Biosimilar

From Wikipedia, the free encyclopedia Biosimilars also known as follow-on biologics are biologic medical products whose active drug substance is made by a living organism or derived from a living organism by means of recombinant DNA or controlled gene expression methods. iosimilars !or follow"on biologics# are terms used to describe officially approved subse$uent versions of innovator biopharmaceutical products made by a different sponsor following patent and exclusivity expiry on the innovator product.%&' iosimilars are also referred to as subsequent entry biologics !() s# in *anada.%+' ,eference to the innovator product is an integral component of the approval. -nlike the more common small"molecule drugs, biologics generally exhibit high molecular complexity, and may be $uite sensitive to changes in manufacturing processes. Follow"on manufacturers do not have access to the originator.s molecular clone and original cell bank, nor to the exact fermentation and purification process, nor to the active drug substance. /hey do have access to the commerciali0ed innovator product. Differences in impurities and1or breakdown products can have serious health implications. /his has created a concern that copies of biologics might perform differently than the original branded version of the product. *onse$uently only a few subse$uent versions of biologics have been authori0ed in the -( through the simplified procedures allowed for small molecule generics, namely 2enotropins !3anuary &445# and )noxaparin !3uly +6&6#, and a further eight biologics through the 767!b#!+# pathway.

Contents

& Approval processes + ackground 8 -nited (tates of America

o o

8.& 9*: Act 8.+ Data exclusivity

; 2arket implications 7 ,eferences

Approval processes
/he )uropean regulatory authorities led with a specially adapted approval procedure to authori0e subse$uent versions of previously approved biologics, termed <similar biological medicinal products< " often called biosimilars for short. /his procedure is based on a thorough demonstration of <comparability< of the <similar< product to an existing approved product.%8' :n the -( the Food and Drug Administration !FDA# held that new legislation was re$uired to enable them to approve biosimilars to those biologics originally approved through the 9=( Act pathway.%;' Additional *ongressional hearings have been held,.%7' >n 2arch &5, +664, the 9athway for iosimilars Act was introduced in the =ouse.%&' (ee the ?ibrary of *ongress website and search =.,. &7;@ in &&&th *ongress (ession. (ince +66; the FDA has held a series of public meetings on biosimilars.%A'%5' /he FDA gained the authority to approve biosimilars !including interchangeables that are substitutable with their reference product# as part of the 9atient 9rotection and Affordable *are Act signed by 9resident >bama on 2arch +8, +6&6 " none have yet been approved. /he FDA has previously approved biologic

products using comparability, for example, >mnitrope in 2ay +66A, but this like )noxaparin was also to a reference product, Benotropin, originally approved as a biologic drug under the FDC* Act %@'# .

Background
*loning of human genetic material and development of in vitro biological production systems has allowed the production of virtually any recombinant DNA based biological substance for eventual development of a drug. 2onoclonal antibody technology combined with recombinant DNA technology has paved the way for tailor"made and targeted medicines. Bene" and cell"based therapies are emerging as new approaches. ,ecombinant therapeutic proteins are of a complex nature !composed of a long chain of amino acids, modified amino acids, derivati0ed by sugar moieties, folded by complex mechanisms#. /hese proteins are made in living cells !bacteria, yeast, animal or human cell lines#. /he ultimate characteristics of a drug containing a recombinant therapeutic protein are to a large part determined by the process through which they are producedD choice of the cell type, development of the genetically modified cell for production, production process, purification process, formulation of the therapeutic protein into a drug. After the expiry of the patent of approved recombinant drugs !e.g. insulin, human growth hormone, interferons, erythropoietin, and more# any other biotech company can <copy< and market these biologics !thus called biosimilars#. =owever, because no two cell lines, developed independently, can be considered identical, biotech medicines cannot be fully copied. /he )uropean 2edicines Agency, )2A, has recogni0ed this fact, which has resulted in the establishment of the term <biosimilar< in recognition that, whilst biosimilar products are similar to the original product, they are not exactly the same.%4' (mall distinctions in the cell line, in the manufacturing process or in the surrounding environment can make a maEor difference in side effects observed during treatment, i.e. two similar biologics can trigger very different immunogenic response. /herefore, and unlike chemical pharmaceuticals, substitution between biologics, including biosimilars, can have clinical conse$uences and does create putative health concerns. iosimilars are subEect to an approval process%&6'%&&' which re$uires substantial additional data to that re$uired for chemical generics, although not as comprehensive as for the original biotech medicine. >riginally the complexity of biological molecules led to re$uests for substantial efficacy and safety data for a biosimilar approval. /his has been progressively replaced with a greater dependence on assays, from $uality through to clinical, that show assay sensitivity sufficient to detect any significant difference in dose. %&+' =owever, the safe application of biologics depends on an informed and appropriate use by healthcare professionals and patients. :ntroduction of biosimilars also re$uires a specifically designed pharmacovigilance plan. :t is difficult and costly to recreate biologics because the complex proteins are derived from living organisms that are genetically modified. :n contrast, small molecule drugs made up of a chemically based compound can be easily replicated and are considerably less expensive to reproduce. :n order to be released to the public, biosimilars must be shown to be as close to identical to the parent biological product based on data compiled through clinical, animal and analytical studies. /he results must demonstrate that they produce the same clinical results. )2A and FDA regulations as well as scientific considerations indicate that biosimilarity does not imply interchangeability. %&8'

United States of America

BPCI Act
/he iologics 9rice *ompetition and :nnovation Act of +664 ! 9*: Act# was originally sponsored and introduced on 3une +A, +665 by (enator )dward Fennedy !D"2A#. :t was formally passed under the

9atient 9rotection and Affordable *are Act !99A* Act#, signed into law by 9resident arack >bama on 2arch +8, +6&6. /he 9*: Act was an amendment to the 9ublic =ealth (ervice Act !9=( Act# to create an abbreviated approval pathway for biological products that are demonstrated to be highly similar !biosimilar# to a Food and Drug Administration !FDA# approved biological product. /he 9*: Act is similar, conceptually, to the Drug 9rice *ompetition and 9atent /erm ,estoration Act of &4@; !also referred to as the <=atch"Waxman Act<# which created biological drug approval through the Federal Food, Drug, and *osmetic Act !FFDC* Act#. /he 9*: Act aligns with the FDA.s longstanding policy of permitting appropriate reliance on what is already known about a drug, thereby saving time and resources and avoiding unnecessary duplication of human or animal testing. /he FDA has released a total of four draft guidelines related to biosimilar or follow"on biologics development. -pon the release of the first three guidance documents the FDA held a public hearing on 2ay &&, +6&+. A summary of the key issues raised is available for review in the Eournal New 9harma /hinkers.%&;'

ata e!clusivity
Data exclusivity is an important piece of the amendment in the 9atient 9rotection and Affordable *are Act for biosimilars. :t is the period of time between FDA approval and an abbreviated filing for a biosimilar on the original producer.s data. Data exclusivity is designed to preserve innovation and recogni0e the long, costly, and risky process involved while the innovator waits to gain FDA approval. /he time allowed for data exclusivity is critical for the future of biologics. A number of provisions for data exclusivity in recent legislative proposals ranged up to &; years, however, the passing of the 99A* Act guarantees a &+ year time period from the time of FDA approval.%&7' /his is supposed to compensate for perceived shortcomings in patent protection for biologics. Data exclusivity extends from the date of product approval, and this protection period runs concurrently with any remaining patent term protection for the biologic. /hat is to say, data exclusivity provides additional protection to the innovator when the remaining patent length is shorter than the data exclusivity period at the time of approval !which can occur due to lengthy pre"clinical and clinical research re$uired to obtain FDA approval#, or to the extent that the patent term is circumvented by a biosimilar prior to its expiry.

"arket implications

/he +6&+G+6&4 patent cliff.%&A' 9eriod of market exclusivity up to date of patent expiration for the /op &6 selling biologics for +6&&. H)nbrel has been granted approval in +6&& for a patent filed in &447, extending its patent life further &5 years. /he legal re$uirements of approval pathways, together with the costly manufacturing processes, escalates the developing costs for biosimilars that could be between 57G+76 million -(D per molecule.%&A' /his market entry barrier affects not only the companies willing to produce them but could also delay availability of inexpensive alternatives for public healthcare institutions that subsidi0e treatment for their patients. )ven"though the biosimilars market is rising, the price drop for biological drugs at risk of patent expiration will not be as great as for other generic drugsI in fact it has been estimated that the price for biosimilar products will be A7J"@7J of their originators.%&A' iosimilars are drawing market.s attention since there is an upcoming patent cliff, which will put nearly 8AJ of the &;6bn -(D market for biologic drugs at risk !as for +6&&#, this considering only the top &6 selling products.%&A'