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News
(miscellaneous commentary)
2009
Update on Congressional Legislation - As of early November, Congress has largely completed consideration of
biosimilars legislation in it current forms, including
the Senate Health, Education, Labor and Pensions (HELP) Committee and the House Committee on Energy and Commerce both adopting 12 years of data exclusivity for reference (innovator) products.
The House has incorporated its biosimilars' bill within the much larger, primarily Democrat-supported, health care reform package, the "Affordable Health Care for America Act, H. R. 3962
(starting on p. 1528).
The House bill includes attempts to firm-up language defining what is a reference product, e.g., to prevent perpetuation of data
exclusivity by obtaining full BLA approvals for nonrelevant or trivial changes in an already-approved product. Reference product status (for purposes of determining data
exclusivity) will not be granted to subsequent BLA filings for products involving
nonstructural modifications involving a new or change in indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength; or structure modifications
of the biological product that do not result in a change in safety, purity, or potency. While a significant improvement over prior language (none), this still leaves much totally unclear (a mess for FDA
likely to take years to fully resolve).
For example, would a change, such as switch from use of an animal-derived product in culure or formulation to a non-animal one, presumed or proven to improve safety allow a new BLA with full data
exclusivity for a previously
BLA-approved product? Are such changes significant improvements in safety, such that they should be rewarded with exclusivity, or are they trivial changes not deserving reward (which may disincentivize
such safety-related improvements)?
The House bill also requires that labeling and packaging for each biosimilar "bears a name that uniquely identifies the
biological product and distinguishes it from the reference product and any other biological products." But there is no guidance on what types of names, e.g., descriptive or meaningless/arbitrary,
indicative of a relationship (e.g. common/shared part of name) or not, etc. will be
assigned; how many and what types of other names may be assigned or used by the sponsor for the myriad of purposes other than labeling and packaging; who will propose and have the final decision on names
(e.g., will sponsors, USAN/INN, FDA or other bodies propose names?; how will differences of opinion be resolved?; will input be allowed from industry, health care professionals and the general public?:
will there be any mechanisms to appeal names prior to codification by FDA?), etc. Nomenclature is yet another ill-defined mess for FDA to deal with, likely requiring years to resolve.
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 such 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. 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.
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