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GET THIS BOOK Amanda Wagner Gee, Erin Balogh, Margie Patlak, and Sharyl J. Nass, Rapporteurs;
National Cancer Policy Forum; Board on Health Care Services; Health and
Medicine Division; National Academies of Sciences, Engineering, and Medicine
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Project Staff
ERIN BALOGH, Senior Program Officer
MORGAN L. BONAME, Associate Program Officer
SYLARA MARIE CRUZ, Senior Program Assistant (until June 2017)
REBECCA A. ENGLISH, Program Officer
CYNDI TRANG, Research Assistant
AMANDA WAGNER GEE, Program Officer
ANNE B. CLAIBORNE, Director, Forum on Drug Discovery,
Development, and Translation
SHARYL J. NASS, Director, National Cancer Policy Forum and Board
on Health Care Services
vi
1 The National Academies of Sciences, Engineering, and Medicine’s forums and round-
tables do not issue, review, or approve individual documents. The responsibility for the pub-
lished Proceedings of a Workshop rests with the workshop rapporteurs and the institution.
vii
viii
ix
Reviewers
xi
xii REVIEWERS
In Memoriam
xiii
Acknowledgments
xv
Contents
INTRODUCTION 1
BACKGROUND ON DRUG DEVELOPMENT AND
REGULATORY REVIEW 3
Types of FDA Drug Development and Approval Pathways, 3
Ethical Requirements of Clinical Research, 11
EXPLORING THE CHALLENGES WITH TRADITIONAL
CLINICAL DRUG DEVELOPMENT 12
Inefficiencies and Long Development Timelines, 12
Generalizability of Clinical Trial Results to Clinical Practice, 14
Appropriate Use of Biomarkers and Surrogate Endpoints, 15
Finding the Right Dose, 16
NEW STRATEGIES IN ONCOLOGY DRUG DEVELOPMENT 18
Patient-Centered Drug Development, 18
Informed Consent, 21
Patient Risk, 22
Mechanism-Informed Cancer Drug Development, 23
Targeting Mutations in Breast Cancer, 24
Targeting the Microenvironment in Multiple Myeloma, 25
Functional Imaging, 27
New Endpoints, 29
xvii
xviii CONTENTS
Modeling, 31
Process Modeling the Drug Development Pathway, 31
Dosage Modeling, 32
Modeling Benefits and Risks, 34
Development and Use of Biomarkers in Cancer Clinical Trials, 35
Innovative Clinical Trial Designs, 41
Adaptive Designs, 42
Seamless (Continuous) Clinical Trial Designs, 43
Master Protocols, 50
Clinical Trials with Common Control Arms, 59
Issues to Consider with Innovative Clinical Trial Designs, 60
Leveraging Real-World Evidence from Clinical Practice, 66
Pragmatic Trials, 69
Using EHR Data in Studies, 70
When to Use Real-World Evidence, 72
Standardization, 75
Guidance on Standardizing and Using Real-World Evidence, 76
Patient Privacy, 77
Expanding Clinical Trial Eligibility, 77
Collaboration, 81
POTENTIAL POLICY OPPORTUNITIES 85
Innovations at CMS, 85
FDA Oncology Center of Excellence, 85
Expanded Access, 86
Cancer Moonshot, 88
EXAMPLES OF INNOVATIONS IN CANCER DRUG
DEVELOPMENT 91
Development of Crizotinib, 92
Development of Avelumab, 94
Development of Pembrolizumab, 95
Development of Vemurafenib, 96
T790M EGFR Inhibitors, 98
WORKSHOP WRAP-UP 101
REFERENCES 104
BOXES
1 Many Suggestions Were Made by Individual Workshop Participants
to Improve Cancer Drug Development, 4
2 21st Century Cures Act, 19
3 Questions Regarding the Design of Large, Seamless First-in-Human
Cancer Clinical Trials, 46
4 Discussions Regarding Dose Challenges with Seamless Trials, 47
5 Lung Cancer Master Protocol Trial, 51
6 Precision Promise, 54
7 National Cancer Institute-Molecular Analysis for Therapy Choice
(NCI-MATCH) Trial, 56
8 Targeted Agent Profiling Utilization Registry Study, 80
9 A Contrasting Development Story of Rociletinib, a T790M EGFR
Inhibitor, 99
10 Potential Strategies to Improve the Drug Development Paradigm in
Oncology Summarized by Richard Schilsky, 104
xix
FIGURES
1 Drug discovery and development timeline, 13
2 Complete remission of metastatic prostate cancer in a 71-year-old
man who received four cycles of 177Lu-PSMA-I&T (177Lu labeled
prostate-specific membrane antigen ligand for imaging and therapy)
as fifth line therapy, 29
3 Response surface design of predicted median human epidermal
growth factor receptor 2 (HER2)-specific antibody responses as a
function of doxorubicin (DOX) and cyclophosphamide (CY) dose
combinations to produce the highest vaccine response in breast
cancer, 34
4 Analysis of the benefits and risks for non-small cell lung cancer
therapies, 36
5 Designs to evaluate biomarkers/subgroups, 37
6 Traditional and seamless oncology drug development paradigms, 45
7 The KEYNOTE-001 dose expansion cohorts in solid tumors,
melanoma, and non-small cell lung cancer, 57
8 The Pragmatic-Explanatory Continuum Indicator Summary 2
(PRECIS-2) wheel, 70
9 Utilization of cancer drugs outpaces trial evidence contributing to the
evidence gap, 73
10 The crizotinib drug development timeline from 2006 to 2011, 93
11 Key milestones in the discovery and development of osimertinib, 100
TABLES
1 Traditional Phases of Drug Development, 9
2 Types of Expedited Drug Development Pathways for Serious
Conditions Designated by the Food and Drug Administration
(FDA), 10
3 Statistical Power to Detect Different Response Rates in Biomarker-
Defined Subgroups in a Single-Arm Study of 100 Patients, 38
xxi
Proceedings of a Workshop
INTRODUCTION1
Advances in cancer research have led to an improved understanding of
the molecular mechanisms underpinning the development of cancer and
how the immune system responds to cancer. This influx of research has led
to an increasing number and variety of therapies in the drug development
pipeline, including targeted therapies and associated biomarker2 tests that
can select which patients are most likely to respond, and immunotherapies
that harness the body’s immune system to destroy cancer cells. Compared
with standard chemotherapies, these new cancer therapies may demonstrate
evidence of benefit at an earlier stage of development. However, there
is a concern that the traditional processes for cancer drug development,
evaluation, and regulatory approval could impede or delay the use of these
promising cancer treatments in clinical practice. This has led to a number
1 The planning committee’s role was limited to planning the workshop. The Proceedings
of a Workshop was prepared by the rapporteurs as a factual account of what occurred at the
workshop. Statements, recommendations, and opinions expressed are those of individual
presenters and participants and are not necessarily endorsed or verified by the National
Academies of Sciences, Engineering, and Medicine. They should not be construed as reflect-
ing any group consensus.
2 In this proceedings, a biomarker is defined as “a characteristic that is objectively measured
3 Although
some workshop speakers noted that improving the efficiency of drug develop-
ment could potentially result in lower drug development costs, particularly as therapies are
targeted to smaller patient populations, a detailed analysis of the cost of drug development
was beyond the scope of this workshop.
PROCEEDINGS OF A WORKSHOP 3
4 See http://www.nationalacademies.org/hmd/Activities/Disease/NCPF/2016-DEC-12.
BOX 1
Many Suggestions Were Made by Individual Workshop
Participants to Improve Cancer Drug Development
PROCEEDINGS OF A WORKSHOP 5
continued
BOX 1 Continued
PROCEEDINGS OF A WORKSHOP 7
• E
nsure the independence of DSMBs to assess the data and provide
oversight for a seamless trial design. (Rockhold)
• U
se central Institutional Review Boards (IRBs) for oversight of
seamless trials, with appropriate methodological expertise and the
ability to rapidly review protocol modifications in coordination with
DSMBs, patients, and clinicians. (Flaherty, Joffe)
• A
ddress gaps in knowledge about seamless and adaptive trial
designs among existing members of DSMBs and IRBs and ensure
an adequate workforce pipeline by recruiting the involvement of new
participants in DSMBs and IRBs, especially statisticians with clinical
trial expertise. (Piantadosi, Rockhold, Rothenberg)
• U
se integrated regulatory approval processes, such as the newly
instituted parallel approval process of FDA and the Centers for
Medicare & Medicaid Services for devices and diagnostics or FDA’s
Oncology Center of Excellence for review of combination products.
(Kline, Woodcock)
continued
BOX 1 Continued
PROCEEDINGS OF A WORKSHOP 9
In line with the expedited pathways for drug evaluation and approval,
there is also interest in more flexible and efficient mechanisms for cancer
drug development, Theoret said (see section titled New Strategies in
Oncology Drug Development). Staff from FDA’s OHOP recently authored
an article outlining an evolving drug development paradigm, indicating
their willingness to consider alternatives to the traditional phased drug
development process (Prowell et al., 2016; Theoret et al., 2015), said Janet
Woodcock, director of CDER at FDA.
“Based on better scientific understanding of the biological under-
pinnings of cancer and the host response to cancer, some investigational
products are demonstrating a very large magnitude of antitumor activity
very early on in drug development. These unprecedented response rates
have brought us into this new era of oncology drug development; the
lines between distinct trial phases are becoming blurred, and a single trial
may serve as the entire clinical drug development program supporting at
PROCEEDINGS OF A WORKSHOP 11
least an initial FDA approval,” Theoret said. He added that “discrete drug
development objectives might not be evaluated in [sequential] stand-alone
trials, but will be evaluated seamlessly in cohorts within an existing trial in
some cases, in treatment refractory settings with clear, high unmet medical
need.” For example, a single-arm trial demonstrating a treatment effect on
a surrogate endpoint may provide the preliminary and primary evidence
for an accelerated approval, while confirmatory trials are ongoing, he said.
that oversees clinical research. IRBs approve the clinical trial protocols, which describe the
type of people who may participate in the clinical trial, the schedule of tests and procedures,
the medications and dosages to be studied, the length of the study, the study’s objectives, and
other details. IRBs make sure that the study is acceptable, that participants have given con-
sent and are fully informed of the risks, and that researchers take appropriate steps to protect
patients from harm (FDA, 2014a).
6 The Declaration of Helsinki outlines ethical principles for conduct of human subjects
research, written by the World Medicine Association for the medical community (WMA,
2017).
or immediately stop the study. Rockhold added that data and safety moni-
toring boards (DSMBs)7 serve this purpose and are integral to the ethical
conduct of clinical trials. He noted that at certain intervals during the trial,
the DSMB integrates interim data and determines if the benefit–risk ratio
to continuing the trial is still favorable, and if there is still clinical equipoise,
which he defined as a state of genuine uncertainty about the advantages or
disadvantages of each therapeutic arm in a clinical trial.
PROCEEDINGS OF A WORKSHOP 15
and collaborations at Pfizer Inc. This is because clinical trials often enroll
patients who are healthier than many patients in clinical practice settings,
who frequently have multiple comorbidities (IOM, 2013). She noted that
the problem is also exacerbated by low participation rates in trials and a lack
of diversity in cancer clinical trial enrollments (Chen et al., 2014; IOM,
2010). Therefore, payers often require additional testing and confirmation
of clinical trial results in more representative populations in order to make
coverage decisions, she said.
PROCEEDINGS OF A WORKSHOP 17
8 Maximum tolerated dose is “the highest dose of a drug or treatment that does not cause
unacceptable side effects. The maximum tolerated dose is determined in clinical trials by
testing increasing doses on different groups of people until the highest dose with accept-
able side effects is found.” See https://www.cancer.gov/publications/dictionaries/cancer-
terms?cdrid=546597 (accessed May 18, 2017).
PROCEEDINGS OF A WORKSHOP 19
BOX 2
21st Century Cures Acta
Institute.9 “Patients want efficacy, but they also want quality of life,” Sigal
stressed, suggesting that drug development incorporate patient-reported
outcomes as a means to assess quality of life. Woodcock agreed that using
quality-of-life endpoints that consider patient perspectives would improve
drug development. Ratain agreed, noting that in addition to assessing
tumor response in clinical trials, there should be assessment of meaningful
symptom control or relief through patient-reported outcomes.
Sigal also stressed the importance of real-world clinical data to patients
and clinicians when making decisions about treatments that have similar
efficacy, but may have different impacts on quality of life. These impacts
may be detected by analyzing real-world data from clinical practice, such
as patient-reported outcomes in electronic health records (EHRs). Lynn
Matrisian, chief research officer of the Pancreatic Cancer Action Network,
agreed, noting that “real-world evidence is something patients really care
about.” Koehler added that real-world evidence can facilitate patient-
centered drug development by
PROCEEDINGS OF A WORKSHOP 21
School, pointed out that many health apps do not have privacy policies and
patients are not aware of this. “We . . . need to use health apps because they
are the future, but we have to think about some of these privacy issues,”
Brown said.
Informed Consent
Brown said that ethicists have differing opinions on whether and how
patient consent should be obtained for the use of their data for research
purposes. He noted that some ethicists view it acceptable to use some
patient data in research without consent when there is minimal risk to the
patient or in cases of public health activities. Some ethicists do not believe
that any patient data should be used for research purposes without express
patient consent, Brown said. Other ethicists propose that the default option
should be to allow patient data to be used in research, but to offer patients
the opportunity to “opt out” of using their data in studies. “There is debate
about this in the ethical field and we need to move forward, come to con-
sensus, and come up with a solution,” he said.
Brown noted that obtaining informed consent from patients for studies
that use data collected from EHRs and other sources of real-world data can
be challenging. He suggested it might be feasible to have patients agree
that if they enter a hospital or other medical facility that uses EHRs, they
automatically agree to share their EHR data for research purposes. “That
may be needed for a pragmatic, clustered randomized clinical trial,” he said.
He noted that garnering such consent is currently difficult to accomplish
because of current regulations that restrict access to patient information for
research, such as the Privacy Rule promulgated under the Health Insurance
Portability and Accountability Act (HIPAA) (IOM, 2009).
Brown suggested using broad consent forms for research on patient
data in EHRs, similar to those used for patient consent for future research
on patients’ biospecimens. He said that many patients do not have concerns
with such broad consent forms, with the exception of a minority of patients
who have expressed the concern that others will profit from the use of their
biospecimens in research (Grady et al., 2015).
John Burch, a member of the Mid-America Angels Capital Investment
Network, suggested using patient-centered repositories of patient data. “Not
the clinician’s EHR, but the patient’s own EHR,” he stressed. A patient could
put his or her data into the repository, own and control the use of the data,
and could make the data available for research, he said. Pentz noted that this
could serve the patient well, and there would be an ethical advantage to hav-
ing patient-centered repositories of data. “From an ethical standpoint, it is
the patient’s information and they would be empowered to use and control
it,” she said.
Patient Risk
Joffe noted that there is increasing pressure to accelerate cancer drug
development in order to provide patients who have life-threatening diseases
with earlier access to promising new therapies. But he said an analysis of
more than 100 Phase I cancer clinical trials found that faster approaches
to escalating doses in studies was linked to increased toxicity rates, without
improving efficacy (Koyfman et al., 2007).10 “In this case, it was hard to
make the argument that these accelerated designs were better for patients
than traditional designs,” Joffe said.
Joffe added that reports of life-threatening autoimmune reactions to
immunotherapies have recently emerged, many of which did not become
apparent until these agents entered the market after accelerated FDA
approval.11 He cautioned that “as we move more quickly and have smaller
numbers of patients involved in our drug development programs, we are
going to be much more reliant on the postmarketing period to get a sense
of what the safety data are.” He noted that the 21st Century Cures Act has
provisions aimed at speeding FDA approval of new drugs, but cautioned
that there are ethical concerns about whether accelerating cancer drug
development will lower the bar for patient safety (Kaplan, 2016). Brown
suggested that the goal should not simply be acceleration of drug develop-
ment, but rather optimizing data collection and getting the right data at
the right time. “We have to get the right data for the right patient without
putting them at undue risk,” he said.
Joffe stressed that the push for speed and accelerated approvals “has
trade-offs we can decide to make, and by ‘we’ I do not just mean the clini-
cians, investigators, and statisticians, but also the patients and the broader
community. We can decide to accept those increased risks to get that
speed.”
10 The study results may not be applicable for newer cancer therapies, such as targeted
therapies and immunotherapies.
11 See https://www.nytimes.com/2016/12/03/health/immunotherapy-cancer.html
PROCEEDINGS OF A WORKSHOP 23
12 See https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm454678.
htm (accessed May 21, 2017).
13 Letrozole is an aromatase inhibitor that inhibits the growth of estrogen-dependent breast
PROCEEDINGS OF A WORKSHOP 25
combination with letrozole. This has since been confirmed in a Phase III
study (Finn et al., 2016).
During the Phase II study, Finn recalled the deliberation by the spon-
soring team to determine which patients to enroll. They were concerned
that they might not see a significant effect if all patients presenting with
ER-positive cancer were enrolled. At the same time, they thought they
might miss a treatment benefit if they selectively enrolled patients with
mutations affecting proteins that interact with CDKs and might be driving
cancer growth. Thus, they included two sequential cohorts in PALOMA-1/
TRIO 18: the first cohort included patients with ER-positive/HER2-
negative breast cancer, while the second cohort included only patients with
ER-positive/HER2-negative breast cancer who also had amplification of
cyclin D1, loss of p16, or both.
Finn pointed out that if they had limited patient selection in initial
trials of palbociclib to only patients who had these additional biomarkers,
the study would have generated positive outcomes, “but we would
have missed the other 80 percent of patients who might benefit from a
compound like this.” These deliberations about defining the right study
population is relevant to the design of future trials, and is reflective of the
choices that sponsors must make in drug development, said Finn and Mace
Rothenberg, chief development officer of oncology at Pfizer Inc.
Finn noted that since palbociclib’s approval, several other CDK inhibi-
tors have progressed from the laboratory to Phase III studies, including
ribociclib (Hortobagyi et al., 2016).14 “The greatest advances in patient
outcomes have come from integrating biology into clinical practice and
critical use of preclinical models can guide that process. They can help us
design hypothesis-driven Phase I/Phase II studies,” Finn concluded.
has approved 18 new drugs for multiple myeloma, and patients with mul-
tiple myeloma are living three to four times as long as they did previously,
Anderson reported. “It is fair to say that there are some patients now who
end up having a normal life span,” he said.
In traditional drug development, academic laboratories complete basic
cancer biology research that can suggest new pathways and mechanisms
of action for how cancer grows and spreads, Anderson explained. Industry
then discovers new agents that act on these pathways and develops these
agents further with preclinical testing before working with academia to
conduct clinical trials. However, the development of innovative drugs for
multiple myeloma has instead used a more efficient, collaborative approach,
with academia conducting more drug discovery and validation work along
with input from patients and industry. This has resulted in quicker transla-
tion of treatments to clinical practice, Anderson said.
For example, Anderson’s lab showed that lenaliodmide, a derivative of
thalidomide, affects the tumor microenvironment primarily by stimulating
the host’s immune response against the cancer, but also by blocking adhe-
sion of cells and inhibiting the generation of blood vessels. Research also
demonstrated that triggering protein degradation mediated thalidomide’s
effects on tumor cells. These findings fostered the development of additional
drugs targeting protein degradation in different areas of the cell (Krönke et
al., 2014; Lu et al., 2014; Winter et al., 2015).
Conversely, by focusing on the importance of preventing protein
degradation in order to destroy cancer cells using proteasome inhibitor
bortezomib, investigators were able to devise drug combinations that could
inhibit that protein degradation in multiple ways and achieve higher efficacy
in some patients. Anderson said that such combination approaches with
different classes of drugs that have different mechanisms of action have
been quite effective in multiple myeloma. “Combinations of novel agents,
predicated [by] preclinical science, have achieved unprecedented results,”
said Anderson. For example, when bortezomib was combined with histone
deacetylase (HDAC) inhibitors to block both proteasomal and aggresomal
protein degradation, dramatic suppression of multiple myeloma tumor cell
growth occurred (Catley et al., 2006). This finding led to a Phase III trial
testing the combination of an HDAC inhibitor with bortezomib, and the
first FDA-approved HDAC inhibitor, panobinostat (Richardson et al.,
2013; San-Miguel et al., 2014).
Anderson said that although immunotherapy directed at blocking the
checkpoint inhibitor programmed death-1 (PD-1) has not been effective
PROCEEDINGS OF A WORKSHOP 27
Functional Imaging
Weber discussed the use of functional imaging as a diagnostic tool to
assess tumor response to treatments. He reported on the preclinical and
clinical uses of functional imaging to assess tumor response to therapeutic
agents, including assessment of tumor characteristics (e.g., blood perfusion
and glucose metabolism) through magnetic resonance imaging (MRI) and
positron emission tomography (PET). Weber stressed that functional imag-
ing can overcome many of the limitations of traditional imaging approaches
and RECIST criteria. Unlike traditional imaging, functional imaging can
distinguish between scar tissue and viable tumor tissue; detect tumors in
bone and other areas that are difficult to image with computed t omography
(CT) scans or traditional MRI; quantify relevant physiological and bio-
chemical changes; and show tumor responses more quickly, Weber said
(Johnson et al., 2016). In addition, PET also can be used to assess whether
an agent has hit its target, he added.
Because of the widespread use of PET-CTs for tumor staging, imag-
ing technologies and the infrastructure to make imaging agents are also
available throughout the country, Weber added (Buck et al., 2010). Weber
noted that because PET infrastructure is in place at most institutions, the
technology is primed for application in drug development. “We now have
the opportunity to go beyond glucose imaging [with fluorodeoxyglucose]
and look into molecules that are of interest in drug development,” he said.
Traditional imaging is generally done infrequently (e.g., before therapy
begins and then several months later), leading to a loss of information about
the tumor status and changes in growth between those two widely spaced
time points. By contrast, innovative PET imaging can document details
during that interim time period, such as the location of the therapy and
its concentration at tumor sites, and whether it interacts with the intended
PROCEEDINGS OF A WORKSHOP 29
patients with metastatic castration resistant prostate cancer, 382-391, Copyright 2016,
with permission from Elsevier and the American Urological Association.
of results that can accurately inform clinical trial designs and patient care.
Weber noted that such criteria have been developed for PET imaging of
tumors—PET Response Criteria in Solid Tumors (PERCIST)—and could
be used in clinical trials (Wahl et al., 2009).
New Endpoints
Several workshop participants discussed the need to develop new end-
points to assess therapeutic responses more quickly, compared with current
endpoints used in cancer clinical trials, such as progression-free and overall
survival. For example, Anderson said that patients with multiple myeloma
may have a progression-free survival rate of 7 to 10 years when they are
PROCEEDINGS OF A WORKSHOP 31
Modeling
Many workshop participants discussed the concept of modeling in a
variety of contexts throughout the workshop. Several participants discussed
how process modeling can help researchers predict the optimal drug devel-
opment pathway for a therapy, as well as dosage modeling to determine
optimal dosing for a therapy or combinations of therapies. In addition,
DSMBs and FDA can use benefit–risk modeling to better ascertain the
potential benefits and risks of an investigational new drug when making
decisions about whether clinical trials should proceed, and whether it
should receive FDA approval for use in clinical practice.
Finn cautioned that models are subject to inherent biases and need to
be carefully constructed. For example, he pointed out that the development
of EGFR inhibitors included preclinical models that used tumor cell lines
that were highly dependent on epidermal growth factor. Finn said that
these cell lines were not representative of the range of tumors seen in vivo,
and that the EGFR pathway is much more complex than initial modeling
suggested.
15 See http://clincancerres.aacrjournals.org/content/early/2017/04/26/1078-0432.CCR-
Dosage Modeling
Piantadosi said that the best dosing designs are guided by mathematical
dosage modeling, especially for combination therapies. “[Dosage] models
are essential because they embody knowledge from outside the experimental
realm, enabling incorporation of key ancillary information into dose find-
ing,” such as pharmacokinetic data or patient characteristics, he said.
Piantadosi suggested that dosage modeling can be used to help titrate
a therapy’s dose to meet a prespecified outcome. He also suggested that
researchers use dosage modeling to ascertain the range of active and tolera-
ble doses, and to define the minimum active dose rather than the maximum
tolerated dose. “Our old clinical designs were not defective, but were highly
optimized for the types of questions we had for agents in development then.
New questions require new designs,” Piantadosi said.
Piantadosi noted that optimizing dosing for combination therapies is
particularly complex because it requires determination of dose–response
curves for multiple agents (Tighiouart et al., 2014, 2017). He added that
this can require approximately four times more study participants compared
to a standard dose escalation trials for a single agent. “Our conventional
dose escalation approaches are unlikely to adequately solve the problem,”
he said, and added that investigating interactions between or among drugs
in combination therapies is expensive, so investigators need to know in
advance whether interactions are expected and design their clinical trials
accordingly. “With drug combinations, we will need larger designs and we
have no alternative but to pay the price when those drug interactions are
clinically important,” he said.
He noted that there is no standard dosage modeling approach for
such dosing, and gave examples of several possibilities. One approach,
PROCEEDINGS OF A WORKSHOP 33
PROCEEDINGS OF A WORKSHOP 35
Joffe said that assessing the risks of harm and potential benefits of a drug
agent has often relied on the clinical judgment of experts on the DSMB,
but benefit–risk modeling during an ongoing trial could help the DSMBs
integrate the vast amount of data they need to review and lend more rigor
to their discussions. He noted that researchers have made recent advances in
quantifying and modeling predictable harms and benefits in clinical trials,
and he suggested that leveraging these advances would help to foster more
rigorous and reproducible decision making within DSMBs. He added that
new methods to prevent or treat a harm, or to identify patients who are not
at risk of developing severe side effects from a treatment, could be incor-
porated in these benefit–risk models with updated appropriate weighting.
Raju noted that FDA weighs risks and benefits when assessing whether
to approve a therapy, but these assessments traditionally have been made
from a qualitative review of the evidence. He suggested that FDA use a
more quantitative approach by estimating the impact a therapy will have
on both the length and quality of life for a patient (Raju et al., 2016a).
For example, he performed a benefit–risk analysis on 22 FDA decisions
for drugs used to treat non-small cell lung cancer (Raju et al., 2016b) (see
Figure 4). In this analysis, he calculated the estimated benefit–hazard ratio
for each therapy’s primary endpoint, the estimated benefit of each therapy,
and total risk exposure compared to the control arm, as well as FDA’s deci-
sion for each therapy. He found that the analyses of estimated risks and
benefits were able to distinguish among the therapies that had been FDA
approved from the therapies that had been approved through the acceler-
ated approval pathway but were later withdrawn from the market. Raju has
conducted those analyses in nine other cancers, but noted that the quality of
data for adverse event reporting limits the benefit–risk model. He said that
the benefit of conducting these analyses is that it provides the rationale for
FDA decision making, and added that this type of benefit–risk modeling
could also inform earlier development decisions and trial designs, as well as
at later stages when more data have been collected.
FIGURE 4 Analysis of the benefits and risks for non-small cell lung cancer therapies.
(a): First line therapy. (b): Non first line therapy.
NOTE: Afa = afatinib; Ale = alectinib; ALK+ = anaplastic lymphoma kinase-positive;
Bev = bevacizumab; Cer = ceritinib; Cet = cetuximab; Cri = crizotinib; EGFR = epi-
dermal growth factor receptor; Erl = erlotinib; Gef = gefitinib; Nec = necitumumab;
Niv = nivolumab; NSq = nonsquamous; ORR = overall response rate; OS = overall sur-
vival; Osi = osimertinib; PD-L = programmed death-ligand; Pemb = pembrolizumab;
PFS = progression-free survival; Ram = ramucirumab; Sq = squamous.
SOURCES: Raju presentation, December 13, 2016; Raju et al., 2016b.
PROCEEDINGS OF A WORKSHOP 37
Subgroup Subgroup
Split type I error?
Entire Study
Entire Study
Population
Population
Targeted or Master Protocol Design
PROCEEDINGS OF A WORKSHOP 39
16 See https://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/index.
PROCEEDINGS OF A WORKSHOP 41
ferent results than early-stage tumors. “We really do have to move beyond
CAP and CLIA, and there are many companies selling diagnostic tests from
CLIA-certified laboratories that have little or no clinical validity, and payers
are paying for them,” Ratain said.
Flaherty described the efforts that were undertaken in advance of
the National Cancer Institute-Molecular Analysis for Therapy Choice
(NCI-MATCH) clinical trial to ensure validation and standardization of
the test used to assess patients’ biospecimens for genomics biomarkers at
four different institutions (see section on Innovative Clinical Trial Designs).
This entailed using the same testing platform in each laboratory and hav-
ing all the laboratories involved undergo proficiency testing using the same
reference samples, with oversight by the FDA Center for Devices and
Radiological Health, Flaherty said. Near the end of the NCI-MATCH trial,
two for-profit laboratories underwent the same proficiency testing so they
could also be involved with the study. The end result was a high degree of
concordance across these academic and commercial laboratories using a
platform that tested hundreds of genes, he said.
Adaptive Designs
Rajeshwari Sridhara, director of the Division of Biometrics V at CDER,
reported on the different types of adaptive study designs that investigators
have used to assess clinical tests. Adaptive studies can be broadly grouped
into two main categories. One category—sequential designs—involves
analyzing and reviewing the data at periodic prespecified time points in a
study and deciding whether to continue the trial based on the results. At
these points, investigators can also decide to amend the study to increase the
sample size or to narrow the clinical trial to a subset of patients. The second
category—Bayesian design—uses probability theory to assess the likelihood
that the accruing trial data suggest a trend that require adjustments to the
study protocol.
A subcategory of adaptive study designs is an adaptive enrichment pro-
tocol that uses biomarkers to predict response to a therapy. With adaptive
enrichment trials, all patients are tested for a potential predictive biomarker
when they are treated with a therapeutic agent or standard of care. If an
interim analysis finds that the biomarker predicts response to treatment, then
the biomarker is used to stratify patients—those who are biomarker neg-
ative are no longer accrued into the trial, while those who are biomarker posi-
tive are randomized to the therapeutic agent or standard of care.
Sridhara stressed that an adaptive design by definition enables pre-
planned study design modifications based on blinded or unblinded interim
results. Adaptive designs can be used for exploratory or confirmatory
studies. With exploratory adaptive studies, “you can explore as much as you
want without adjusting for multiple looks [or] multiple adaptations to gen-
erate hypotheses to be further tested. There is a lot of leeway here,” Sridhara
said. By contrast, she said that confirmatory adaptive studies require careful
planning to specify decision rules for each trial adaptation and to ensure
that they are statistically valid, Sridhara reported. “We are not saying you
cannot have many adaptations, but you need to prespecify your threshold
when you are thinking of this adaptation,” she said, emphasizing that the
requirement is for specifying the thresholds that would alter the course of
the treatment, rather than specifying the expected change. Piantadosi noted
that the rationale for prespecifying whenever possible is to reduce bias and
statistical errors in subsequent statistical analyses of the trial data.
Richard Schilsky, senior vice president and chief medical officer of the
American Society of Clinical Oncology (ASCO), noted that having prespec-
ified adaptive designs can be challenging or counterintuitive because “part
PROCEEDINGS OF A WORKSHOP 43
of the issue of being able to adapt your trial design might be in response to
information that you cannot foresee or anticipate and only become aware
of it during the course of the trial.”
Finn added that the need to prespecify depends on the context of the
study. If a randomized Phase II trial that is intended to collect data that
can be used to mitigate risk in a subsequent Phase III trial has a strong
hypothesis, scientific rationale, and trend, it would be acceptable to not
preregister adaptations, he said. David Feltquate, head of early clinical
development in oncology at Bristol-Myers Squibb, noted that analysis of
results from single-arm studies often preempts design changes to ongoing
randomized studies, such as a change in endpoint or study size, illustrating
the practice of making an adaptation that is not prespecified.
Keegan said that prespecifying adaptations can increase efficiency
and enable more appropriate decision making. She said that evaluating
results at specific time points to assess whether the hypothesis needs to be
altered is more appropriate than an open-ended enrollment without pre-
specified cohort sizes and evaluation time points. For example, an early
prespecified assessment of the use of response rate as an endpoint could
indicate that progression-free survival may be a more reliable endpoint, and
in an adaptive trial this change can be made, she said.
Rockhold suggested using what is known about the mechanism of
action of agents to model and predict potential results that would require
modification of a study design. If predictive modeling is not performed,
investigators respond reactively to unexpected results because no response
procedure has been defined, he said.
Feltquate noted that although adaptive designs aim to make trials more
efficient, the embedded feedback loops in which new data are analyzed and
findings are incorporated into study amendments can be time consuming.
“Our experience is that it adds an enormous amount of time onto the learn-
ing that goes on, unless you choose a surrogate endpoint, such as functional
imaging, that can give you a much quicker answer. Otherwise, I do not see
adaptive trials as having a lot of utility, but instead they have an opportunity
to provide false negative signals, causing us to stop something too early in
the testing process,” he said.
PROCEEDINGS OF A WORKSHOP 45
FIGURE 6 (A) Traditional and (B) seamless oncology drug development paradigms.
SOURCES: Theoret presentation, December 13, 2016; Reprinted from Clinical Cancer
Research, © 2015, 21(20):4545-4551, Theoret, M. R., L. H. Pai-Scherf, M. K. Chuk,
T. M. Prowell, S. Balasubramaniam, T. Kim, G. Kim, P. G. Kluetz, P. Keegan, and R.
Pazdur, Expansion cohorts in first-in-human solid tumor oncology trials, with permis-
sion from the American Association for Cancer Research.
BOX 3
Questions Regarding the Design of Large, Seamless
First-in-Human Cancer Clinical Trials
assess if greater efficacy is achieved with doses greater than the minimal
effective dose (see Box 4 for more information on the challenges of dosing
in seamless clinical trials).
The beta phase would include a randomized dose-ranging design that
would assign patients to doses under consideration for labeling, based on
the results of the alpha phase. The gamma phase, similar to the traditional
Phase III trial, would confirm acceptable safety and efficacy at the selected
dose or doses by using an adaptive randomized trial to confirm the results
of the beta phase. Ideally, Ratain said that the gamma phase would have an
80 percent chance of leading to a drug approval.
He said that all three phases of development could theoretically fall
under the umbrella of a single protocol. “It can all be done in a continuous
paradigm,” Ratain said, with the next steps only implemented after the
PROCEEDINGS OF A WORKSHOP 47
BOX 4
Discussions Regarding Dose
Challenges with Seamless Trials
continued
BOX 4 Continued
protocol is amended based on what has been learned. This protocol would
be reviewed like a traditional protocol, with the understanding that it will
be amended as the data accrue and before subsequent parts of the study are
activated. “It is all done as a single, efficient but phased trial,” Ratain said.
“This way oncology drug development can be efficient without sacrificing
scientific rigor.”
There also has to be clarity on how information and responsibilities are
handed off from investigators from one phase to the other, Ratain added.
“Operationally in industry, the same group may not be responsible for
PROCEEDINGS OF A WORKSHOP 49
preclinical, early clinical, late clinical, registrational, and life cycle develop-
ment for a single medicine.” We will have to coordinate these efforts across
groups, he said. Rothenberg agreed, saying, “It really is incumbent upon us
to make sure we see things from end to end and coordinate.” He suggested
reaching across organizational silos to ensure coordination. “We can try
and have more formal and extensive discussions to make sure drugs we are
getting from the early development laboratories are drugs that are going to
be meaningful and successful in the clinic,” Rothenberg said.
Schilsky asked how much confirming needs to be done before a drug
Master Protocols
Sridhara said that master protocols enable the conduct of complex
clinical trials because multiple diseases, treatments, and/or biomarkers
can be assessed in one overarching protocol. “With master protocols, you
are trying to answer multiple questions, or you have multiple objectives,”
Sridhara said. For example, investigators may use a master protocol to test
one treatment on multiple types of cancer, or to test multiple treatments
on a single type of cancer, or even to test multiple types of treatments on
multiple types of cancer.
Many master protocols are seamless clinical trials with adaptive
design features to enable investigators to set up evolving treatment arms of
a single trial protocol. With a master protocol, tested agents can be more
rapidly advanced for further study if they are showing good responses or
can be discarded if they do not demonstrate efficacy and replaced with
new agents that undergo testing, without stopping the entire protocol,
Woodcock said.
Master protocols usually have a centralized governance structure,
including central IRBs, DSMBs, independent review committees, and data
and biospecimens repositories, said Sridhara.
Examples of trials that use a master protocol design include the Lung
Cancer Master Protocol (Lung-MAP) (see Box 5), Precision Promise (see
Box 6), the NCI-MATCH trial (see Box 7), as well as the BATTLE-1
(Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer
Elimination) trial (Kim et al., 2011) and the I-SPY TRIAL (Investigation
of Serial Studies to Predict Your Therapeutic Response with Imaging and
Molecular Analysis) for breast cancer (I-SPY, 2017).
Sridhara described the KEYNOTE-001 trial as a Phase I dose-
PROCEEDINGS OF A WORKSHOP 51
BOX 5
Lung Cancer Master Protocol Trial
continued
BOX 5 Continued
histology provided the tumor is positive for the biomarker being tested.
These proposed modifications would add screening for immunotherapy
combinations with some exploratory biomarker testing.
Redman said that the Lung-MAP protocol has been described as
having several advantages (Herbst et al., 2015; Lung-MAP Clinical Tri-
als, 2017), including
BOX 6
Precision Promise
BOX 7
National Cancer Institute-Molecular Analysis
for Therapy Choice (NCI-MATCH) Trial
FIGURE 7 The KEYNOTE-001 dose expansion cohorts in solid tumors, melanoma, and non-small cell lung cancer.
NOTE: IPI = ipilimumab; NSCLC = non-small cell lung cancer; PD-L1 = programmed death-ligand 1; Q2W = once every 2 weeks; Q3W = once
PROCEEDINGS OF A WORKSHOP 59
17 A case report form is “a printed, optical, or electronic document designed to record all
of the protocol-required information to be reported to the sponsor on each trial subject.” See
https://www.fda.gov/downloads/drugs/guidances/ucm073122.pdf (accessed May 22, 2017).
PROCEEDINGS OF A WORKSHOP 61
talking about something that has a small-to-moderate effect size, then I think
there is a very high risk of mistaken decisions based upon seamless designs.”
He noted that there will be increasing pressure to use seamless trials when
there are smaller and more moderate effect sizes, but stressed that “the designs
and decisions that are made along the way really have to be contingent on the
effect sizes that emerge at various stages of the pathway.” He cautioned that a
plan for making decisions about whether a seamless trial progresses needs to
be deliberate in order to ensure that ethical requirements are met to protect
patients participating in the trials and to make the safest decisions possible
for future recipients of the treatments being tested.
Decision making and oversight Seamless clinical trials raise new issues
related to decision making processes, including who should be making
the decision to advance clinical testing and what stakeholder input should
be solicited. Joffe pointed out that with rapid protocol modifications and
seamless study designs, it is challenging for IRBs to quickly assess the risks
and benefits to patients in the trials. “We are going to need highly special-
ized and nimble central IRBs to make this a practicality,” he said.
“Who should be at the table when new data—very early or intermedi-
ate data—are emerging regarding a therapy and what its real limitations
may be?” Flaherty asked, adding, “Physicians and patients both are going to
gravitate toward the best available option, even when it may not really be a
great one,” especially when patients have advanced, life-threatening diseases
and there is an unmet need for an effective therapy. “Others need to be
involved in this discussion,” Flaherty said, and suggested having a small set
of representative stakeholders present for such discussions. Flaherty added
that it is not in FDA’s purview to provide such input, and that patients
and investigators tend to be biased in favor of proceeding to the next stage.
Rockhold noted that an independent DSMB needs to assess the data
and provide oversight in a continuous trial design, in order to adequately
address ethical concerns and protect patients and make sound scientific
decisions. He cited a paper written by FDA staff that found that indepen-
dent DSMBs provide important quality control in seamless clinical trials
(Prowell et al., 2016). Rockhold added that to maintain independence and
minimize bias, Principal Investigators and sponsors of a study should not
be on a DSMB, particularly for seamless trial designs. However, “there is
a fine line between independence and ignorance. You do not want to pick a
[DSMB] that is so independent, its members are never allowed to talk to
the people doing the research . . . sometimes people carry the concept of
PROCEEDINGS OF A WORKSHOP 63
conflict of interest too far and they want people who are so removed they
do not actually understand what is going on,” Rockhold said.
Joffe suggested that it would be appropriate to have Principal Investiga-
tors on DSMBs for single-center studies, but for multicenter studies, having
all the investigators participate on a DSMB could pose a potential conflict
of interest. He added that in hybrid Phase I/II or Phase II/III studies, there
are defined points where the investigator or sponsor is part of decision
making process about whether to continue the trial. He suggested that
investigators and sponsors should also be involved in decision making at
similar transition points in seamless trials. “These sorts of transition points
cannot all be decided by the DSMB with all the sponsors and investigators
blinded as to what is going on with the data,” he said.
Rockhold added that a DSMB review of a seamless trial aimed at
answering multiple questions involves assessing much more information
than it would for a typical trial asking a single question. “Somebody gives
you 5,000 pages of tables of interim data, so one of the challenges for a
DSMB is to outline upfront which is the right information to focus on,”
he said. An advantage to having a DSMB established for Phase II or earlier
studies is that “You now have a single group of people who are quite knowl-
edgeable about the product, [and] once it gets into Phase III testing, [they]
know what safety issues to expect,” Rockhold added.
Rockhold also suggested there be more clarity on the communication
pathways in seamless trial designs. “If an independent [DSMB] wants to
drop a group from testing, which requires changing the protocol, they
might notify the IRB or the steering committee. Who they should notify
has to be completely specified upfront to protect patients adequately,” he
said.
An additional challenge with accelerated seamless trials and knowing
when to transition from one phase to another is whether decision makers are
“keeping up to date with changes in scientific understanding,” Rothenberg
said. “I do not think clinical development is able right now to keep up with
the rapidly evolving science, so how do we keep clinical evaluation from
being the bottleneck?” Woodcock asked.
One participant suggested developing training programs for data safety
monitors to stay current with newer technologies, study designs, and sta-
tistical methods. “I do not think we have a structure or framework now to
train this new generation of monitors to do adequate monitoring jobs,” the
participant said. Rockhold noted that DSMB training programs are being
established based on recommendations from Duke University’s Clinical
18 See https://www.ctti-clinicaltrials.org/projects/data-monitoring-committees-dmcs
PROCEEDINGS OF A WORKSHOP 65
PROCEEDINGS OF A WORKSHOP 67
2007). Such health care data include registries, EHRs, claims data, data
gathered from health apps and social media, and large patient databases.
Registries are usually designed for research on a single disease, are
expensive, lack direct access to data, and tend to have smaller, biased sam-
ples, said Koehler. In contrast, claims data are large datasets that can indicate
treatment patterns and costs, and can also enable follow-up across health
care settings. However, there is usually a 6-month lag between when the
data are accrued and when they are reported in claims databases. In addi-
tion, claims data provide information on what interventions were provided
to patients, but these data do not provide any clinical information about
the patient. Because of this limitation, Koehler said that ongoing research
focuses on how to use newer sources of data, such as EHRs and health apps.
“These types of data could and should be incorporated in the drug label if
we only knew how to do that.”
Abernethy stressed that real-world evidence may not come solely from
EHRs or other databases, but rather from the production of “big data,” or
the amalgamation of different datasets (including EHRs, administrative
claims databases, registries, as well as patient-generated health data) that
is intended to complement clinical trials by providing more generalizable
knowledge. “Big data more clearly complete the picture of what is hap-
pening to patients in the real world in routine clinical practice,” she said.
Big data involve rapidly accumulating, high-volume datasets with different
types of data that should be verified and improved over time, according to
Abernethy. She stressed that big data should not be viewed as amorphous,
but rather as an organizing framework that can be applied to research
questions in a competent, consistent, and reliable way. “Real-world data
analyzed in a consistent manner can generate clinically meaningful and
generalizable evidence,” she said.
For researchers to be able to use real-world data in a study, the data
have to be accurate, of high quality, complete, longitudinal, reproducible,
and traceable back to their source, Abernethy said. There also needs to be
patient-level data linkages when appropriate for the research question, and
endpoints and outcomes need to be embedded in the datasets. The study
analysis approach needs to include objectives and strict analysis plans that
are reproducible and credible, Abernethy stressed, adding, “We cannot
cherry pick but need to be systematic in our cohort selection.” In addition,
real-world data can be used retrospectively to identify patients with rare
diseases who can be followed longitudinally over time, to observe outcomes
PROCEEDINGS OF A WORKSHOP 69
Pragmatic Trials
Koehler said that a pragmatic trial is a study that uses real-world data
and usually answers practical questions about risk, benefit, and cost of one
intervention versus competing interventions. In contrast, an explanatory
trial determines how well a drug works and how safe the drug is when it
is evaluated under ideal conditions in a clinical trial setting (Roland and
Torgerson, 1998). Randomization and placebo controls are often critical
for explanatory studies to maximize the chance of revealing true biological
effects of new treatments, Koehler noted. Because pragmatic trials compare
multiple treatments used in clinical practice, they typically do not use
control arms. Pragmatic trials are randomized, but this could include ran-
domization in which outcomes in an entire group of patients is compared
with those of another similar group of patients. Although blinding is usually
required in an explanatory study, it is usually not possible in a pragmatic
trial, she added.
Koehler emphasized that pragmatic trials should have strict require-
ments aimed at reducing many types of bias in the study. These include set-
ting randomization requirements to address selection bias, defining similar
conditions to study arms to address performance bias, and ensuring that the
groups being compared have the same performance standards for collecting
data on patients who drop out of the studies and conducting intention-to-
treat analyses to address attrition bias.
Explanatory trials are conducted in a carefully controlled population
of patients, who tend to be relatively homogeneous, lack concomitant ill-
nesses, and often have less ethnic diversity (Roland and Torgerson, 1998).
By contrast, pragmatic trials are conducted in more heterogeneous patient
populations in a variety of clinical settings, Koehler said. Compared to
explanatory trials, pragmatic trials tend to be simpler and can potentially be
less expensive to run, she said. Koehler stressed that pragmatic trials tend to
answer questions that patients and payers care about, such as how a treat-
ment affects symptoms, patient quality of life, and costs, in addition to the
mortality and morbidity usually assessed in explanatory studies. She also
described nine dimensions to characterize the level of pragmatism of a trial
(see Figure 8). For example, she said that a study comparing self-supervised
tuberculosis treatment with directly observed treatment is considered highly
PROCEEDINGS OF A WORKSHOP 71
data are linkable, and they can be used to document and improve quality.
Abernethy outlined several key steps undertaken at Flatiron Health to
gather evidence from EHRs to derive usable real-world evidence:
1,000 of whom had been treated with Kadcyla. Sixty-six of these women
had ejection fractions of 50 or less prior to being treated with Kadcyla.
These patients are now being followed to assess treatment outcomes.
“We now are starting to understand what happens to these women both
in terms of their ejection fraction over time as well as their breast cancer
outcomes,” Abernethy said.
PROCEEDINGS OF A WORKSHOP 73
their clinicians or the standard of care. Koehler noted that it was one of the
first times that data were used from community clinician practices to sup-
port regulatory approval of an investigational drug (Vestbo et al., 2016).
Koehler is currently conducting a study assessing whether patient outcomes
using EHR data is similar to patient outcomes observed in a clinical trial
(with a similar patient population) for women with metastatic breast cancer
receiving the drug letrozole.
Koehler emphasized that although evidence on the safety and efficacy
of a drug is gathered as it goes through preapproval clinical trials, the evi-
dence generated is from a much smaller and more homogeneous patient
population than in the real-world setting once the drug enters the market.
Because the drug’s use in patients in the general population outpaces the
collection of evidence on how it will affect them, there is an evidence gap
that could be addressed by real-world data (see Figure 9).
Redman noted that real-world data can help in an iterative fashion
to expand findings from clinical trials. She suggested using real-world
data to evaluate the eligibility criteria used in clinical trials and potentially
modify a clinical trial design in the future that expands eligibility. Brown
agreed that real-world data can be useful when determining the eligibility
criteria of clinical trials. Abernethy concurred, adding that researchers are
using the data when designing their clinical trials because “you have a lot
of the key features that will help you pressure test, for example, eligibility
criteria and how to better design your studies.” Sridhara added, “You can use
all of these data to learn more about a disease, which will help us in future
clinical trials to determine what we should be targeting or how we can run
these studies and what should be the control.” Ratain said that such data
also enable detection of adverse drug reactions.
Sridhara noted that prospective observational studies using real-world
data could affect drug labeling. Studies may also randomize the clinicians
rather than the patients. However, she raised the issue of determining end-
points in pragmatic oncology studies. “We cannot really use progression-
free survival or tumor response rate because RECIST criteria are used
by specialists and that is not going to be available in every community
hospital,” she said. Although it is possible to follow patients over time, she
added that in general, the formal recordkeeping and follow-up observed in
traditional clinical trials are not possible with pragmatic trials because the
records of patients are not often carried over when they switch from one
provider to another.
Ratain noted that real-world evidence has been used to establish proof
of concept at Vanderbilt University (Denny et al., 2013). This institution
has a large patient database20 that includes genomic data and diagnostic
coding data on tens of thousands of patients. Researchers have used the
database to discover and validate genetic differences linked to various dis-
orders. “The area where real-world data may be most useful is to discover
and validate patient response biomarkers,” he said. Abernethy agreed, not-
ing that some institutions have processed their EHR data so they can act
as clinical annotation for biospecimens in their biorepositories. “This helps
biologic discovery and understanding and identifying biomarkers,” she said.
Brown stressed that “there is no single data source that is going to
answer all your questions, so thinking about how to match your question
to the data and method you need is critically important. You cannot answer
everything with the data sources we have, but you can usually get pretty far.”
2017).
PROCEEDINGS OF A WORKSHOP 75
Standardization
Several speakers described the need to ensure that real-world data are
accurate and of high quality. Data need to be reproducible, said Abernethy:
“One of the biggest problems with real-world evidence and the reason why
it is so easily dismissed is because we are so worried about the quality of the
data. So we need to be transparent about the current quality and how we
are going to improve it over time.” Monica Bertagnolli, chief of the Divi-
sion of Surgical Oncology at Dana-Farber/Brigham and Women’s Cancer
Center, added, “We are deluged by data and sometimes the data gathering
that is done is very accurate and other times it is very inaccurate. How do we
understand it and make sense of it, especially since in oncology, the stakes
are so incredibly high?”
Rubin noted that information technology efforts are under way to stan-
dardize and harmonize data, and make them easily transferrable from one
platform to another. He described the efforts of the South Texas Accelerated
Research Therapeutics (START), which uses a high-quality and innovative
information technology infrastructure to ensure accurate and rapid clinical
trials of novel anticancer agents (START, 2017). Bernard Munos, senior
fellow at FasterCures, suggested using a model that constantly merges and
extracts knowledge from raw data without the need for a common template,
which is done by entities such as Google and the National Security Agency,
to find answers to clinical questions. Abernethy said that she has taken an
approach of starting with a parsimonious model that has flexibility to add
new data points as needed over time, such as heart failure data in breast
cancer patients. She pointed out that “there is great excitement about artifi-
cial intelligence and machine learning” that can curate and harmonize data,
but she suggested caution in how those technologies are applied until their
effectiveness for clinical applications is better understood.
Ronald Kline, medical officer of the Patient Care Models Group at the
Centers for Medicare & Medicaid Services’ (CMS’s) Center for M edicare
& Medicaid Innovation, noted that with the Oncology Care Model, par-
ticipating physicians are required to use a data registry that collects ana-
PROCEEDINGS OF A WORKSHOP 77
Patient Privacy
Piantadosi asked if using real-world clinical data in research will neces-
sitate changes to the Privacy Rule that was promulgated under HIPAA.
Brown noted that the HIPAA Privacy Rule is unclear about what types
of data sharing is acceptable, and therefore leads to many inefficiencies in
data management and analysis. “We are so horrified of doing the wrong
thing, and there is plenty of work we could do that we just do not because
it involves linking information; there is no single source of information
good enough. But linking it requires identifiers, and then it becomes a big
mess,” Brown said.
Pentz added that “we have to be careful about how we protect patient
data because there is no privacy if you are on the grid,” but “in the medical
field we have these artificial [regulations] that make it almost impossible for
us to do good things.” She said that we have to modify these regulations so
they are more realistic and provide real abilities to prevent the wrong people
from misusing patients’ medical information while facilitating access by
clinicians and researchers who might actually cure diseases and help people.
Pentz pointed out that some of the patient privacy concerns regarding the
use of real-world data, particularly for prospective pragmatic studies, could
be addressed by a broad consent process, similar to that used for performing
future research on biospecimens.
21 See https://am.asco.org/daily-news/eligibility-criteria-project-seeks-benefit-patients
PROCEEDINGS OF A WORKSHOP 79
BOX 8
Targeted Agent Profiling Utilization Registry Study
come along, children are able to tolerate higher doses corrected for body
surface area than adults, so this is something that is very much in our aware-
ness and we are going to try and make that happen,” he said.
Sridhara agreed that subgroup analyses are a way to make trial popula-
tions more heterogeneous. “There is nothing written in the study designs
that say you cannot include, for example, patients with a performance status
PROCEEDINGS OF A WORKSHOP 81
Collaboration
Several speakers stated that the new drug development paradigm
requires greater collaboration among companies and other stakeholders,
and provided several examples of how companies are sharing their data, and
in some cases, participating in the same clinical trials. Sigal stressed that due
to the growing complexity of cancer diagnostics and treatments, there also is
a growing need for collaboration in the testing of these agents. “Everybody
used to do their own thing individually, but the complexity of the science
and the new models that emerged started to show us we better start to do
this together because if we do not, everybody pays for it,” she said.
Blumenthal noted several collaborative data-sharing efforts to improve
the development of drugs and diagnostics:
23 The Eastern Cooperative Oncology Group performance score helps clinicians to assess
patients’ performance status and guide treatment decisions. A performance status score of
2 indicates patients are “ambulatory and capable of all self care but unable to carry out any
work activities; up and about more than 50 percent of waking hours.” See https://www.ncbi.
nlm.nih.gov/pubmed/7165009 (accessed May 22, 2017).
PROCEEDINGS OF A WORKSHOP 83
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Innovations at CMS
Kline outlined the newly instituted parallel review process of FDA
and CMS for medical devices.24 Such parallel reviews should alleviate the
lag time between FDA marketing approval for a device or diagnostic and
a national coverage determination by CMS, enabling reimbursement for
clinical use concomitant with market approval. “It is a CMS–FDA col-
laboration to move things forward on a more timely basis,” Kline said.
As previously mentioned, CMS has also developed an Oncology Care
Model, which is an episode-based payment model25 for 6 months of care,
and includes performance-based payments when clinicians achieve various
quality measures (CMS, 2017). “This provides incentives to use high-value
drugs and we are hoping to push the field toward value-based reimburse-
ment,” Kline said.
24 See https://www.federalregister.gov/documents/2016/10/24/2016-25659/program-for-
Expanded Access
Steven Lemery, lead medical officer in the Division of Oncology
roducts 2 at FDA’s OHOP, provided a summary of FDA’s Expanded
P
Access Program. This program enables patients to receive investigational
agents if they have a serious or immediately life-threatening disease or con-
dition and meet all of the following conditions26:
26 See https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=
PROCEEDINGS OF A WORKSHOP 87
submit a form to FDA (Jarow et al., 2017). Expanded access also requires
IRB consent except in emergency cases.
Of 1,332 single-patient expanded access requests made to FDA for
oncology drugs between 2014 and 2016, only 1 request was declined by
the agency, and 4 were withdrawn prior to an FDA decision. About two-
thirds were for drugs that subsequently were approved for market (Lemery
et al., 2016).
Although most expanded access requests are not intended to support
drug development or provide information about drug performance, in some
instances data from expanded access cases could be used to support approval
of a drug, according to Lemery. He noted that FDA’s OHOP approved
four drugs for oncology indications based in part on data from the use of
these drugs in its expanded access program. Two drugs were to provide a
treatment alternative for patients who had to discontinue the standard che-
motherapy because of toxicity, and two others were used to treat pediatric
patients, with one drug already approved for adults. These drug approvals
depended in part on safety, survival, or pharmacodynamics data collected
from patients who were granted expanded access to the drugs, Lemery
reported. He said the expanded access program could be useful in other
cases as well, such as for patients with rare cancers or who have rare genetic
mutations targeted by the drug. Lemery noted that often it is not feasible
to enroll patients with rare cancer mutations into a clinical trial because
they do not live in a location where the trial is offered, “so expanded access
might be a good way to obtain information about the use of your drug in
these rare populations. You could maybe get data on patients who do not
meet eligibility criteria, but can give you some real-world experience. You
may not be getting all the data you would get in a clinical trial, but you can
at least get scans and demographic information,” he said. Theoret agreed,
noting that expanded access could be useful once an investigational new
drug has Breakthrough Therapy designation, for those patients who would
like to receive the drug, but are unable to enroll in a clinical trial testing it.
“As development programs receive their Breakthrough Therapy Designa-
tion, it is often very early in the discussions that we should start thinking
about what their expanded access program is going to look like,” he said.
The expanded access program has not posed undue risks for drug
development, according to a study of the program over a 10-year period.
This study found that with more than 10,000 expanded access requests,
only two commercial development programs involving more than 1,000
patients were placed on hold or partial hold due to a serious adverse event
observed in a patient who received the drug via expanded access. One hold
was removed months later and the other, a partial hold limited to a specific
patient population, was eventually removed as well (Jarow et al., 2017).
Another study of failed oncology trials found that none of these studies
failed in clinical development due to data collected from expanded access
cases (Khozin et al., 2015).
Ison noted that many informed consents are based on the side effect
profiles in populations being studied and are not always applicable to those
subjects who are applying for expanded access. Therefore, she cautioned
that patients and clinicians be accurately informed of the benefits and risks
of an experimental intervention and suggested that clinicians be proactive
about informed consent.
Cancer Moonshot
Elizabeth Jaffee, deputy director of the Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins University, presented the recommenda-
tions of the Cancer Moonshot’s Blue Ribbon Panel related to improving
cancer drug development. She noted that the Cancer Moonshot was initi-
ated based on the recognition that there has been unprecedented progress
in cancer research recently, but that there is insufficient coordination, data
sharing, and funding to reap the benefits of this progress. “The science is
ripe, but the progress made in getting it to benefit patients is too slow and
lacks efficient coordination,” Jaffee stressed.
The overarching goals of the Cancer Moonshot are to accelerate prog-
ress in cancer research; encourage greater cooperation and collaboration
among academia, government, and the private sector; and enhance sharing
of data (The White House, 2016). To carry out its goals, a federal task force
was convened to determine policy measures to pursue, and a Blue Ribbon
Panel was convened to delineate research goals.
The federal task force delineated several policy goals, including the
following:
PROCEEDINGS OF A WORKSHOP 89
More specific strategic goals are to expand use of mobile devices and
create tracking systems for patients to unleash the power of data, deter-
mine best practices for consent, develop a seamless data environment with
open platforms, and develop the necessary workforce. The task force also
recommended bringing new therapies to patients faster by modernizing
eligibility criteria for clinical trials, and developing trials for patients with
specific genetic defects rather than tissue-specific types of cancer, such as
the NCI-MATCH trial, and using real-world evidence.
The Working Groups of the Blue Ribbon Panel made several recom-
mendations focused on research that also have policy implications in drug
development (Cancer Moonshot Blue Ribbon Panel, 2016):
discern biomarkers that reveal the most effective therapeutic agents for
individual patients.
Jaffee also described current ongoing Cancer Moonshot programs,
including the following components (NCI, 2017b):
• NCI Drug Formulary that will leverage lessons learned from the
NCI-MATCH trial to forge relationships with 20 to 30 public–
private partners to expedite researcher access to investigational
agents and approved drugs for combination trials. One goal is to
reduce negotiation time for collaborations.
• Application Programming Interface, an endeavor in which several
third-party innovators, including Smart Patients, Synapse, Cure
Forward, and Antidote, are participating to build applications, inte-
grations, search tools, and digital platforms to disseminate clinical
information to the community.
• Strategic Computing Partnership between the Department of
Energy (DOE) and the NCI to accelerate precision oncology, that
is, getting the right treatments to the right patients. There are three
new pilots to apply the most advanced supercomputing capabilities
to analyze data from preclinical models of molecular interaction data.
• Open-access resource for sharing cancer data via the Genomic Data
Commons. Foundation Medicine is participating in this endeavor
and hopes to double the total number of patients who provide
information to this database. This will provide a mechanism for
broad sharing and partnerships among government agencies,
academia, and industry that will be complemented by the NCI’s
Genomics Cloud Pilots, which will provide imaging, proteomics,
and immunotherapeutics datasets.
• Public–private Partnership for Accelerating Cancer Therapies
that involves collaborations of 12 biopharmaceutical companies,
research foundations, philanthropies and the FNIH. This partner-
ship will fund precompetitive cancer research and share broadly
all data generated for further research, with initial focus areas
that include identifying and validating biomarkers for treatment
response and resistance to cancer therapies, clinical trial platforms
for combination therapies, and predictive modeling approaches and
therapies for rare cancers.
• Applied Proteogenomics Organizational Learning Outcomes,
which is a partnership between DOE, the NCI, and the Depart-
PROCEEDINGS OF A WORKSHOP 91
• coverage of the costs of routine care and clinical trials for patients
with cancer
• uniform patient consent forms and patient access to data
• use of a central IRB, data sharing among federal agencies, and
adequate clinical trial site evaluation processes
• improved delivery of cancer care in communities through reducing
economic burden of clinical trial enrollment on patients and prac-
titioners, sharing EHR data, and releasing best practices for state
vaccine registries
• incentives for development of pediatric cancer drugs, especially
molecularly targeted therapies
• data-sharing mechanisms, including standardization and harmoni-
zation of data, licensing, and sharing among the private sector
EXAMPLES OF INNOVATIONS IN
CANCER DRUG DEVELOPMENT
A number of workshop speakers discussed examples of drug develop-
ment pathways and clinical trial designs reflective of the move toward a
new drug development paradigm for oncology. These examples included
the development of
• crizotinib,
• avelumab,
• pembrolizumab,
• vemurafenib, and
• EGFR T790M inhibitors.
Development of Crizotinib
Rothenberg said that the development of crizotinib serves as a good
example of how new scientific information led to an amendment in the
clinical trial protocol. The strong signal seen in first-in-human tests, com-
bined with the understanding of its molecular mechanism of action, led to
crizotinib’s rapid approval, Rothenberg added.
Crizotinib targets c-MET, a molecular signaling pathway that is
thought to be mutated and activated in a large proportion of patients who
became resistant to targeted therapies. Thus, Rothenberg said that “there
was a good preclinical rationale for this drug.” In a Phase I test, 3 out of 37
patients responded to crizotinib, which was not considered a strong signal.
However, it was later discovered, because of preclinical research from an
unrelated group, that all three responders overexpressed a fusion mutation
of anaplastic lymphoma kinase (ALK).27 Therefore, it became apparent that
in addition to targeting c-MET, crizotinib inhibits ALK.
This information led Pfizer to work with FDA to develop a reliable
companion diagnostic for crizotinib to detect the ALK mutation. In addi-
tion, Pfizer expanded the cohort of patients expressing the ALK fusion in
the Phase I study, and a Phase II trial was opened to test the drug in lung
cancer patients with the ALK mutation (Malik et al., 2014). Then Pfizer
opened two Phase III trials simultaneously: One to test crizotinib as a
second-line treatment for lung cancer patients versus single-agent chemo-
therapy (Shaw et al., 2013); the other was to test it as a first-line treatment
in lung cancer patients versus combination chemotherapy (Solomon et al.,
2014).
While the Phase III trials were opening, it was discovered that mutated
versions of the ROS1 gene, another tyrosine kinase closely related to ALK,
also were prevalent in patients with lung cancer. So Pfizer amended the
Phase I trial to include lung cancer patients with this mutation. Accrual
27 This triggers a molecular signaling pathway that fosters the growth and survival of tumor
PROCEEDINGS OF A WORKSHOP 93
FIGURE 10 The crizotinib drug development timeline from 2006 to 2011.
NOTE: ALK = anaplastic lymphoma kinase; CDx = companion diagnostic; FDA = Food
and Drug Administration; NSCLC = non-small cell lung cancer; RP2D = recommended
Phase II dose.
SOURCE: Rothenberg presentation, December 12, 2016.
to the Phase I, II, and III trials occurred simultaneously, as can be seen in
Figure 10, and was completed in 2011.
In August 2011, FDA approved crizotinib for the treatment of patients
with locally advanced or metastatic non-small cell lung cancer that is ALK-
positive, about 6 years after it was first tested in patients (FDA, 2011). FDA
additionally approved crizotinib for ROS1-positive mutations in 2016 on
the basis of the Phase I and Phase II data.28
Rothenberg said a number of lessons can be learned from the crizotinib
drug development experience, including how strong signals of activity can
be seen in Phase I studies and that expansion cohorts in Phase I trials can
provide an opportunity to rapidly and efficiently test a clinical hypothesis
when there is a good scientific understanding of the disease and the drug.
Rothenberg also emphasized that Phase I, II, and III trials of the same inves-
28 See https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm490329.htm
Development of Avelumab
Rothenberg also reported on the development of avelumab, which is
an immunotherapy checkpoint inhibitor of PD-L1. He noted that prior
to avelumab entering clinical testing in 2013, the populations and diseases
most likely to respond to this type of treatment were known from clinical
studies of similar checkpoint inhibitors. This led Merck-Serono to test it
in a Phase I study that had multiple cohorts of likely responders, with the
assumption that the cohorts showing the most response would be expanded.
Currently, there is an expansive international clinical trial program explor-
ing the use of PD-L1 inhibition with avelumab to treat multiple types of
cancer, such as solid tumors, gastric cancer, Merkel cell carcinoma,29 and
non-small cell lung cancer (Pfizer, 2015). Multiple actions were then taken
for different indications following this Phase I study:
29 On March 23, 2017, FDA granted accelerated approval to avelumab for the treatment of
patients 12 years and older with metastatic Merkel cell carcinoma. See https://www.fda.gov/
Drugs/InformationOnDrugs/ApprovedDrugs/ucm547965.htm (accessed May 18, 2017).
PROCEEDINGS OF A WORKSHOP 95
Development of Pembrolizumab
Rubin described the development of the PD-L1 targeted immuno
therapy pembrolizumab. This drug is an example of how a single-arm Phase I
dose-expansion trial involving patients with different types of solid tumors
led to FDA approval. The Phase I protocol prespecified expansion of the
cohort of patients with melanoma if high response rates were demonstrated.
Initial striking responses in melanoma patients led to the expansion of that
cohort, including patients who had previously not responded to ipilimumab,
another cancer immunotherapy, as well as lung cancer patients.
Additional patients were added after an analysis of the melanoma
patients in the Phase I study found that those who had progressed on
ipilimumab might respond to pembrolizumab. A further expansion tested
the appropriate dose in both melanoma and lung cancer patients. Finally,
after initial analyses demonstrated that most patients who responded to
pembrolizumab had high PD-L1 expression levels, Merck KGaA began
developing a companion diagnostic, which involved adding more patients
within the Phase I study. While the Phase I trials were ongoing, FDA
granted pembrolizumab Breakthrough status.
Rubin noted that “we were moving so fast that we did not have the
results back from the randomized dosing study when we had to take cohorts
into our Phase III studies so those were also tested for dose and schedule.”
Ultimately, nine amendments were made to the Phase I protocol and FDA
Development of Vemurafenib
Flaherty reported on the development of vemurafenib, which illus-
trates the advantages of conducting serial biopsies on patients to determine
PROCEEDINGS OF A WORKSHOP 97
whether the drug is acting on its intended target, and to molecularly define
resistance when it develops. Vemurafenib targets the BRAF protein, which
is mutated in 60 percent of melanoma patients, as well as in some colon
and other cancer patients. In vitro studies suggested no plateau in the
dose–response relationship, so in the first Phase II dosing studies, Flaherty
examined not only efficacy, but also biomarker status to verify drug activity
and determine effectiveness at lower doses. Melanoma patients had variable
responses to the drug, but because it was so efficacious in a subset of patients
and there was great unmet medical need for an advanced melanoma treat-
ment, FDA agreed to a single-arm Phase II study in melanoma patients,
rather than randomizing patients to receive standard of care (Sosman et al.,
2012). In August 2011, after conducting a Phase III trial, FDA approved
vemurafenib for the treatment of patients with unresectable or metastatic
melanoma with the BRAF V600E mutation (NCI, 2013). At the time,
there was some debate about whether the randomized Phase III trial was
necessary or ethical, Flaherty noted (Hey and Truog, 2015).
Unfortunately, the responses melanoma patients had to v emurafenib
were often transient. To assess how patients were responding to
vemurafenib, the investigators conducted biopsies before and during their
treatment, as well as when their tumors progressed. These biopsies showed
that the drug consistently blocked its intended target, despite variability
in patients’ durability of responses to it, and that only patients receiving
high doses of the drug responded. “The serial tumor biopsy data were
quite informative because they showed there was a fairly homogeneous
molecular effect on the target pathway that was lost over time when we
did biopsies at the time of relapse,” Flaherty stated.
His analysis of the biopsies suggested that tumors in the relapsed
patients had activated MEK. The analyses therefore suggested a com-
bination therapy for future trials. Accordingly, Flaherty began treating
melanoma patients in 2010 with BRAF-MEK combination therapy in a
Phase I study. Phase II and III trials of a MEK inhibitor in combination
with vemurafenib subsequently demonstrated improved overall survival of
melanoma patients (Ugurel et al., 2016).
Three randomized Phase III trials have now demonstrated that the
combination of a BRAF inhibitor (vemurafenib or dabrafenib) with a MEK
inhibitor is better than BRAF inhibitor therapy alone. Flaherty summed
up his presentation on BRAF inhibitors by stressing, “Interrogating what
happens in patients’ tumors, until the day comes that we can do it purely in
blood, is important and impactful in driving forward benefit in the field.”
PROCEEDINGS OF A WORKSHOP 99
BOX 9
A Contrasting Development Story of Rociletinib,
a T790M EGFR Inhibitor
a See https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/
Drugs/OncologicDrugsAdvisoryCommittee/ucm486395.htm (accessed May 26, 2017).
from the drug, osimertinib was very quickly brought to market and made
available to patients. FDA granted accelerated approval for osimertinib
in 2015,30 just 4 years after it was first synthesized, and 2 years after the
30 See https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm472525.htm
FIGURE 11 Key milestones in the (A) discovery and (B) development of osimertinib.
NOTES: The first patient was treated in March 2013 and the first approval was Novem-
ber 2015. AURA = trial of AZD9291; AZ = AstraZeneca; CE-IVD = Conformité
Européene in Vitro Diagnostic; ctDNA = circulating tumor DNA; EGFR = epidermal
growth factor receptor; EU = European Union; FDA = Food and Drug Administration;
PMA = premarket approval; PMDA = Pharmaceutical and Medical Devices Agency in
Japan.
SOURCES: Jänne presentation, December 12, 2016; Yver, A., Osimertinib
(AZD9291)—a science-driven, collaborative approach to rapid drug design and
development, Annals of Oncology, 2016, 27(6):1165-1170, by permission of Oxford
University Press.
first clinical tests of the drug (see Figure 11). “This was one of the fastest
oncology drug approvals ever,”31 Jänne stated.
31 On March 30, 2017, FDA granted regular approval to osimertinib. See https://www.
WORKSHOP WRAP-UP
Schilsky said that improving the drug development paradigm in oncol-
ogy is critical, given that cancer will soon become the leading cause of death
in the United States. “There are more cancer cases than ever before despite
our progress in treating cancer because of the ag[ing] of the population and
the increasing prevalence of the disease,” Schilsky said. He said rapid prog-
ress in cancer research has led to a better biological understanding of cancer
that has fostered the identification of new drug targets, including genetic
aberrations that stimulate tumor growth, and those involved in the immune
system’s response to tumors. New classes of cancer drugs often have a wider
range of doses that are both more effective and less toxic than previous
chemotherapies. There also has been rapid development of biomarker tests
to stratify and characterize patient populations with differential prognoses
and sensitivities to treatment. In addition, there are new sources of data,
and although they may lack the precision and accuracy of clinical trial data,
Schilsky noted that this challenge could be overcome through methodologi-
cal tactics. Therefore, he said, “We should not make more of the distinction
than we need to between real-world data and clinical trial data.”
FDA recognizes the novel strategies being used in oncology drug devel-
opment and supports improvements aimed at making the process more effi-
cient and expedient, Schilsky noted. FDA also has broader authority than
it did in the past with passage of the 21st Century Cures Act, and despite
some concerns voiced that this Act might make FDA too permissive at the
sacrifice of patient safety, Schilsky stressed that “I do not expect FDA would
suddenly abandon all of its standards for regulatory approval.”
Given all the recent changes in cancer drug development and its regula-
tion, much of the discussion in the workshop focused on potential ways to
capitalize on all of these changes to improve the drug development process.
Schilsky pointed out several recurring themes at the workshop, the first
and foremost being to put patients at the center of the drug development
paradigm. “At the end of the day, the reason we do what we do and try to
advance new drugs into the clinical workplace is to help improve outcomes
for patients. So let us continue to think about this as patient-centered
drug development and not product-centered drug development,” Schilsky
stressed. To that end, there needs to be a focus on clinically meaningful out-
comes and endpoints in clinical trials, including patient-reported outcomes.
Another recurrent topic of discussion at the workshop was that bio-
marker or diagnostic test development tends to lag behind therapeutic
who have been involved in drug development plans at certain points in the
process can end up being excluded from key decisions later, Schilsky said.
Many workshop discussions focused on the information needed to
confidently advance investigational agents in the drug development process,
Schilsky noted. “We have numerous endpoints in oncology, none of which
are perfect and each of which has its own challenges. We have to be able
to integrate our assessment of a drug using as much information as we can
glean from all the endpoints available to us at any particular point in time,”
he said. A related point made repetitively throughout the workshop was the
need to learn throughout the drug development process and beyond FDA
approval, not just from individual trials or individual cohorts, Schilsky said.
With rapid clinical testing, many drugs are entering the market with
less learning behind them, Schilsky said. Some of that learning about new
drugs could come with postmarketing studies, but such research is difficult
to conduct in the United States. “Once that drug is on the market, it can
be prescribed and if it gets paid for, it is a huge disincentive for either the
doctor or the patient to participate in a postmarketing research study, which
is one of the reasons why so many of these studies take so long to complete
or in some cases, are never completed,” he said.
He summarized several potential strategies for improving drug develop-
ment (see Box 10). “It all comes down to clearly articulating the question
we want to answer and the best approach to answering that question among
an entire range of clinical trial designs and data sources available to us.” He
added that the Cancer Moonshot offers many opportunities for improving
drug development. “It is incumbent on us all to take advantage of them
and try to use the new funding and infrastructures that will be available to
continue to address some of these issues.”
“Drug development is inherently risky and the drug development
paradigm is essentially about managing uncertainty in the context of unmet
medical need and business opportunity,” Schilsky concluded. “The more
that we, as a community, can get comfortable with how to manage that
uncertainty and make key decisions about regulatory approval, clinical use,
and reimbursement in the face of that uncertainty and then continue to
develop the information to reduce that uncertainty, then the better off we
will be and the better off our patients will be.”
BOX 10
Potential Strategies to Improve the
Drug Development Paradigm in Oncology
Summarized by Richard Schilsky
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Appendix A
Statement of Task
The committee will develop the agenda for the workshop sessions, select
and invite speakers and discussants, and moderate the discussions. A sum-
mary of the presentations and discussions at the workshop will be prepared
by a designated rapporteur in accordance with institutional guidelines.
115
Appendix B
Workshop Agenda
Panel Discussion
10:00 am Break
117
Anti-PD-1 Immunotherapy
• Eric Rubin, Merck
12:15 pm Lunch
APPENDIX B 119
3:15 pm Break
Q&A
Panel Discussion
11:15 am Break
APPENDIX B 121
1:00 pm Adjourn