biosimilarspipeline.com

Miscellaneous News and Commentary
 (Mostly Historical and Following U.S. Biosimilars Legistlative and Regulatory Issues)

2012

  • As of Dec. 2012, still no biosmilar filings, but FDA has received 50 requests from sponsors for meetings for 12 reference products and has held 34 meetings to discuss biosimilar product development programs. FDA has received 12 IND applications for biosimilar development programs. With hardly any U.S. biosimilar trials showing up in clinicaltrials.gov, it can presumed that these are still just Phase I studies (with all post Phase I studies to be used for filings now having to be reported up-front to clinicaltrials.gov).
  • On Aug. 2, FDA granted a full BLA to Zaltrap, giving it a unique, i.e., different, established/official/non-proprietary name (ziv-aflibercept) than for previously full BLA-approved Eylea, which has aflibercept as its established/official name and also its USAN and INN name. The developed and manufacturer are the same (Regeneron) and both products contain absolutely the same active agent (confirmed by Regeneron and Sanofi, the Zaltrap U.S. license-holder), a recombinant mAb acting-like Trap protein developed and manufactured by Regeneron. Does this tell us anything about FDA's likely approach to biosimilar nomenclature/naming?
          Sanofi reports that FDA requested the name Zaltrap name change late, prior to approval, to differentiate Zaltrap (administered systemically for cancer treatment) from Eylea (administered into the eye for macular degeneration treatment). This suggests that safety (associated with unique names) will trump cost savings (associated with using the same/generic names) in the granting of biosimliar names. In my view, this tends to confirm that FDA will go with unique names for biosimilars, i.e., the established//official/non-proprietary names for reference and biosimilars products will all be unique/different. But the name assigned to Zaltrap is problematic and raises a number of issues.
          Why did FDA go against the vast majority of its own precedents, including not using INN/USAN nomenclature/names? What about all of the preexisting similarly differentiated (e.g., different delivery methods, formulations, bioprocessing, indications, etc.) products that now all use the same established name but contain identical active agents, essentially all using INN/USAN-assigned names? Why did FDA totally avoid INN and USAN in adopting this name? Will the 'ziv' name be adopted after-the-fact by INN/USAN to match FDA's decisions (which would result in 2 names for the same active agent, a violation of core INN/USAN and chemical nomenclature principles)? What does this recent action say about the (dys)functionality, (un)suitability and future of INN/USAN for U.S. biosimilar and broader biopharmaceutical nomenclature/naming? As I've commented before, INN/USAN is simply inappropriate, inconsistent, incongruous (e.g., basing product names solely on active agents) and was never designed for biopharmaceuticals, much less more highly-nuanced biosimilars (so abandoning INN/USAN is good). And biobetters need to have suitable names too, further complicating granting names. Why did FDA use a prefix vs. suffix to differentiate the more recently-approved approved product; and a prefix, "ziv," that is not part of INN/USAN or any other nomenclature system? Why a prefix vs. suffix for differentiation? Here, using a suffix (vs. adding a prefix) at least would make it simpler to note that these are similar products, e.g., in alphabetical lists and database searching, while still differentiating the products for prescription purposes. Interferons alfa, beta, gamma, etc. are vastly different, but all use the common 'interferon' stem. Will such names now be reviewed and modified? Was this an arbitrary decision or did high-level management concur (including in the context of this surely being viewed as a significanat precedent, perhaps, foreshadowing FDA future biosimilar nomenclature policies)?
          This recent action seems to indicate FDA willingnes to move away or even abandon INN/USAN as the primary source for US biosimilar and biopharmaceutical established/nonproprietary names (which is needed in my opinion). Here, FDA decided in favor of totally not using the basic INN/USAN nomenclature framework, which incongruously assigns nonproprietary names to biopharmaceutical products based solely on their active agents (ignoring differences in bioprocessing, formulation, indications, delivery methods, etc.), and totally avoiding the INN and USAN prccesses, bureaucracies and committees (as described by Sanofi, and with no relevant INN or USAN recommendations retrievable online). Here, FDA went against the prior assignment of aflibercept as the INN and its own established name for the active agent, with USAN yet to adopt a name for Zaltrap. Will USAN ever assign a name to Zaltrap, or will things remain fully ambiguous, with aflibercept the INN (but with no assigned USAN) used worldwide for the active agent?
          Many aspects remain unknown why and how a unique established name was selected for Zaltrap vs. Eylea. But this recent designation of a differentiated quasi-generic, but definitely unique, name for a product containing an active agent identical to a product assigned a different name indicates that FDA may take a rational approach to biosimilar nomenclature. In my view, this means doing what is right and needed for U.S. needs, not blindly accepting INN (determined by WHO/UN committees) and derivative USAN names, with this nomenclature system simply not working with biopharmaceuticals (while it has been has been fined-tuned for over 50 years and works well for chemical substances/drugs).
          Hurray for FDA! It has set a major post-biosimilars legislation precedent for its avoiding INN/USAN and for differentiating a unique biopharmaceutical product (different formulation and delivery system) by assigning a new unique name (for Zaltrap), despite Zaltrap deservng the same name by essentially all FDA, INN, USAN and chemical/drug nomenclature precedents. So, the agency is both on the right track and making a mess of things.
          For those seeking more information about biosimilar nomenclature issues, see an article I authored, "Nomenclature of Biosimilars Will Be Highly Controversial, published in BioProcess Intl. online at www.biopharmacopeia.com/BPI_Biosimilars_article_6.2011.pdf and much other information available at www.biopharmacopeia.com.
  • On June 28, the U.S. Supreme Court upheld the overall constitutionality of (did not strike down) the "Patient Protection and Affordable Care Act" (broad health care reform act; referred to as 'Obamacare' by critics) enacted on March 23, 2010, with the "Biologics Price, Competition and Innovation Act" (BPCIA), the law enabling FDA approval of biosimilars, surviving. >EMA, EU, has released EMA Procedural advice for users of the centralised procedure for similar biological medicinal products applications, a set of questions and answers portrayed as largely consolidating prior advice.
  • On March 28, the EMA, EU, accepted its first filing for a biosimilar monoclonal antibody, a version of infliximab (Remicade, marketed in the EU by Merck and Johnson & Johnson/J&J), with this appearing on its list of list of pending applications. This is presumably an application from Celltrion (S. Korea) and Hospira, with the product developed and manufactured by Celltrion and marketed by Hospira. Patents are likely to delay filing in the U.S. and marketing in some EU countries for at least a few years.
  • In Feb., FDA released initial draft (proposed) biosimilar guidance and related documents:  [Note, hardly any of the major issues discussed on this site are even mentioned in these documents]. : 
    a) Guidance for Industry on Biosimilars: Q & As Regarding Implementation of the BPCI Act of 2009
    b) Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009
    c) Guidance for Industry Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product
    d) Fact Sheet: Issuance of Draft Guidances on Biosimilar Product Development
    See also the main FDA biosimilars page. 

2011

2010

  • FDA has published a Federal Register notice soliciting comments on implementation of user fees for biosimilar BLA applications. Most of the fees are upfront, e.g., collected during the IND/prefiling phase along with the application fee, with fees largely matching those of regular BLA filings.
  • Transcripts from the FDA Public Meeting are Now Online:  See the transcripts for the first day and second day.
  • Nomenclature Will Replace Data Exclusivity as the Major Biosimilars Controversy;  The U.S. BIOPHARMACOPEIA Registry of Biopharmaceutical Products
          It was evident to anyone attending the Nov. 3 and 4 FDA public meeting concerning its implementation of the BPCI Act that product nomenclature could well be the next major controversy, displacing data exclusivity which was largely covered in the Act.  
          The issue of nomenclature (the names to be used in commerce, including for prescriptions) will likely be as or even more contentious than data exclusivity, with the names to be used largely determining the core perceptions and methods of marketing of biosimilars. For many users and uses, right or wrong, names will determine how and to what extent biosimilars are unique or (bio)generic, while also only supporting safe use.  With "name" and "nomenclature" not even mentioned in the BPCI Act and testimony (Congressional intent) all over the place on this (much like at the recent public meeting), FDA has no guidance for what to do.  Obviously, for safety sake, FDA will go with unique names (until a fully substitutable biosimilar is approved).  But whose names?; how unique or how generic?; tailored for use by what constituencies?; how informative, useful or not; etc.?  And what about other types of names for other uses/users?
          Who will propose nomenclature and what will FDA's criteria/rules be? Will FDA allow use of trade names (usually trademarks; easily gamed; with every mention of a product essentially being an advertisement); NDCs (useless for nearly all but computer systems); fully unique, arbitrary, meaningless names (what innovators want most); a biogeneric name (including it being used as the name for the innovator product; what biosimilar/biogeneric interests want most); a biogeneric name followed by company name (again more like advertising; susceptible to frequent changes; innovator products likely to be indistinguishable from biosimilars); names indicative of a relationship with the reference product (how and what relationships?); names indicative of common mode of action or drug class; etc.? Will FDA adopt INN (USAN) names, largely controlled and designed for lesser-developed countries (WHO/UN), generic drug substitution and very haphazard, inconsistent, etc.; try to jury-rig USANs with suffix modifiers; etc.? Will FDA add prefixes to base names, making it impossible to search for similar products in lists/databases, or will FDA adopt addition of suffixes, perhaps obscuring essential safety-related differences among products? What happens when a product is substantially changed, e.g., it is totally reformulated, but receives sBLA approval (is recognized by FDA as being the same product)? Should major product changes (different versions) be recorded in product names, e.g., add subscripts to names? How do you deal with nomenclature for biosimilars approved for just one/some indications approved for the reference product?
          Nomenclature/names invariably involve compromises; there will be no neat or simple resolution to naming; and most everyone is going to be unhappy to some extent (which is why everyone needs to at least follow these developments).
          FDA rulings regarding established/official (compendial) names are only part of the problem. In the real world, there are many other uses and user communities with different needs (e.g., quasi- and fully biogeneric names), e.g., payers will prefer and use their own names/identifiers indicative of real-world substitution (likely to become mandated by payers for biosimilars, if at all possible, irrespective of formal approvals); and essentially every pharmaceutical reference, formulary, pharmacopeia, etc., inherently treats all pharmaceuticals as generics (uses generic names), making no distinctions between similar/generic products. Along these lines, the general public, press, analysts, etc. will invariably use biogeneric names. And these and many users/user communities will also use quasi- or fully generic names for biobetters/biosuperiors, despite these being distinct, innovative products themselves. Who will propose and coordinate such unofficial names?
          To help resolve nomenclature problems, the Biotechnology Information Institute (me, this site's owner) is proposing the U.S. BIOPHARMACOPEIA Registry of Biopharmaceutical Products as a ideally a collaborative, industry-based project to propose candidate product nomenclature, both unique and (bio)generic, and provide public access to a related registry tracking biophamaceuticals/biosimilars in U.S. commerce. See www.biopharmacopeia.com. This would be similar in many respects to the CTFA (cosmetics trade assoc., now renamed) Dictionary, with an industry-based committee proposing the nonproprietary names accepted by FDA for cosmetic ingredient product labeling since the early 1970s (and largely responsible for cosmetics managing to continue to totally avoid FDA premarket filings/clearance). Regrettably, despite biopharmaceuticals being a distinct >$85 billion/year industry primarily based in the U.S., this industry lacks its own U.S. trade association or similar representation willing to get involved in nomenclature or other product-specific technical issues, other than lobbying, PR, broad public pronouncements, expropriating biopharmaceuticals' good public image for their own purposes (e.g., PhRMA laying the foundation to rename itself as 'biopharmaceutical'), etc.  
          The alternative to industry and/or others proposing biosimilar nomenclature is to leave everything, even proposing of candidate names, fully to FDA. Beside almost everyone presuming (knowing) that FDA would make a mess of things, FDA has no clear mandate and (until we learn otherwise) no budget to take on more resource-intensive regulatory responsibilities.
  • FDA Holds Public Meeting on Biosimilars Regulation:  FDA held a 2-day public meeting on Nov. 2 and 3 to receive comments regarding implementation of biosimilars regulations. Over 40 stakeholders presented brief comments (limited to 6 minutes each).
  • FDA Delaying Implementation of Biosimilar Regulations:   With the biosimilars approvals-enabling legislation enacted, It is now up to FDA to interpret the law passed by Congress and develop related regulations and precedures.  And with the incredible lack of clarity, ambiguity and critical omissions in the enabling legislation, this will not be easy. Although FDA has had many years to prepare for this and some biosimilars applications have already been filed, it remains fully unclear how long it will take FDA to get its act together and establish regulations and precedents for biosimilars approvals.  Despite few, if any, surprizes in the legislation passed by Congress, FDA has apparently not yet started to accept and process biosimilars applications, or at least has been reported to be telling sponsors seeking meetings regarding planned biosimilar BLA filings to please wait several months while they continue to finalize plans for policies and procedures. If anything, the surprises in legislation probably involve what was deleted or totally ignored, leaving FDA with no guidance and having to resolve politically/economically important issues. While some might think this ideal, giving FDA the freedom to do things right, that is often not how it works with government agencies, where lack of direction can mean years of delays; providing opportunities along the way for adversaries to confound and delay the process. Otherwise, we can expect FDA to set up advisory committees for biosimilars, perhaps one each for CBER and CDER, with each of these FDA divisions handling different classes of biologics.
         It remains to be seen whether FDA will view development of biosimilars regulations more as a politcal vs. science-driven activity. For example, all mention of the issue of product nomenclature/names was deleted from final legislation, and it remains to be seen how FDA will deal with this (see related article below).  Other unresolved issues with no real guidance from Congress include transparency and information disclosure/access, e.g., with a biosimilar sponsor's absolute worse commercial enemy, the reference product manufacturer, provided the full BLA for the biosimilar, what product safety, including manufacturing process and QA/QC, information will publicly disclosed (or not)? This author has spoken to at least one major biosimilars player that apparently submitted biosimilar applications the very first day after recent legislation became law, so it is possible that we may see decisions on biosimilar applications delayed past their PDUFA (target approval decision) date.  
         It will be interesting to see how and how long it will take for FDA to actually implement biosimilars regulations (or not), such as will the agency implement regulations in coming months or will it just propose them (or just parts), seek extensive public comment, etc. with this effectively delaying both implentation of policies and presumably consideration of pending applications. With biosimilars, by basic definition, not being new/innovative and not providing significant improvements in patient care, but providing more choices/alternatives and potentially lowering costs, will FDA simply give biosimilars low priority? Will resolution of remaining biosimilar issues, implementation of regulations and approvals (precedents) continue to be delayed and will what results be coherent and workable? Will biosimilars get needed agency staff, budget and support? Has the agency already moved on to other higher priorities, now that biosimilars are no longer being debated in Congress? Judging FDA by its actions (or inaction) so far, including issuance of nothing useful despite the laws being in force for months (since March), biosimilars simply do not appear to be a high priority.
  • Biosimilars Legislation Enacted by Congress:  H.R. 3590, the "Biologics Price, Competition and Innovation (BPCI) Act, part of the "Patient Protection and Affordable Care Act" (broad health care reform act) was enacted on March 23, 2010. This was a very large bill incorporating many changes in the U.S. health care system, with biosimilars approval-enabling legislation just a small part.  The biosimilars portion of the bill is "TITLE VII--IMPROVING ACCESS TO INNOVATIVE MEDICAL THERAPIES, Subtitle A--Biologics Price Competition and Innovation."  See the full text of this section. 
  • Commentary regarding U.S. legislation, posted April 7, 2010
    Biosimilars Legislation Fails to Resolve Major Issues/Problems: Evergreening and Names:  Congress failed to deal with probably the two most important issues that will shape the future of the U.S biosimilars market and through this the broader biopharmaceutical markets -- evergreening and product names!  Stripping out the hard, substantive parts and avoiding key issues is one way of achieving consensus and getting a bill passed.  Among the issues obfuscated or otherwise left fully undefined or ambiguous in recent legislatation are "reference product," with this determining "evergreening" opportunities, and the names to be used in commerce for biosimilars.
         "Evergreening:"  The law is unclear regarding opportunities for infinite evergreening or the pepetuation of data exclusivity for "reference products" based on BLA holders simply making a change in their product (other than a change in structure or affecting safety, efficacy, use, etc.), such as as significantly updated manufacturing process or formulation, claiming it is new based on this (remember the "process=product" innovator slogan) and filing and obtaining a full BLA for the "new" product. The section from the bill concerning granting of 12 years exclusivity states:
    "(7) EXCLUSIVITY FOR REFERENCE PRODUCT-
    (A) EFFECTIVE DATE OF BIOSIMILAR APPLICATION APPROVAL- Approval of an application under this subsection may not be made effective by the Secretary until the date that is 12 years after the date on which the reference product was first licensed under subsection (a)."
    Thus, "reference" products receive 12 years of data exclusivity after the date of their approval.  BUT "REFERENCE PRODUCT" IS NEVER DEFINED, SUCH AS LINKED WITH EITHER A SPECIFIC APPROVAL OR DEFINITION OF NEW PRODUCTS, LEAVING THIS WIDE OPEN TO INTRERPRETATION!  What approval and what product?  Do we base defining "reference product" on consideration of the product, including manufacturing processes and formulations; the product's original BLA (which can be hard to determine for products on the market for decades); or upon the most recent BLA approval for the current version of the product (which is the simplest method but is easily gamed to allow evergreening)?  Full BLAs can be obtained by making some change regarding a product and filing a full BLA, with there being no regulations stipulating what changes in a biologic require or allow filiing a supplemental or full BLA.  There are even multiple recent examples of biologics receiving new full BLAs where absolutely nothing related to the product was changed, e.g., a new indication was approved or the product was relabelled for marketing by a different company.  So, BLAs have little meaning in terms of defining products or new products (with this something BLAs were never designed to do).  It is fully ambiguous whether a reference product is defined by its latest or its original BLA (however that may be defined). Does receipt of a BLA automatically define a new reference product that receives data exclusivity? This is certainly the simplest (or most simplistic) way of defining a "reference product" (and granting data exclusivity), and surely the definition favored by innovator product manufacturers. Or will FDA look at the product, ignore obvious follow-on versions (however these may be defined), often involving updated versions (new BLA, maybe a rejuggered proccess and/or new name, swapped in for prior product) and not consider these to be "reference products" deserving 12 years data exclusivity?  If the later option, i.e., making case-by-case decisions regarding "reference products, is to be used by FDA, it seems logical that the well-established guidelines used to determine whether orphan products deserve related exclusivity should be adapted by FDA. No matter how nomeclature is resolved, law suits regarding product names appear likely.
          Further complicating the situation concerning "reference products," the law rules out granting of data exclusiviity based on supplemental BLAs.  This has major implications.  There will often be two different "reference products:" 1) the product/approval (i.e., version) used to determine the data exclusivity start date, as exemplified by a BLA approval (either the latest or original for that product); and 2) the actual, the real "reference product" used in the biosimilar BLA filing, with the biosimilar sponsor obligated to use the current or a recent version of the referenced product, which in most cases will involve a product defined by its latest supplemental BLA (sBLA), with the current product perhaps substantively different (but still "comparable") to its prior version (exemplified by its own sBLA or BLA).

2009
  • Update on Congressional Legislation - As 2009 ends, biosimilars legislation has been included in the overall health care reform bill. Thus, enactment of biosimilars legislation is linked to this bill with all of its complications and baggage, including controversial provisions that may (or may not) allow federal payment for abortions, access by immigrants to health care and many other issues affecting a large number and variety of constituencies. So far, 12 years of data exclusivity is proposed for reference (innovator) products, with biosimilars to be treated as fully independent products with their own unique names (no generic-like substitution or interchangeablility).
          With the U.S. biopharmaceutical industry lacking its own trade association or other dedicated representation, with trade organizations with much broader interests (all biotech, all pharma, all generics, etc.) claiming to represent the industry's best interests, with no one willing to publicly discusss the fundamental issues here (considered too complex for politicians and public discussion), and with legislators happy to ignore difficult technical issues, any legislation will likely remain vague and inadequate in these and other respects. The prevailing attitude among those involved appears to be:  pass a bill giving us or our constituencies what we want (e.g., 12 years exclusivity; unique names for products, etc.), including considerable vagueness and ambiguity (wiggle room), and let FDA and the courts sort things out later (and I haven't even mentioned the complex patent-related aspects of the bill).
  • Will biosimilar regulations in the U.S. result in lower prices?  In this author's view, probably not.  Biosimilars are simply biopharmaceuticals approved by a different approval mechanism.  These will not be generics.  There will be no interchangeability/substitution with these products (at least for many years), and these will be marketed as branded products.  Most "biosimilars" currently in development, particularly those from major players, will be improved versions of older products, and with their novel aspects will not even qualify for biosimilar approval.  With 12 years data exclusivity and an associated label of being "innovative" assigned to products receiving full approval, and with "biosimilars," like the term "generic," having negative connotations (if not now, surely after innovator and their and other sponsored public and professional educations efforts), why would any company seeking significant sales and profits want their product to be marketed as as "biosimilar?"  As shown by the pitiful market penetration of biosimilars in the European Union (at best 5-10% in just a few countries), lower prices do not translate into market share and sales (although European (bio)pharmaceutical marketing is much different from the U.S.).  Products approved in the U.S. as "biosimilars" could well end up being lower-end products, particularly knock-offs or copies of old products, mostly from no-name, small, virtual and foreign companies. And with more new and improved products in the market and these probably providing some (but minimal) cost savings, why would anyone want to use copies of decades old reference products no longer considered the standard-of-care, much less state-of-the-art? The U.S. health care system has an inherent bias towards using the best and innovative pharmaceuticals, and biosimilars will not change this.
          But things could get ugly, e.g., with physician, prescriber and patient coercion and lack of choice, and the outcome could be much different, with biosimilars attaining significant U.S. market share and lower costs. This could happen, if insurance companies and/or health care rationing broadly force use of cheaper products (something payers already commonly do with their refusing to reimburse for anything but their preferred or forumulary-listed products). 
  • FDA Official Comments on Biosimilars Legislation/Regulation - Finally, in late June, after years of this Web master writing articles, making presentations, communicating with the various parties involved in legislation, and the main recurring theme discussed at this site, someone in authority has publically stated the obvious, which has been assiduously ignored and avoided by all involved parties ((because it is defintely not a simple or trivial task) -- You cannot regulate something, particularly something as complex as biopharmaceutical products, without defining what is being regulated!  Dr. R.A. Yetter, Associate Director Review Management, CBER/FDA, at the recent Drug Information Association (DIA) conference stated, "The first challenge to a pathway is getting regulations in place that will actually define what biosimilars are.  What is the scope of biosimilars?  Is everything that is a biologic included?  Where do vaccines lay in this approach?"  Answering these questions is the first step that needs to be taken."  To date, all proposed legislation has avoided issues related to the most basic, requisite definitions (and also avoided or simplistically handled issues of terminology and product nomenclature).  Will Congress heed this advice?  Or will U.S. legislation follow that of the European Union and never actually define 'biosimilar' other than circularly - as products approved or on track for approval by the regulatory pathway commonly labeled with this term (with the official term being 'similar biotechnology medicinal products')?
          Related to the issue of defining what is a 'biosimilar' is the the broader issue of defining what is a distinct/unique biopharmaceutical (or biologic) product. Particularly, what changes in an innovator/reference product allow it to be considered new and different (enough), allowing it to receive 5-14 years of data exclusivity? As discussed below, such as in the "What Products Deserve Exclusivity" section, approvals (BLAs) do not define new products and were never designed for this purpose, so presumably FDA will be making product-specific judgments, much as it long has with orphan products and related exclusivity disputes.
  • FTC Issues Report on Follow-on Biologic Drug Competition: Following-up from a prior public workshop, commnents received and agency analyses, the Federal Trade Commission (FTC) has issued Emerging Health Care Issues: Follow-On Biologic Drug Com. Among the conclusions are that "Pioneer manufacturers are likely to retain 70 to 90 percent of their market share and, therefore, will likely continue to reap substantial profits years after entry by FOB drugs;" "A Twelve- to Fourteen-Year Exclusivity Period is Unnecessary to Promote Innovation by Pioneer Biologic Drug Manufacturers;" "Special Procedures to Resolve Patent Issues Between Pioneer and FOB Drug Manufacturers Prior to FDA Approval Are Unnecessary and They Could Undermine Patent Incentives and Harm Consumers;" and "FOB Drug Manufacturers Are Unlikely to Need Additional Incentives to Develop Interchangeable FOB Products." Apparently, FTC believes that an appropriate legislative/regulatory pathway for biosimilars/FOBs should larglely involve giving FDA authority to grant these types of approvals, with much of the other proposed baggage, such as decade-plus data exclusivity periods, elaborately choreographed patent disclosures and litigation and other add-on provisions simply not needed or desireable.
  • Canada Approves Its First Subsequent Entry Biologic (SEB): Canada granted approval to Omnitrope, recombinant somatropin (human growth hormone), from Sandoz/Novartis on April 20, 2009. Omnitrope was approved under preexisting pharmaceutical approval regulations, but Health Canada is working to develop clearer guidelines and a "guidance document" regarding SEB approvals.
  • Study Points Out Data Exclusivity-Related "No Man's Land" and Other Problems: On April 14, Deloitte Consulting LLP released a "paper" (essay), "Avoiding no man's land: Potential unintended consequences of follow-on biologics," pointing out problems with Hatch-Waxman-like data exclusivity provisions included in biosimilars-favoring pending Congressional legislation. Presumably, this was sponsored by one or more established/innovator companies. See the press release/summary and full article.
  • Congress Again Considering Biosimilars/FOBs Legislation; The Difference This Year is That Enactment of a Bill (In some form) is Very Likely: Recycled versions of bills introduced last year (see article below at the start of the 2008 entries) are being (re)introduced this session. Everyone agrees that biosimilars/follow-on biologics legistlation will likely be enacted, with the main point of contention expected to be data exclusivity - how many years. So far, Rep. Waxman and colleagues have introduced H.R. 1427; the Promoting Innovation and Access to Life Saving Medicines Act; and Rep. Eshoo and colleagues have introduced H.R. 1548, the Pathway for Biosimilars Act.
          The Waxman bill is definitely not a compromise bill and clearly favors biosimilar/biogeneric interests. It is basically much the same as, a recycled version of, the bill proposed by Waxman and supporters last year - essentially imposing a Hatch-Waxman generic drug-like regulatory regimen clearly favoring biosimilar interests, including offering just 3-5 years of data exclusivity for reference products and restricting patent royalties for any product found to be infringing another to "reasonable" royalties (something else besides length of data exclusivity likely to be highly contested). This bill also will have (bio)generic-type names assigned to each product.
          The Eshoo bill, like the Waxman bill, is by no means a compromise bill and, in this case, clearly favors referenence/innnovator product interests. Compared to the Waxman bill, this is much shorter. The bill allows for 12 years of exclusivity for referenence products with a two year extension available, if approved for a new indication. The bill also includes FDA providing public "guidance" documents for public comment regardng approvability of products in each class of biologics before a member of this class receives approval, with most presuming such public review and comment can only work in favor of reference product interests, e.g., pressing FDA to essentially seek consensus prior to approval. This bill also will have unique names assigned to each product. Both bills include somewhat elaborate requirements for the exchange of information between biosimilar applicants and reference product companies concerning patents and alleged infringement.
          Looking over these bills briefly, this author saw some improvements (in terms of language, clarity, better definitions) in a few places, but the bills (perhaps, like every Congressional bill) are still full of language and terminology that is unclear, ambiguous, improperly defined and subject to multiple (mis)interpretations (dependent on the vested interests of those interpreting it). These or any other biosimilars bill enacted this year could well turn out to be a stimulus package for attorneys and lobbyists, keeping many employed for many years. Further analysis of these and other bills will be provided, particularly, once one or more actually moves forward and pass through Commiittee(s) for broader consideration by the House and Senate.
          As this author has long noted, everyone appears fixated on biosimilar approvals and how many years of data exclusivity to grant. But in this author's opinion major problems that need to be resolved in legislation and FDA implemention of biosimilars do not involve approvals based partially on similarities, which is a relatively simple matter that will largely be left to FDA. Rather, issues need to be resolved concerning determining when a product becomes a new/different product (what defines a biophamaceutical as a new/different/unique product from other, including its own prior iterations), particularly if data exclusivity is to be granted for new or innovative products. (with this basis for exclusivity never really defined; see the entry below concerning this).
  • FTC Meeting Transcripts Now Available: The transcripts from the Federal Trade Commission's (FTC) Roundtable on Follow-on Biologics: Framework for Competition and Continued Innovation conference are now available.
  • What Products Deserve Exclusivity? Failure to Define New (Different/Unique) Reference Products Provides Opportunities for Infinite Evergreening: While good arguments can be made for providing a period of data exclusivity (inability of FDA to evaluate/approve a biosimilar/FOB application using data from and comparisons with an already-approved product application), there seems to be little thought as to how to determine which approved products/approvals to grant this to. Or, restated, what exactly is a reference product, and when does such a product become a new one (presumably receiving exclusivity)? Proposed legislation and ongoing discussions appear to solely rely on the "BLA standard," i.e., new products, by definition deserving some protection from competition, are defined by their receiving a full BLA approval. However, BLA's have little to do with whether products (final formulation and active agents) are new and different! And looking at precedents, there is no consistency or logic in what products have received a BLA vs. suppplemental BLA (e.g., there are many products with very substantial changes in their nature and manufacture that have received sBLAs, even an example of a change from a human to a monkey host cell line for a live viral vaccine, and there are products with trivial or no changes that receive new full BLAs). Simply stated, BLAs need not define new products. There are multiple recent examples of complex biologics, the exact same product (absolutely no changes), receiving multiple BLAs, generally for new indications. This includes multiple applications filed by their manufacturers as sBLAs, but which only months later were inexplicably approved by FDA as full BLAs (was this because FDA gets higher user fees from full applications?). Apparently, all one has to do to get a new, additional, full BLA for one's biologic is do some clinical trials and receive approval for a new indication or make some changes in manufacture, formulation, etc. and file for and receive a new, additional, full BLA. So, in the context of data exclusivity, full biologics approvals (BLAs) are very gameable, and need not involve any change at all in the product. Current legislation and discussions would grant data exclusivity (period to be determined) to a product based on it having received a BLA(s), with a new BLA defining a new product and restarting the clock, even when there has been no change in the product, its active agent or manufacture; with exclusivity granted to the product (and its active agent) for all, not just for its new, indication(s)!
          About the only alternative to the "BLA standard" is to have FDA make qualitative or subjective judgements as to when approved biologics (to be used as reference products for biosimilar approval) received approval for their current approved form/version. This invoves determining when a marketed product has changed in some respect and become a new product. FDA has long done much this same type of evaluation with orphan exclusivity determinations (based on looking at the product and its active agent, including clinical superiority for a similar product defining it as a new/different product). As this author has repeatedly pointed out, the real issues (which everyone ignores) concerning biosimilars/biogenerics involve determining differences between products and when a product becomes a new/different product (what defines a biophamaceutical as a new/different/unique product from other, including its own prior iterations), with making comparisons and even approvals based on similarities being a relatively simple matter.
    Will Reference Product Manufacturers Be Able to Prevent Approvals for All Biosimilars?: If as indicated in proposed legislation, Congress is going to require biosimilar comparisons with only currently marketed products, many reference products manufacturers can simply keep changing these or even simply take them off the market as biosimilar competition nears (with most every innovator company likely to have 2nd or even 3rd generation improved versions of its likely 20+ years old reference product already on the market). This could be a very effective strategy to prevent approvals of biosimilar versions of reference products. For example, from its perspective, it might be very prudent for Amgen to halt manufacture of its first-generation recombinant erythropoietin (EPO; marketed as Epogen and by Ortho/J&J as Procrit) as expiration of related patents near, negating the possibility of approval of biosimilars and forcing the market to switch to its 2nd-generation, improved EPO variant, Aranesp (until competing 1st-generation-type EPO products with full BLA appovals enter the market).
    Patents and Their Licensing Will Pose Problems for Biosimilars:  Major problems can be foreseen for biosimilar developers. Many patent disputes are likely, not just involving those concerning the usual active agent identity/composition-of-matter patents (e.g., sequence-related, patents in the case of recombinant proteins/Mabs) with the generic drug industry seeming to habitually challenge these patents for every candidate generic drug, often irrespective of these patents seeming to clearly be indisputable. Much more than with small-molecule drugs, there will be complex situations where reference products involve multiple third-party technologies licensed with some or full exclusivity. The complex webs and stacking of these licensed technologies, particularly process-related patents, will likely cause problems for biosimilar entrants, with these enforced by their owners/assignees/licensors, not the reference products companies. With biopharmaceuticals being more complex and typically involving more patents/licensing than drugs, manufacturers of candidate biosimilar reference products have or will surely figure out that licensing (renegotiating, if needed) with full or partial exclusivity the many patents often related to their products will confound and delay biosimilar product entry (while also allowing the reference products companies to deflect blame for patent infringement-related biosimilar entrant delays and blockages).

2008 and earlier
  • Overview of biosimilars approvals-enabling bills considered by Congress in 2008.
    "Access to Life Saving Medicine Act," (S. 623 and H.R. 1038), introduced by Congressman Henry Waxman and Senator Charles Schumer in February 2007;
    "The Patient Protection and Innovative Biologic Medicines Act of 2007" (H.R. 1956), introduced by Rep. Jay Inslee in April 2007;
    "The Biologics Price Competition and Innovation Act of 2007" (S. 1695), introduced by Senator Edward Kennedy in June 2007; and
    "The Pathway for Biosimilars Act" (H.R. 5629), introduced by Rep. Anna Eshoo and Congressman Joseph Barton in March 2008.
  • Fall 2008 presentations by Ron Rader, this site's Webmaster:
    1) "What Will the Market for FOB's Be?  What Forces Will Shape the Market?  How Will New Entrants Compete and Innovators Adapt?," Global Follow-On Biologics:  Preparing for a Post-FOB Approval World, IBC USA Conferences, Bethesda, MD, Nov. 17-18, 2008. As a presenter, I can offer a 25% discount on registration. To obtain this rate, use code IB8194SKR when registering or use this form.
    2) "Information:  The Next Battleground," Biosimilars Conference 2008, Visiongain, Philadelphia, PA, Nov. 11-13, 2008.
  • Industry Comments on Legislative Issues: In April 2008, Rep. Frank Pallone, Jr. (D-N.J.), chairman of the Energy and Commerce Committee Subcommittee on Health, and Rep. Nathan Deal (R-Ga.), ranking member of the Subcommittee on Health, sent a letter to various involved companies and organizations requesting answers/comments to a variety of questions concerning biosimilars/FOBs legislation. The responses released in mid-June are rather informative, and show considerable disagreement on many, if not most, issues.
  • "Stealth" Follow-on Protein Approval by FDA?: Valtropin, a recombinant somatropin (human growth hormone) product best known as one of the the first approvals by the European Union under its biosimilar regulations, received 505(b)(2) FDA approval, i.e., as a follow-on protein based on an abbreviated filing, in April 2007. This author just recently (mid-March 2008) noticed this in reviewing a list of 2007 NDA approvals. Incredibly, absolutely not a single news story in nearly a year has even mentioned this high-profile approval (other than Signals magazine). Seemingly, FDA never reported Valtropin's approval through its normal channels at the time, and the sponsor, LG Life Sciences, never put out a press release. [Is this representative of the level of transparency, disclosures and public oversight we can expect regarding prospective follow-on protein and biologics approvals?].
  • New Follow-on Biologics Bill: The "Pathway for Biosimilars Act" is being introduced (late Feb. 2008) by Rep. A. Eshoo in the House of Representatives. Note, the term now being used is biosimilars. This includes exclusivity provisions for both innovator and biosimilar versions, while giving FDA broad authority to regulate products one-at-a-time, including determining needed clinical trials. But, it does require FDA to issue product class guidance before approving a product, and requires use of a full unique (not generic) name for the product (unstated what this will be and who selects it). Strangely, the bill requires biosimilar sponsor to provide the sponsor of the reference product with a copy of the BLA and detailed information about its manufacture [with biosimilar sponsors providing all of their proprietary information to their prime competitor, with absolutely no provision for public disclosure of any information (no transparancy, public oversight)], and the reference product sponsor must then provide the biosimilar sponsor with a list of any patents that it intends to assert against the biosimilar. This provision is useless without requiring the innovator to report the patents it has licensed exclusively or otherwise in relation to its product, not just patents for which it is the assignee.
  • Congression Research Service Issues Study of Follow-on Biologics Issues: See the full study.
  • Canada Issues Draft Guidelines for "Subsequent Entry Biologics (SEBs):" (late 2/2008). One interesting aspect, unlike proposed U.S. legislation, is that this rules out use of "non-analogous" manufacturing methods, effectively negating use of modern manufacturing technologies and requiring use of technologies similar to those used the innovator, which are likely to be 20+ years old. The guidelines require use of analogous expression systems, cell lines and culture methods. Thus, it appears that a follow-on erythropoietin (EPO) product must be manufactured using the same 1970s technology as used by Amgen, i.e., 1000s of roller bottles in a sprawling plant with complex automated harvesting of media; and for many other products, use of large, often multi-1000-Liter, stainless steel fermentation tanks. Seems like a good way to stall innovation and cripple the competitiveness of Canadian follow-on products in the world market; and a blow to companies developing and offering improved bioprocessing technologies.
  • U.S. Elections Likely to Delay Follow-on Biologics Legislation: With pharmaceutical companies and costs already targeted by the leading Presidential candidates, with each on the record favoring generics, and with one candidate, Sen. Clinton, the sponsor of a biogenerics bill, its seems likely that no legislation will pass Congress before the November elections and biogenerics/biosimilars may become an election issue. Established/innnovator companies may have made an incredible strategic blunder in not compromising this past Congressional session and obtaining a bill before the election started heating up. Currently, they continue to push for 12-14 years of market exclusivity (although I am not aware of any substantive studies that support such a new entitlements program, including how and why the patent system is failing to adequately protect novel products; why FDA should be an arbitor of product innovativeness; and what actual criteria would actually be used). Pro-biogeneric supporters appear very happy to wait, presuming that a more favorable bill will pass after the elections.
  • FDA Getting Involved in Legislation (2/2008): FDA/DHHS will be working with Congress (Sen. Schumer) to propose legislation authorizing FDA approvals of follow-on biologics (or will they now be called biosimilars or something else?). It will be interesting to see what results. For example, as included in prior innovator-friendly proposed legislation, will there be a new entitlement program providing years of market exclusivity for innovator products. [One might presume that FDA does not want be the arbitor of what's new/innovative, leaving the patent system to do what it was designed to; but maybe, it wants more power; and with legislation and FDA never really defining similiarity, identicalness, etc., how will FDA define innovative/unique/original products in yes/no terms, granting exclusivity or not for these finely nuanced, complex products (and prevent gaming of the system?). And will FDA instutute an Orange Book/generic drugs-like patent reporting system, as proposed in an early biogenerics-friendly bill, or totally ignore (never even mention) patents, as in a later innovator-friendly proposed bill?] In other news, the President's FY2009 budget includes funds for FDA follow-on/biosimilars regulation (coming from user fees).
  • Generic Biologics Bill(s) on Hold in U.S. (early 2008); Will Biogenerics Be a 2008 Election issue? - Congress never reached requisite compromises and no bill was passed in 2007. Any bill granting FDA the ability to approve biologics (follow-on proteins or biologics, or some now favoring calling them biosimilars) based on abbreviated filings and similarities to other approved products is on hold until 2008. This could well become an election issue, particularly with Sen. H. Clinton, a likely presidential candidate, a co-sponsor of one of the proposed biogenerics-friendly bills.
  • Generic Biologics Compromise Bill - A compromise bill, the Biologics Price Competition and Innovation Act of 2007 has been introduced in the Senate. This was not appended to the PDUFA/FDA reauthorization bill, which lessened its chances of passing.
  • EU Finally Defines "Biosimilar" [Not really] - Perhaps prodded by this author's noting that EU regulations never actually define what a biosimilar is (other than a product filed for or approved through related regulations), the EU has issued Questions and Answers on biosimilar medicines (similar biological medicinal products). Although . This was hailed by EuropaBio as a "technical" or "guidance" document, but it is obviously meant for public clarification, and is not very technical or officially integrated into regulations.
  • 2nd Generic Biologics Bill Introduced in Congress - The Patient Protection and Innovative Biologic Medicines Act of 2007, reflecting the desires of innovator companies, has been introduced in Congress. As worded, the bill grants 12 or more years of approval exclusivity to innovator/reference products (even if off-patent!), requires FDA to develop product class guidelines before an application can be considered, requires a public advisory committee, completely rules out therapeutic equivalence, requires fully unique names for every product and warnings about substitution on labeling, and never mentions patents, periods of exclusivity or other incentives for pioneer biogenerics, and many other aspects in the earlier, biogenerics-favoring bill (see below).
  • Senate Hearings on Generic Biologics Bill - The U.S. Senate Committee on Health, Education, Labor, & Pensions, chaired by Sen. Edward M. Kennedy (D-MA), held a full committee hearing on follow-on biologics (Access to Life-Saving Medicine Act; see entry below) on March 8. This bill may be attached to the Prescription Drug User Fee Act, which must be renewed before Oct. 1 of this year. Although unlikely to become law in its current form (seemingly a wish list authored by the generic drug industry), some form of generic biologics-enabling bill seems likely this or next year. Many Congressmen, even those who generally support Big Pharma interests, are eager for the tax-payer savings that most presume generic biologics will provide.
  • Studies Project Huge Cost Savings from Generic Biologics - Two recent studies sponsored by pharmacy benefits organizations obviously favoring generic biologics, the Pharmaceutical Care Management Association (PCMA) (see press release and full report) and Express Scripts (see press release and full study), have projected considerable cost savings from implementation of laws allowing FDA approvals of generic biologics. However, the reports adopt some overly simplistic and incorrect assumptions leading to unrealistically high estimates for cost savings (but, they were obviously designed to influence public debate, not as rigorous studies that would pass any peer review). See the response from the Biotechnology Industry Organization (BIO) (press release and full study); and a more realistic, innovator-friendly study.
  • Generics Biologics Bill Introduced in Congress - The "Access to Life-Saving Medicine Act" (summary) authorizes FDA approval of generic biopharmaceuticals, including allowing abbreviated applications based on comparabilty with reference products, designation of interchangeability (therapeutic substitution) and provisions for post-approval periods of exclusivity and disclosures of relevant patents. In terms of products covered, the bill concentrates on recombinant proteins, with only vague references to vaccines, and with no mention of other biologics, e.g., blood/plasma products, cellular products, etc. The bill was originally introduced in the House in late Sept., and has recently been (re)introduced in the Senate (S.623). The bill largely extends Hatch-Waxman provisions to biologics, and in this respect largely reflects the desires and favors biogeneric vs. innovator companies.
  • FDA Treats a Synthetic Drug as a Follow-on Protein? - In July 2006, the FDA refused to approve an ANDA generic drug application filed by Nastech for its generic form of Miacalcin nasal spray (from Sandoz/Novartis) containing synthetic calcitonin, a peptide even smaller/simpler than insulin. FDA cited potential immunogenicity concerns 30 months after filing, and had not previously mentioned this concern to the sponsor. See related article. Apparently spooked by the immunogenicity problems encountered with Eprex (recombinant erythropoietin from Ortho/J&J marketed in Europe), FDA is concerned that chlorobutanol, used as an antimicrobial preservative, including in other nasal sprays, might react with calcitonin, resulting in immunogenic by-products. The company was "completely surprised when the FDA asked us for antigenicity data because this information cannot be used in a generic drug application." The FDA had previously approved an abbreviated 505(b)(2) generic drug application for a recombinant calcitonin (Fortical) nasal spray from Unigene Labs, based on comparisons with Miacalcin.
  • Biosimilar Interferon Filing Rejected in EU - On June 30, 2006, the Committee on Medicinal Products for Human Use (CHMP), European Union, issued a negative opinion (rejected) a biosimilar application filed by BioPartners GmbH for recombinant interferon alpha-2a (Alpheon), essentially a copy of Roferon-A from Hoffmann-La Roche, including posing questions (raising issues to be resolved) concerning basic manufacturing aspects and demonstration of biosilimarity. This shows that obtaining biosimilar approvals may not be as easy as some companies hope/expect. The rejection can not simply be dismissed as due to inexperience, since the company had received the second EU biosimilar approval granted (for Valtropin; recombinant somatropin). With the company admitting that their product had an inferior clinical profile (more relapses after stopping treatment vs. Roferon-A) and that the immunogenicity testing "had not been sufficiently validated," the application appears to be in serious trouble (probably dead).
  • Somatropin Approved as Follow-on Protein by FDA - On May 30, 2006, the FDA approved Omnitrope, recombinant E. coli-expressed somatropin (human growth hormone) from Sandoz/Novartis. Omnitrope, itself, is not particularly significant -- it now joins multiple other E. coli-expressed somatropin products in the U.S. market. Omnitrope's approval is significant, because it is the first biopharmaceutical product (follow-on protein) to be dragged into the courts and receive a much-publicized approval as a generic drug under 505(b)(2) regulations. Prior approvals of somatropins had been based on full NDAs, including traditional-type safety and efficacy trials, while Omnitrope was approved primarily based on comparisons, including clinical studies of bioequivalence, with Genotropin from Pfizer, the current market leader among somatropin products in the U.S. Omnitrope's approval does not establish new precedents, since FDA has recently granted other abbreviated 505(b)(2) generic drug approvals to other biopharmaceuticals, e.g., calcitonin, glucagon and multiple hyaluronidase products, including a recombinant form (see FDA's Q&A concerning the Omnitrope approval). FDA has not yet issued guidelines, which it has been working on for years, for even the simplest drug-like products (e.g., somatropins, insulins), much less more complex biopharmaceuticals, including those regulated as biologics. In all likelihood, Omnitrope could have been approved by FDA years ago (the NDA was filed in July 2003), if Sandoz had simply conducted the usual Phase III-type safety and efficacy studies (i.e., submitted a full, not abbreviated application), and likely at a cost comparable or less than that now including considerable legal fees. [Sandoz recently won a suit against FDA in federal court requiring FDA to rule on its NDA. FDA had been putting this off while it works on guidelines for 505(b)(2) follow-on protein-type approvals]. Sandoz/Novartis obviously wanted to press FDA on the issue, and along with the related recent European Union approval of Omnitrope as the first biosimilar product, be recognized as a leader in biogenerics.
  • Several Biosimilar Somatropins Approved in EU - The European Union (EU) has approved two recombinant somatropin (human growth hormone) products under its "biosimilar" guidelines - Omnitrope from Sandoz/Novartis and Valtropin from Biopartners. The EU has issued guidelines for some simpler, more drug-like products, e.g., somatropins and insulins. However, these are not as simple and abbreviated as many had hoped; and already at least one company (Pliva) has abandoned fairly advanced development of a biosimilar product (erythropoietin) due to projected clinical trial costs.