21 164:4 note 6:6 20:6 45:12 113:19 133:13 294:17 347:4 349:3 369:2 noted 17:6 132:11 237:17,19 238:22 247:6 250:8 296:14 notice 11:22 12:2 12:20 301:1 317:20 318:10 319:15 326:7,16 330:17 345:6,14 347:1,11 374:16 notwithstanding 157:11 326:14 370:12 nourished 201:10 Novak 238:13 239:2 Novartis 3:10 87:16,18 88:6 89:7 97:7 novel 37:6 38:19 43:3 73:8 88:10 89:8 94:4 171:4 299:3,6 348:19 NOVEMBER 1:10 novo 50:19 number 39:1 62:17 68:14,18 78:16,17 81:1 106:20 107:3 119:7,15 121:7 147:22 173:17 178:15,16 188:1 192:15 200:13,18 209:7,11,11 211:4 211:9,14 212:1 220:14 223:19 225:10 234:8 235:9,15 272:17 279:3,22 280:9 290:12 293:1,19 303:2 304:10 307:8,8 349:15 355:11,15,21 365:16 numbered 132:12 numbers 15:14 20:2,2,11 53:12 60:12 62:20,21 344:3,4,5,9 356:19 numerous 296:22 300:3 362:13 Nuron 3:18 155:6,9 155:20 N-glycolylneura... 170:5 80:9 112:19 164:5 189:20 243:19 observing 44:5 obstacles 35:22 obstruct 372:5 obtain 159:1 252:15 293:11 345:10 347:17 348:13 355:14 obtained 7:6 obtaining 223:9 355:4 obvious 280:2 obviously 11:19 44:21 50:19 53:17 64:5 66:9 194:8 194:22 236:20 355:4 361:15 374:12 occur 16:12 30:19 159:10,10,11 170:21 173:6 208:10 234:1 300:10 occurred 104:20 228:21 occurs 207:6 October 220:1,5 offer 35:14 36:3 200:9 offered 140:17 165:8 offers 32:21 34:15 141:20 165:12 223:19 O Office 8:12,15,17 O 338:9 9:2,3 49:17 Oak 1:13 155:14 201:1 objective 70:8 373:20 77:22 78:4,9 80:4 officer 1:14,18 3:2 80:7,12 308:5 5:13 32:1 objectives 309:9 offices 217:11 objectivity 42:12 officials 182:12 OBP 42:22 oh 123:3 200:5 observation 162:10 310:14 317:2 162:14 354:1 observed 44:19 okay 31:16 80:14
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82:14 83:8 106:14 108:12 117:7 122:22 123:3 140:11 153:14,20 159:14 196:19 234:12 238:17 269:11 311:16 316:14 317:1 353:21 360:2 368:21 373:13 old 31:14 100:21 103:5 Omnitrope 231:3 once 31:9 54:4,6,17 58:14 91:8 94:6 101:20 158:2 162:12 166:19,21 288:22 323:6 oncology 38:16 95:13 126:22 127:2 129:20 130:1 132:15 138:8,9 154:9 262:3 263:10 266:12 267:17 268:6 onerous 151:3 ones 16:5,6 56:14 71:16 216:6 223:7 225:1 236:12 ongoing 37:2 92:22 105:7 327:15 on-rates 178:7 open 4:17 11:7,16 20:22 22:7 28:15 113:14 133:12 134:9 147:14 154:21 156:4 167:22 221:20 318:15 327:16 359:18 374:8 opened 5:20 Opening 3:2 openly 224:18 open-label 116:21 operability 147:7 opinion 49:7 73:16 84:19 86:3 103:1 155:8 198:6 opportunities 141:4 259:3 318:1 334:14 367:16 opportunity 32:22 34:16 42:16 109:2 123:12 140:16 141:8,21 155:8 166:3 169:19 199:6 238:21 250:19 255:16 275:11 292:10 293:20 301:22 309:4 317:16 328:8 339:14 349:9 360:14 374:13 opposed 81:14 151:3 267:1 359:11 opposite 266:10 291:1 optimal 7:17 options 231:13 327:9 368:13 oral 11:5 209:12 orange 78:2 order 9:16 13:10 16:18 21:8 61:9 104:1 142:1 146:8 202:20 232:22 238:9 319:2 324:17 358:4 362:11 ordered 10:15 ordering 362:8 orderly 361:12 ordinarily 226:10 ordinary 227:8,14 234:16 organisms 184:7 organization 4:14 67:9 186:16 292:14 294:11 339:17 374:1 organizations 9:14 275:6 369:10 organizers 292:9 oriented 238:4 origin 97:11 original 59:21 65:20 70:1 114:2 131:10 188:5 257:6 304:6,6,10 304:22 310:17 326:17 347:20 originating 111:17 originator 66:12 68:9 70:11 78:4 92:20 93:12,14 100:16 106:7,12 108:7 112:8 113:20 158:17 333:12 originators 311:5 orthogonal 33:17 242:22 320:18 osteoporosis 154:1 ought 366:20 outcome 16:4 59:3 127:17 136:3 268:16 outcomes 16:17 127:12 128:11 203:9 297:20 321:8 outline 93:11 94:20 156:8 outlined 94:13 186:10 322:21 outlines 57:13 92:19 output 165:3 outside 102:8 109:13 160:18 195:16 218:18 225:10 241:10 247:5 out-the-door 175:3 ovary 34:1 170:2 overall 78:17 127:2 133:1,10 138:17 154:7 178:15 192:14 228:11 244:21 262:3,15 266:15 370:2 overarching 239:19 250:2 overlap 254:8 overlapping 96:17 332:14 overnight 105:19 overriding 183:13 overview 67:21 370:8 ownership 282:10 285:3 owns 282:8 P P 2:2,11 199:1 pack 134:3 package 48:20 49:6 49:11,15 50:13 51:11 52:11 338:18 351:10 352:20 packaged 201:12 packets 23:3 paid 229:4 painting 196:16 pair 365:21 panel 1:12,17 8:10 9:22 10:22 12:15 21:12 43:12 52:21 62:2 77:9 98:12 117:3 132:8 150:5 166:7 168:1 169:3 174:1 181:18 194:2 199:6 208:3 228:5 266:6 275:10,18 287:11 301:11 309:15 327:22 337:22 339:7 364:14 368:20,22 369:4 373:14 panelists 250:22 paper 33:21 371:12 papers 222:9 paradigm 35:16 139:10 157:14 250:16 paradigms 181:2 paragraph 277:8 277:10 parallel 57:17 223:12 parameters 14:19 30:18 124:19 147:16 243:14 270:19 274:7 paramount 41:20 42:4 116:7 256:19 264:6 paraphrase 12:21 PAREXEL 4:4 255:11,13,13 256:3 267:4 269:20 Parliament 220:4 part 1:6 5:6 10:5 19:4 23:8 24:3 29:15 145:9,19 155:17 162:15 166:19 197:3,3 226:4 231:6 253:18 255:13 268:8,10 277:16 277:20 278:15 280:6,9 292:9 299:6 338:9 342:3 365:9 participant 9:21,22 participate 140:17 222:21 participated 141:10 217:21 256:3 participation 12:9 229:3 374:19 particular 28:19,22 124:15 126:12 136:7 153:9 163:21 165:10 189:16 191:4,20 213:10 215:12
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1:18 3:2 5:13 pressure 165:3 presumably 35:12 Presuming 71:17 presuppose 279:4 pretty 135:3 214:6 214:8 228:18 238:5 266:10 310:9 370:7 prevent 121:12 278:4 280:21 294:7 325:20 prevention 109:7 prevents 190:3 previous 43:17 111:11 153:14 167:13 233:19 241:13 326:11 346:5 previously 244:4 247:6 255:6 294:2 pre-change 40:5 91:22 pre-clinical 36:10 36:16 37:4,7 91:5 91:10 98:5 131:8 136:17 137:5,10 161:21 175:20 195:7 203:10 359:7 370:10 pre-market 24:22 167:7 229:12 353:17 354:2,11 pre-marketing 225:19 pre-specified 203:17 pre-survival 262:9 267:22 price 6:19 78:15 293:13 328:10 329:7,9 priced 337:6 prices 79:4 165:8 173:19 329:17 pricing 76:2 77:3 335:8 prided 41:4 primarily 192:15 243:12 265:10 290:21 primary 65:3 89:5 123:15 134:7 169:10 172:19 173:5 220:3 242:3 244:2 249:4 262:14 267:21 268:20 275:20 293:8 361:22 primates 195:3 prime 30:11,12,12 30:13 87:7,11 principle 90:12 97:10 239:21 257:8 principles 39:8 142:7 303:14 318:6,12 prior 63:13 81:14 155:11 157:16,20 158:12 166:1 172:9 260:2 272:21 338:3 353:13 360:12 372:3 priori 179:18 242:15 263:18 priorities 7:20 61:4 369:14 private 111:8 112:6 159:3 privilege 87:18 pro 287:20 288:16 288:16,17,17 proactive 335:15 337:4 probability 130:15 probably 29:14 58:13 59:16 65:6 81:9 87:3 92:18 138:16 145:5 157:18 159:1 164:21 205:16,18 225:7 232:7 probe 311:8 problem 46:18 115:18 135:4,7 167:1 201:14 202:3 216:4,8 278:9 279:1 problems 23:4 24:6 24:8,8,21 41:6 210:8,12,18 236:8 236:8 288:8 309:21 310:2,3 procedure 166:10 procedures 10:6 218:21 225:17 345:19 proceed 12:11 244:14 proceedings 10:8 10:12 218:1 proceeds 361:12 process 22:7 28:15 32:7,17,18 40:18 43:1 44:8,10,14 70:17 90:19,20 91:1,16 93:4,22 94:5 100:17 102:22 106:11 110:17 111:13,19 112:16,20 123:19 143:16 144:6 157:21 158:1,2,7 159:6 163:5 171:5 184:11 185:8 193:5 203:7,18 208:13 215:9,12 215:18 217:18 219:18 221:14,20 222:3,8,19 223:1 223:17,19 228:10 228:18,19 229:5 229:16 230:22 235:11 254:5 280:8 296:6 297:17 299:12 303:20 304:20 318:16 319:22 327:16 331:10 334:6 345:9,15 348:11,12 350:5,9 353:16 361:10,14 362:4,19 367:14 372:10 processes 90:14 91:21 110:15 143:7 144:13 169:18 185:12 217:19 240:1 254:4 319:8 processing 242:14 produce 34:1 71:19 144:3 171:8 183:22 273:17 298:11 342:5 produced 170:1,7 171:14,18,20 361:4 362:3 produces 361:14 product 7:4,20,22 8:2 15:13,22 16:1 16:1,1 18:17 19:2 20:12,16,22 21:4 23:10,10,14,15,17 23:21 24:18 26:8 28:5,8,9,13,22 32:6,13,14,17 35:10 36:14,19 37:12,16,20 38:4 38:10 39:1,13,15 40:3,6,9,11,12,14 40:18 41:12 44:4 44:4,11,12,16,17 44:18,20 46:11,14 46:17,20,22 47:10 47:15,22 48:4,16 49:15 51:17 52:19 54:3,10 57:10 63:11 68:9 70:11 71:18 72:7 77:13 78:4 80:22 81:21 83:21 89:15,21 90:21 91:4,11,12 91:22 92:10,15,16 92:21 93:21 94:3 94:4,8,14 95:18 95:22 96:16,17,17 97:4,11,12 98:2,3 98:4 99:1,3,9,13 99:17 100:6,13 102:5,11 103:2,5 103:13,14 104:1,4 104:9,12,18 105:16 106:5,6,7 106:8 108:8 111:14,16,17 112:18 113:20 114:2,3,7,13,16 118:9,16 119:12 120:15 122:21 123:22 126:1,12 126:19 131:10 133:11,21 134:5 134:18 135:21 136:1 138:2 142:6 142:9,20 143:15 143:17 146:15,19 153:9 154:17 156:10,11 157:10 157:11,21 158:3,8 158:10,12,13,18 158:20,21,21,22 159:1,4,6,7,11,12 159:22,22 160:5,5 160:12,12,12 161:2,8,12 162:11 162:22 164:2,14 165:9,21 174:6 176:14 180:1 183:21 184:1,10 184:22 185:1,8,10 185:18,22 186:5,8 186:10,21 187:9 187:12,14 188:22 190:10,11 191:9 191:16,22 192:10 192:12,21 193:7 193:13 194:10,17 196:6,15 197:4,10 198:5,15 200:12 201:16 202:9 204:15 208:14 211:3,18 219:9
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Robert 1:22 2:15 4:6 274:21 275:2 robust 57:16 97:15 113:9 115:13 162:10 229:12 Roche 3:14 123:6 123:10,17 Rojkjaer 2:21 4:13 328:3,5,5,12 338:12 339:10 371:2 role 16:10 37:5,8 47:3,18 120:18 141:13 199:18 262:1 293:19 336:12 339:1 345:8 room 1:13 5:17 6:8 11:11 212:16 216:18 route 17:20,22 18:2 24:12,14,15 238:1 238:3 routine 146:11 225:20,21 routinely 76:2 Ruckman 2:13 4:2 238:15,16,18,20 238:22 251:8,15 252:10 253:4,17 254:17 255:5 rug 289:15 rule 178:16 180:15 306:8 rules 9:18,20 35:4 134:12 178:15 227:14 run 48:13 117:21 272:9 runaway 77:4 running 164:9 rush 34:8 Russ 4:18 360:4 Ryan 2:9 3:20 167:21,22 174:12 174:16 175:1 176:5 177:3 179:4 179:12 180:10 181:6,11 R&D 165:4 326:2 328:13 348:15 360:10,11 R.Ph 2:17 187:7,18 189:1,4 189:15 190:13,20 191:1,7,11 193:1 193:3,10 195:18 196:1 210:8 225:5 238:4 240:7 244:4 245:13 246:22 S 247:19 249:10 safe 13:19 31:4 250:5 256:19,20 34:13 49:8 73:14 257:14 258:10 118:16 140:22 259:20 263:7,20 168:19 207:7 264:5,6 265:9 286:14,15 291:21 269:11 272:4,5,12 310:8 311:12 272:14 279:5 312:4 318:14 286:9,12 289:8,18 319:9 321:13 290:6,14 291:18 322:9 329:1 336:5 295:13 298:19 337:11 339:22 299:15 302:18 safely 302:18 309:5 312:15 319:18 safest 213:15 320:2 321:9 safety 15:11,15 323:13 325:1,6 18:1 19:8 20:13 326:10 330:12 22:1 24:7 35:10 332:5 333:19 37:6,14 38:3 336:17,21 337:4 41:19 42:2 43:4 342:8,10,18 343:9 47:8 53:22 54:8 343:16 346:5 56:15,16 59:10 347:17 348:5 73:20 76:16 94:17 349:5,7 359:11 113:4,14 115:12 363:2 373:1 116:6,10,22 safety-related 38:8 120:17 121:1 salads 6:12 123:15 124:3 Sales 283:7,22 126:1,10,13 sameness 13:7 128:19 129:5,8 32:19 42:7 343:14 131:19 134:21 sample 60:2,9 135:20,20 139:5 64:12 117:15 140:4 142:11 Sandoz 90:2 146:2 148:12,13 sandwiches 6:12 149:6 153:5 Sandy 11:10 156:10 163:10,14 373:22 164:3 166:16,17 Sara 2:22 4:15 166:22 169:9 339:12,15 170:16 172:16 satisfactory 56:8 173:7 178:14 satisfied 228:19 179:20 180:6 saturable 271:22 183:14,15 184:21 272:2,7 185:19 186:9 Saudi 221:9 save 64:11 saved 69:19 savings 70:21 75:5 165:7 169:20 334:19 saying 76:20 80:5 104:21 118:17 175:19 195:5,10 251:5 303:7 354:8 365:8 368:9 says 103:19 122:1 283:9 scalable 171:6 scale 177:21 scenario 48:11 196:15 247:2 282:22 283:16,17 283:17 284:12 scenarios 139:18 248:7 282:19 schedule 12:7 scheduled 5:21 6:10 9:15 329:11 Schwartz 1:22 9:5 9:5 98:13,14 99:18 251:1,2,9 349:12,13 science 32:6 36:18 42:12 44:22 52:5 69:9 71:3 77:1 90:7,8 97:21 112:22 137:4 143:21 156:19 157:22 174:10 295:17 305:1 309:6 318:19 322:8 327:13 332:15 336:15 348:20 sciences 70:18 360:5 science-based 318:15 science-driven 22:8 scientific 7:11,21 7:22 17:12 20:22 25:13 35:6,11,15 35:18 37:1 89:17 92:12 94:12 107:8 110:5,7 116:9 141:16,22 142:1 143:20 149:22 157:8 160:6 163:16 165:19 200:21 206:16 207:15 222:21 223:9 224:10 239:8,13 240:19 269:5 288:22 289:22 296:18,21 297:4 303:14 317:6 322:5,14 324:14 329:13 331:13 336:1 scientifically 94:22 95:2 321:20 341:8 scientist 177:10 178:10 scientists 368:16 sclerosis 362:1 scope 7:18 33:10 36:16 186:3 245:5 247:9 257:18 screening 105:7 107:22 108:1 se 62:22 99:9 second 5:9 24:3 55:3,4 58:6 105:5 109:15 129:9 134:14 140:21 190:5 200:12 208:13,16 221:1 224:16 277:4,20 278:15 283:11,13 283:17 284:8,17 285:19 311:21 314:5 326:16 332:19 342:1 347:11,13 367:3 369:16 secondary 219:22 242:5 262:16 272:11,12 315:9 secondly 103:22
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similarly 38:12 68:16 296:7 simple 57:16 67:13 158:8 199:15 245:7 simpler 29:6 simply 26:1 78:22 81:3 95:12 103:8 177:15 199:21 222:10 232:15,21 Simponi 109:16 sincerely 42:9 Singapore 221:9 single 31:3 55:16 55:16 62:4,13 70:2,14 78:12 81:7 130:12 145:20,21 146:5 147:5 148:8,16 149:16 192:9 264:14 278:5,20 324:5 335:10 338:20 single-arm 77:16 78:2,8 79:7,15 82:3,7 85:13 sir 98:22 312:22 site 97:4 219:1 sites 18:13 situation 46:19 54:20 218:8,12 282:22 285:2,4,18 291:5 316:10 360:16 situations 49:18 154:22 281:6 284:12 six 204:10 205:20 sixfold 68:20 76:13 79:5 size 33:5 48:14 60:2 60:10,22 64:12 66:4,13 81:10 117:15 118:22 142:17 148:18 177:1 182:2 184:13 256:11 352:5 366:6 slide 45:12 51:21 64:15 67:21 68:11 77:7,12 78:7 79:14 83:1,1 92:18,19 94:20 102:19 104:17,18 117:6 121:1,22 132:12 139:1 150:7 166:9 251:4 286:8 290:16 291:12 311:20 315:7 349:15 slides 33:12 132:12 340:4 slight 308:16 slightly 233:12 slot 10:20 11:1 slots 9:15 small 49:19 107:17 131:15,16 139:4 157:21 175:17 184:4 185:5 214:6 214:14 235:11,13 237:19,20 243:18 245:14 274:2 277:8 279:16 288:17 296:7 297:12 298:8 299:3,7,19 329:21 360:8 361:18 363:10 365:10 368:3 smaller 29:6 66:15 79:22 137:11 225:1 snapshots 69:22 sold 23:10 sole 127:13 solely 39:16 solid 42:12 97:21 258:7 solution 31:7 158:10 338:19 solutions 35:14 115:16 solve 41:5 solved 315:3,4 somatropin 220:15 223:7 231:4 263:6 somebody 180:15 someway 273:8 somewhat 57:19 214:14 218:9 256:14 258:15 265:19 269:3 276:20 279:16 291:1 soon 52:7,8 sophisticated 92:22 106:4 224:7 235:3 332:16 sorry 200:5,5 238:17 351:17 sort 45:13 57:6 83:9 136:21 152:11 270:8 289:21 314:8 338:18 367:3,19 368:6 sorting 77:18 sought 188:19 sound 42:10 199:15 318:19 336:1 soundness 122:17 sounds 279:11 290:20 source 142:6 149:20 174:10 178:21 179:6 211:3 231:7,16 233:14 248:4 273:18 292:15 314:18 365:12 366:17 sources 20:10 200:16 201:11 248:10 South 221:8,9 space 33:15 109:7 109:11 158:5 159:13 243:10,15 254:4,7 366:19 speak 11:7,12 71:8 121:6 155:5 181:22 228:9 231:18 238:21 275:11,12 360:14 speaker 10:19,22 12:5,12 31:8,20 43:17 52:15 66:19 87:15 108:19 111:11 153:15 167:13,20 182:6 198:22 217:5 233:19 238:13 266:11 274:19 292:5 301:14 317:2 328:2 339:11 speakers 9:13,14 10:13 11:22 123:2 123:14 140:12 204:21 209:12 210:15 216:12 241:13 255:10 266:11 274:19 290:12 338:3 352:12 355:21 368:22 369:3 373:13,15 speaking 178:9 181:13 238:14 268:11 303:19 359:1,3 361:1 speaks 88:6 spec 202:14 Special 9:2 specialize 67:22 species 71:19 145:21 146:6,7 specific 28:6 129:2 148:14 151:10 169:15 183:2,14 193:14 220:14 221:14,15 222:15 226:3,8,20 236:8 242:15 250:7 257:15 285:4 293:11 294:22 295:3 318:9 325:10 340:7 351:21 360:16 366:11 370:9,11 371:18,22 372:13 specifically 61:16 75:8 127:2 137:14 179:13 189:6 220:10 245:7 275:10 293:15 305:13 308:18 specification 169:5 specifications 28:12 39:4 144:4 158:6,17 159:8 specifics 50:16 specs 94:7 spectrum 76:5 274:4 speed 169:19 365:15 spend 33:12 spending 75:20 spent 199:10 spirit 66:14 spite 112:17 spoke 232:10 spondylitis 89:1 sponsor 28:14 40:7 48:9,18 50:11 72:19 75:12 87:9 89:19 114:10,11 188:17 191:8 192:6 278:1,11,16 279:6 280:15,17 281:11,16 345:13 sponsors 21:2 42:15 49:5 66:1 134:17 165:22 223:11 224:1 249:1 319:1 330:10 333:7 Spring 1:14 St 199:11 stability 184:13 270:16 stabilization 298:10
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Page 1 U.S.

DEPARTMENT OF HEALTH AND HUMAN SERVICES (HHS) + + + + +

PAREXEL Consulting Bruce Babbit. . . . . . . . . . . . . .255

Plasma Protein Therapeutics Association Mary Gustafson. . . . . . . . . . . . .292

Biotechnology Industry Organization Sara Radcliffe. . . . . . . . . . . . .339

Page 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. BEHRMAN: P-R-O-C-E-E-D-I-N-G-S 8:32 a.m. Good morning to both

CDER Office of Regulatory Policy. DR. JENKINS: John Jenkins. I'm

Neal R. Gross & Co., Inc. 202-234-4433

Neal R. Gross & Co., Inc. 202-234-4433

Neal R. Gross & Co., Inc. 202-234-4433

Neal R. Gross & Co., Inc. 202-234-4433

concombinant medications are used.

Neal R. Gross & Co., Inc. 202-234-4433

Are there questions from the panel?

Dr. Jenkins. DR. JENKINS: presentation. Thanks for that

Yesterday, we heard about the

Neal R. Gross & Co., Inc. 202-234-4433

Neal R. Gross & Co., Inc. 202-234-4433

to be given to any of those potential differences in the indication. You know,

You mentioned a standard -- you

I think as the law envisions,

it should be avoided. MS. ESPOSITO: Dr. Siegel, in your

the red light and ask you one question.

Products that are the same can Products manufactured by the

A prime, they may be comparable.

James Roach from Momenta Pharmaceuticals. DR. ROACH: Good morning. I am

Neal R. Gross & Co., Inc. 202-234-4433

envision the concept of switching.

Page 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 We support this approach. As the

Neal R. Gross & Co., Inc. 202-234-4433

Are there questions from the panel?

Dr. Kozlowski. DR. KOZLOWSKI: Dr. Roach, one

Page 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 biosimilarity evaluation? DR. ROACH: Sure. It's a great

Page 45 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 approach it. DR. KOZLOWSKI: So, to follow up,

Page 48 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. ROACH: Yes. Well, I do think

Neal R. Gross & Co., Inc. 202-234-4433

familiar with that model.

example to provide evidence of comparability. DR. BEHRMAN: Just a quick It seems to

question on your slide eight.

I am the Vice President

Neal R. Gross & Co., Inc. 202-234-4433

Page 62 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 comments. DR. BEHRMAN: Thank you for your

get through a feasibility exercise.

week study or a 48-week study? taking you're doing to A to A.

24 weeks or you switch it 12 weeks? DR. REITSMA: The switch in this

Neal R. Gross & Co., Inc. 202-234-4433

Page 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 2001. tackling complex biologics. Our GCSF and

Page 76 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 any other patient in the world. With current

Questions from the panel?

Page 78 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 trial in 67 patients in India. It was a

DR. PATWARDHAN: DR. JENKINS:

Then what's the

Neal R. Gross & Co., Inc. 202-234-4433

Page 80 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 refer to? DR. PATWARDHAN: Yes, the dotted

So, you made a Is that

decision to do a single-arm trial. correct? DR. PATWARDHAN:

been prohibited from doing a -DR. PATWARDHAN: DR. BEHRMAN: No.

Neal R. Gross & Co., Inc. 202-234-4433

sensitivity to their product. DR. PATWARDHAN: Yes.

Neal R. Gross & Co., Inc. 202-234-4433

Page 84 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. KOZLOWSKI: And then, you

Neal R. Gross & Co., Inc. 202-234-4433

Page 86 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 DR. PATWARDHAN: Yes, so In fact, in