Patent Docs

FDA Discusses Initial Considerations for Biosimilar Guidance Documents

By James DeGiulio -- 

Earlier this month, the U.S. Food and Drug Administration recently published its long-awaited guidance documents on Biosimilars/Biosimilarity (see "FDA Publishes Draft Guidelines for Biosimilar Product Development" and "More on FDA Draft Guidelines for "Follow-on" Biologic Drug Approval Pathway").  Some of the first public statements made by the FDA regarding these newly-published biosimilar guidance documents were made in a February 15 presentation by Dr. Rachel E. Sherman, Associate Director for Medical Policy at the Center for Drug Evaluation and Research.  Dr. Sherman moved through the guidance documents quickly, without exploring any particular issues in detail, but there were several notable messages in her presentation that expand beyond the text of the statute and the guidance documents.

Dr. Sherman (at left) opened by noting that the presentation represented the first opportunity for the FDA to interact with the audience targeted by the guidance documents.  The FDA has continually emphasized the guidances' wide target audience, comprising consumers (patients), patient advocacy groups, health care providers, as well as those in the pharmaceutical industry.  The FDA's effort to draft the guidelines so as to be understandable to the average consumer may partially explain the minimal specific requirements throughout the guidance documents.  The presentation continued with an overview of the Biologics Price Competition and Innovation Act (BPCIA) and its effects on the approval of biologics under the current statutory framework (PHSA and FFDCA).  The BPCIA will consolidate the approval of all biologics, as the FDA strongly disapproves the current two-option framework, allowing certain biologics to be approved under either the PHSA or the FFDCA.  The transition to a single approval pathway under the BPCIA is expected to be completed by 2020.

The FDA next responded to the criticism that the abbreviated approval pathway does not promote innovation.  The FDA considers the biosimilarity approval pathway to be innovative because each analytical study required of biosimilar applicants will advance the field of knowledge regarding the molecule of interest.  For example, a biosimilar applicant may have to characterize the function of particular amino acids in binding domains of its biosimilar product, thus providing date to others in the field as to the homology requirements of its biologic.  The FDA would then make a determination of biosimilarity, and consider whether the FDA would require additional testing/studies to support a finding of biosimilarity.  This determination is presented using an entertaining analogy.  Dr. Sherman's presentation contains a line drawing of an elephant (below), where each line represents an analytical or clinical study performed by the biosimilar applicant (Wel J. "Least squares fitting of an elephant." Chemtech Feb. 128-29 (1975)).  The FDA will have to compare the reference product (figure A) with the biosimilar products (figures B-E) to determine what level of detail is required for a determination of biosimilarity (whether the drawing is an elephant or not).  The biosimilar applicant will attempt to draw the minimum amount of lines such that the FDA can make a finding that the biological product is biosimilar to the reference product (elephant).  The FDA will not permit any "tracing" of the lines in the drawing, as these attributes of the biosimilar are already known.  The FDA considers repetition of any animal or human studies to be unethical, therefore they must be avoided.  Each test or study must add something to the whole body of evidence.  This elephant analogy is also used to define "fingerprint" studies, which may tell the biosimilar applicant at an early stage that its product will not qualify for approval under 351(k) (e.g., if early lines in the drawing show a beak or fins).

Animal analogies aside, Dr. Sherman reiterated the importance of meeting with the FDA "early and often" during biosimilar development.  By issuing the guidance documents, the FDA only intended to address the highest priority uncertainty in the biosimilarity standards.  Only the minimum amount of information was included to provide biosimilar applicants with some level of expectation regarding the minimum studies required prior to contacting the FDA.  The FDA expects the minimum characterization outlined in the guidance documents to be performed up front, and then the expectation is that the biosimilar applicant will contact the FDA armed with this subset of data.  The FDA has every intention of, essentially, making up the standards as it goes, and is strongly encouraging anyone who is considering entering the biosimilar space to set up an FDA meeting as soon as possible to discuss.

Perhaps most interesting was the FDA's status report on the current status of received biosimilar proposals.  According to Dr. Sherman, the FDA has currently received 35 pre-IND meeting requests for proposed biosimilar products, corresponding to eleven reference products.  Of course, the applicants and the corresponding reference products were not disclosed.  However, for comparison, the EU has approved fourteen biosimilar products, which correspond to three reference products:  Filgrastim (Amgen's Neupogen), Epoetin (Amgen's Epogen), and Somatropin (Genentech's Nutropin).  From this status report, it appears that many of the biosimilar applicants and sponsors are already aggressively meeting with the FDA regarding the future of their particular biological products.  Other proposals have gone even farther, for there have been 21 pre-IND sponsor meetings held as of February 15, and the FDA has received nine IND applications thus far.

Dr. Sherman commented briefly on interchangeability, confirming that the FDA had not come to any type of conclusions on the standards for interchangeability.  In contrast to the "biosimilarity" standard, the FDA will not be able to rely on the EU guidelines as a model for determining interchangeability, for the EU does not have a comparable provision in its biosimilar regulatory pathway.  The FDA will have to start from scratch in generating this standard, which is unlikely to be clarified anytime soon.  The presentation did note that, under the FDA's step-by-step analysis, the agency would have to first make a finding of biosimilarity before any requests for interchangeability would be accepted.  So the clock on a FDA interchangeability guidance won't start ticking until after the first biologic is approved as a biosimilar.  Unsurprisingly, Dr. Sherman stated that the FDA will "invariably" require at least one human clinical study to show interchangeability once biosimilarity is established.

Finally, Dr. Sherman indicated that the FDA intends to publish future guidance documents on several issues directed to biosimilars (beyond interchangeability):  Package inserts; Product Naming and Pharmacovigilance; and an Orange Book-like publication listing which products are biosimilar and/or interchangeable for a particular reference product.

For those that are interested in viewing the full webinar, a link to the webinar can be found on the FDA's Biosimilars webpage.

FDA Publishes Draft Guidelines for Biosimilar Product Development

By James DeGiulio --

The U.S. Food and Drug Administration published its long-awaited draft guidance on the development of biosimilar products today (see FDA press release), taking a significant step toward the utilization of § 351(k) of the Public Health Service Act (amended by the Biologics Price Competition and Innovation Act (BPCIA)).  Section 351(k) creates a biologics pathway that is reminiscent of the pathway set forth by the Hatch-Waxman Act for small molecule drugs.  The FDA promised that it would release the guidance materials by the end of 2011, but failed to meet this deadline, most likely due to the complexities of the many issues surrounding biosimilar products.  The agency indicates that these guidance documents provide the FDA's current thinking on key scientific and regulatory factors involved in submitting applications for biosimilar products.  As expected, the FDA is seeking public comment on each of draft guidance documents within 60 days of the notice of publication in the Federal Register.

The BPCIA and section 351(k) have been in force since March 2010.  However, without any indication as to how the statute will be implemented by the FDA, the pathway has not gained much traction as an alternative to filing a full Biologics License Application (BLA) for a biologic under the PHSA (42 U.S.C. § 262).  Today's guidance documents provide some direction to companies involved in biosimilar development regarding the factors the FDA will use to evaluate whether to grant a license to their biosimilar products in the United States, despite the draft status of the guidance documents.  Now the biologics industry awaits public notification of the first 351(k) application filing, which under the statute, would set in motion a complex exchange of documents pertaining to the biologic, eventually progressing to litigation between the reference drug BLA holder and the 351(k) biosimilar applicant.

The FDA published the following three draft guidance documents:

1.  Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

The first guidance document is intended to assist companies in demonstrating that a proposed therapeutic protein product is biosimilar to a reference product for the purpose of submitting a 351(k) application.  As the FDA hinted last year, a stepwise approach to demonstrate biosimilarity is suggested, beginning first with structural and functional assays, and followed up with animal and clinical studies.  The FDA intends to evaluate such a demonstration based on a "totality-of-the-evidence," focusing on the assessment of the effects of any differences in the products, rather than requiring an independent safety determination of the biosimilar product.  Following this determination, if the differences in the two products are not "clinically meaningful," the FDA will require fewer or narrower human studies.  Also discussed briefly are post-marketing safety monitoring considerations.

2.  Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product

The second guidance document provides an overview of the analytical factors the FDA will consider when assessing biosimilarity between a 351(k) product and a reference product.  Specific analytical factors include functional activities, expression systems/cell types, manufacturing processes, physicochemical and immunochemical properties, quality and quantity of impurities, stability, and drug-specific reference standards based on the scientific literature.  These factors need not be identical between the biosimilar and reference product.

3.  Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

The third guidance document provides answers to common questions about the BPCIA, many of which were raised at the FDA's public hearings on biosimilars on November 2-3, 2010.  The question and answer format addresses primarily administrative questions that may arise during biologic product development, particularly in early stages leading up to BLA or 351(k) application filings.  Questions are directed to the timing and content of FDA meetings, allowable differences in the formulation/delivery from the reference product, varying scope of the FDA licenses, the types of data that a biosimilar applicant can rely on in their application, and questions regarding exclusivity under 351(k)(7).

Patent Docs will provide a more detailed analysis of each of these guidance documents in future posts.

Top Stories of 2011: #12 to #10

By Donald Zuhn --

Reflecting upon the events of the past twelve months, Patent Docs presents its fifth annual list of top biotech/pharma patent stories.  For 2011, we identified a dozen stories that were covered on Patent Docs last year that we believe had (or are likely to have) the greatest impact on biotech/pharma patent practitioners and applicants.  Today, we count down stories #12 to #10, and then throughout the week, we will work our way towards the top three stories of 2011.  As with our other lists (2010, 2009, 2008, and 2007), links to our coverage of these stories (as well as a few links to articles on related topics) have been provided in case you missed the articles the first time around or wish to go back and have another look.  As always, we love to hear from Patent Docs readers, so if you think we left something off the list or disagree with anything we included, please let us know.

12.  Europe Seeks Unified Patent System

In February, the European Parliament approved a request to use "enhanced cooperation" to launch a reform of the European patent system.  At the time, it seemed to be the last major hurdle to reaching agreement on a unified patent system and court in Europe.  By April, this view appeared to have been too optimistic, as the European Court of Justice ruled that a separate European patent court would violate EU law by taking powers away from courts in EU countries.  Despite the adverse ruling on a unified patent court, the European Commission moved ahead with its plans to create a unified EU patent.

For information regarding this and other related topics, please see:

• "European Patent Reform Suffers Another Setback," April 27, 2011
• "European Parliament Approves Enhanced Cooperation Procedure to Create Unified EP Patent System," March 1, 2011

11.  FDA Drug Approvals at Decade High (Almost)

Trying to counter some of its critics, the U.S. Food and Drug Administration announced in November that the agency approved 35 new drugs in FY 2011, which, with the exception of 2009 when 37 new drugs were approved, constituted the most approvals in the past decade.  Criticism of the FDA has centered around the agency's tougher safety standards, which some argue have slowed down the pace of drug approvals and have hurt the drug industry.  Despite the increase in drug approvals, a Health Affairs paper (published in November 2010, but discussed here in January 2011) contends that extending "data exclusivity" for conventional "small molecule" drugs from the present 5 years under the Hatch-Waxman Act to 12 years (the term given biologic drugs under the Affordable Care Act of 2010) would provide a net benefit in new drugs and increased longevity.

For information regarding this and other related topics, please see:

• "FDA Approves 35 New Drugs in FY 2011," November 20, 2011
• "FDA Drug Approvals for 2011 on Pace to Surpass 2010 Despite New Safety Standards," July 13, 2011
• "Authorized Generics Again under Fire in Senate Bill," February 23, 2011
• "Academic Study Supports Longer Data Exclusivity Term for Conventional Drugs," January 17, 2011

10.  Deficit Debate Delays USPTO Plans

During the first few months of the year, the U.S. Patent and Trademark Office announced a number of new initiatives aimed at decreasing application pendency and increasing examination quality.  However, by April the USPTO announced that the programs, including both Track I examination and the Detroit satellite office, were being put on hold due to budgetary constraints following enactment of the budget for FY 2011 on April 15.  The good news is that several of the initiatives that were delayed last spring were part of the Leahy-Smith America Invents Act (a story for another day).  Of course, securing appropriate funding to implement the new programs will be an entirely different matter (despite Congress' promises to the contrary).  Despite the ups and downs of 2011, the USPTO was able to close the year on a good note when it announced that the number of unexamined patent applications had been reduced to 669,625, which constituted a five-year low.

For information regarding this and other related topics, please see:

• "U.S. Application Backlog Falls to Five-Year Low," October 24, 2011
• "USPTO Publishes Notice Regarding Prioritized (Track I) Examination Delay," May 1, 2011
• "USPTO News Briefs," April 27, 2011
• "USPTO Satellite Offices on Hold," April 25, 2011
• "USPTO News Briefs," April 21, 2011
• "USPTO to Launch Prioritized Examination on May 4th," April 10, 2011
• "USPTO Provides More Details Regarding "Three Track" Examination Proposal," February 7, 2011

Rep. Burgess Introduces Genetic Diagnostic Testing Bill

By Kevin E. Noonan --

A decade after completion of the Human Genome Project, and after more than a decade of hyperbole regarding the promise and benefits of "personalized medicine," genetic diagnostic testing has come to the attention of Congress.  For example, Representative Debbie Wasserman Schultz (D-FL) introduced a provision of the Leahy-Smith America Invents Act (LSAIA) that would have "guaranteed" availability of "second opinion" testing for any patented genetic diagnostic test (see "Manager's Amendment (and Others) to H.R. 1249 -- Second Opinions in Genetic Diagnostic Testing").  She withdrew this amendment in the face of strong opposition from the American Civil Liberties Union and other groups, who pursue a complete ban on such testing as well as other aspects of biotechnology; she later introduced a standalone bill (H.R. 2276) that would "require the Director of the United States Patent and Trademark Office to conduct a study on effective ways to provide confirming genetic diagnostic test activity where gene patents and exclusive licensing exist" (see "Bio/Pharm Legislation Watch"); these provisions were added to the LSAIA enacted into law as a mandate that the U.S. Patent and Trademark Office perform a study directed to such a determination.  And Congressman Xavier Becerra continues to introduce a bill that would ban all gene patenting, at least prospectively (see "He's Baaack!").

The latest Congressional foray into genetic diagnostic testing comes from Rep. Michael Burgess (R-TX) (at left), who introduced legislation that would prohibit the Food and Drug Administration from regulating genetic diagnostic testing, based on the apprehension that such regulation would cripple innovation and that such testing would be "subsumed" by the bureaucracy.  Such testing is already regulated (as is all other laboratory testing) by the Centers for Medicare and Medicaid Services (CMS) under the Clinical Laboratory Improvement Amendments (CLIA).  Rep. Burgess discussed his bill on November 17th at a "bi-partisan policy forum" sponsored by The Hill and the American Clinical Laboratory Association.  The bill was prompted, in part, by FDA announcements that it intends to regulate "direct-to-consumer" genetic diagnostic tests.  Rather than cast the legislation as a ban, his bill (the "Modernizing Laboratory Test Standards for Patients Act of 2011," H.R. 3207) provides for regulation of such genetic diagnostic tests under the current CLIA regime, but with new guidelines and regulations directed towards greater clinical validity of such tests.  The bill also provides for the establishment of a Laboratory Developed Test (LDT) Test Registry Data Bank (for promoting "transparency") and a reporting requirement for clinical laboratories regarding death or serious injury that occurred as the result of a LDT.

In this regard, the bill requires disclosure for LDTs of the following information to the Data Bank:

• The location of the laboratory.
• The certification and licensure information of the laboratory.
• The purpose of the test.
• The claimed use or uses of the test.
• A description of the test methodology.
• Information regarding the analytical validity of the test.
• Information regarding the clinical validity of the test for each of its claimed uses.
• Information describing the status of the test as an existing test (as described under paragraph (4)), a new test pending review (under subsection (c)), or an authorized new test (under subsection (c)(4)(B)).

For so-called "direct-to-consumer" (DTC) DNA testing, the information required to be submitted includes all the aforementioned and in addition:

(i)  The identity, location, and registration information of the test-offering entity.
(ii)  The identity of the certified laboratory that will perform the test, and the certification and licensure information for such laboratory.
(iii)  information to demonstrate that the consumer will be provided with access to pre-test and post-test counseling by a physician or qualified genetic counselor.

Rep. Burgess has garnered the support of 4 co-sponsors (Rep. Marsha Blackburn, R-TN; Rep. Howard Coble, R-NC; Rep. Robert Latta, R-OH, and Rep. Erik Paulsen, R-MN).  The bill was referred to the House Committee on Energy and Commerce, and specifically the Subcommittee on Health, on October 14, 2011.

FDA Approves 35 New Drugs in FY 2011

By Donald Zuhn --

Earlier this month, the U.S. Food and Drug Administration announced that the agency has approved 35 new drugs over the past twelve months.  With the exception of 2009, when 37 new drugs were approved, more drugs were approved in fiscal year (FY) 2011, which ended September 30, than in any other year over the past decade.  The largest number of drug approvals occurred in 1996, when the FDA approved 53 new drugs; the number of annual approvals declining since then.

The new drugs approved this year include two new drugs for hepatitis C and drugs for late-stage prostate cancer, Hodgkin's lymphoma, and lupus.  The last two drugs are the first new drugs approved for treating Hodgkin's lymphoma and lupus in 30 and 50 years, respectively.  In addition, two other drugs (for treating melanoma and lung cancer) were approved with a diagnostic test that helps identify patients for whom the drug is most likely to bring benefits.

In a report entitled "FY 2011 Innovative Drug Approvals," the FDA outlined how the agency boosted the number of drug approvals to 35 while maintaining drug safety standards.  The report notes that that the FDA achieved faster approval times than its counterparts around the globe.  In fact, 24 of the 35 drugs were approved in the U.S. before being approved by any other country.  The quick approvals were made possible in part by priority review and accelerated review procedures.  FDA Commissioner of Food and Drugs Dr. Margaret Hamburg said that the FDA is "committed to working with industry to promote the science and innovation it takes to produce breakthrough treatments and to ensure that our nation is fully equipped to address the public health challenges of the 21st century."

Senators Introduce Bill to Encourage Development of New Antibiotics

By James DeGiulio --

Earlier this year, we reported on the fading interest among larger pharmaceutical companies in developing new antibiotics, despite drug-resistant bacteria representing a serious public health issue (see "Increase in Drug-Resistant Bacteria Creating Need for New Antibiotics").  On October 19, Senators Richard Blumenthal (D-CT) (at right) and Bob Corker (R-TN) (below left) introduced the Generating Antibiotic Incentives Now Act of 2011 (S. 1734), a bipartisan bill designed to spur development of new drugs effective against antibiotic resistant bacteria -- drugs that will be critical as the prevalence of bacterial strains resistant to current gold standard antibiotics continue to spread.

Antibiotic-resistant infections are on the rise in the U.S., particularly affecting children and the elderly.  Also vulnerable are troops returning from Iraq and Afghanistan, as many of them have been exposed to new, highly-resistant, and contagious strains of bacteria, such as Acinetobacter.  Eighty-nine percent of infections caused by mutant strains of Acinetobacter are resistant to at least three classes of antibiotics, and 15% are resistant to all forms of treatment.  Even common strains are reaching critical levels of resistance.  For example, nearly 50% of Staph infections are resistant to most antibiotics.

Economically, antibiotic resistance leads to $26 billion in extra costs annually to the U.S. health care system.  However, despite the clear need, only two of the top six drugmakers are currently developing antibiotics.  Antibiotics do not present attractive targets for drug development, for even if reaching the market, they are not large revenue sources.  Antibiotics are only used for a limited time, thus presenting only a discrete sales opportunity.  The top five antibiotics earned a relatively modest combined $6 billion in 2010 in the U.S.  Furthermore, doctors are often advised to limit antibiotic treatment because of concerns that overuse can spur resistance.

The GAIN Act will provide incentives to increase the commercial value of innovative antibiotic drugs and streamline the regulatory process so that pioneering infectious disease products can reach patients.  The bill instructs the Secretary of the Department of Health and Human Services (HHS) to create regulations to implement this legislation.  The legislation sets out specific definitions of which "infectious disease products" will qualify for GAIN eligibility.  If a product is determined to fall within the recognized category, the HHS Secretary will have the discretion to give it priority review.  The bill also proposes to extend the exclusivity period for these products by five years.  This extended period will be in addition to any extension for pediatric exclusivity.  The legislation would not apply to supplement applications for presently approved drugs, a change that results in a new indication, or a modification to a structure of the product.  The bill would also give a product an extended 6 months of exclusivity if the sponsor or manufacturer identifies a companion diagnostic test.

The legislation further asks the Comptroller General to conduct a study on the need for incentives to encourage the research, development, and marketing of qualified infectious disease biological products.  It would also instruct the Secretary to review guidelines for conducting clinical trials for antibiotics drugs and revise them as necessary.

Senator Corker noted that federal dollars would not be required to provide these meaningful market incentives to antibiotic developers through their legislation.  Senators Blumenthal and Corker were joined by co-sponsors Senators Bennet (D-CO), Hatch (R-UT), Casey (D-PA), and Alexander (R-TN).  The bill was referred to the Senate Health, Education, Labor and Pensions (HELP) Committee.  The companion House Bill, H.R. 2182, was introduced back on June 15th, by Phil Gingrey (R-GA) and Diana DeGette (D-CO), and has nineteen co-sponsors.  The House bill was referred to the House Energy and Commerce Committee, Subcommittee on Health.

FDA Approval of Biologic Drugs under 505(b)(2) Expected to Increase

By James DeGiulio --

Choosing the appropriate regulatory pathway for biologics drug approval by the U.S. Food and Drug Administration has historically not been a strategic decision to be made by drugmakers.  In most cases, only one pathway is applicable to the particular drug product.  The traditional NDA 505(b)(1) path is for new drugs, the abbreviated new drug application (ANDA) path is for generics, and the 505(b)(2) path covers the middle ground, including reformulations and combinations of existing drugs.  Most new biologic drugs today are approved via a Biological License Application (BLA) rather than an NDA, and are subject to the provisions of the Biologics Price Competition and Innovation Act (BPCIA).  Historically, however, approval of biological products as "drugs" required a NDA filing under 505(b)(1), even if the drug was "generic" and based on a reference biological drug product.  A recent run of FDA approvals for "generic" biologic drugs

under 505(b)(2), including Sandoz' recombinant human growth hormone Omnitrope, is drawing attention from biotech drugmakers and may influence their choice of approval pathway, according to an October 10 article published in BioWorld.

The 505(b)(2) pathway, often referred to as a "paper NDA," is an attractive alternative for companies seeking to enter a drug market, for it allows a drugmaker to incorporate preexisting data, including data from expensive clinical studies, into its NDA by reference.  This results in a substantial savings in approval costs; the average 505(b)(2) approval costs $3-7 million dollars, which is far less than the estimated $1.3 billion to bring a new drug to market under 505(b)(1).  However, the 505(b)(2) pathway also comprises uncertainty, as approval requirements are determined on a case-by-case basis and can sometimes require extensive trials despite the availability of preexisting data.

Despite this uncertainty, producers of "generic" or "follow-on" biologic drugs and prodrug compounds are currently pursuing the 505(b)(2) pathway as a viable strategy for products in their pipeline, according to XenoPort Inc. CEO Ronald Barrett.  XenoPort's prodrug Horizant, used to treat restless leg syndrome, was recently approved by the FDA only after the drugmaker refilled its NDA under 505(b)(2) after receiving a complete response letter from its first 505(b)(1) filing.  However, others are skeptical that pursuing a 505(b)(2) path from the beginning would have saved XenoPort time or money.  Since the reference drug gabapentin was never approved for restless leg  syndrome, it is possible that more extensive clinical trials than is appropriate for a 505(b)(2) NDA would have been required.  Nonetheless, last month XenoPort filed for approval of Horizant under 505(b)(2) in postherpetic neuralgia, conducting just one Phase Ill trial to support its bid for approval, and also has a 505(b)(2) filing planned for a multiple sclerosis drug.

Of course, if it is available, the 505(b)(2) path is not always the best choice for all prodrugs and follow-on biologic drugs, for there are tradeoffs in the time and money saved with the 505(b)(2) pathway.  Most of the drugs approved via the 505(b)(2) pathway are reformulations such as liposomal encapsulations, and are not blockbusters.  In addition, these reformulations often get just three years of exclusivity.

Today, specialty pharma and drug delivery companies are most active in 505(b)(2) filings, but this is expected to change soon.  As biologics continue to account for an increasing number of new therapeutics approved, utilization of the BPCIA biosimilar pathway will increase, and fewer standard ANDA opportunities will become available to generic drugmakers.  In addition to biosimilars, generic companies are moving into follow-on biologic drugs, and will further look to drug delivery and other ways to reformulate existing drugs.  To compete, brand biotech and pharma companies will be forced to follow the generics in ramping their own reformulation and drug delivery efforts, perhaps calling upon 505(b)(2) for approval.

FDA Biosimilar Guidelines Complete, Awaiting Publication

By James DeGiulio --

Earlier this year, the U.S. Food and Drug Administration declared that it would release regulatory guidelines for biosimilars by the end of 2011, and since the FDA's announcement, the biotechnology industry has eagerly awaited the agency's insight on gaining approval for biosimilars in a potentially multi-billion dollar U.S. market.  Just last month, the FDA seemed to be a ways off from promulgating guidelines, continuing to struggle with many of the issues involved with these complex biological products.  However, according to a September 22 report by the biotechnology and pharmaceutical industry publication, BioCentury, which interviewed Janet Woodcock (at right), the Director of the FDA Center for Drug Evaluation and Research, the FDA as it turns out recently completed the guidelines.

In addition, Reuters reported last week that the deputy director of the FDA's Europe office in London, Janice Soreth, told attendees at Windhover's Pharmaceutical Strategic Alliances Conference that the release of the biosimilar guidelines could come "as early as the next few weeks, maybe even days" ("U.S. FDA guidance on biosimilars may be imminent").  Soreth pointed to last month's New England Journal of Medicine article (see "FDA Looks to Multiple Sources, Including EMA Guidelines, in Developing Biosimilar Approval Standards"), written by FDA officials, as an indicator of what the guidance might look like.  Soreth said the FDA has received about two dozen meeting requests for proposed biosimilar products, involving potential versions of nine or ten reference products.  The biosimilars panel included traditional generic drugmakers, such as Novartis' Sandoz division, as well as brand pharmaceutical companies like Pfizer and Merck, suggesting that industry players on both sides of the field will be involved in biosimilars.  Many predict that the industry will see companies abandon their typical roles, switching sides from "brand" to "generic," and vice versa (although the term "generic" should not be used to describe a "biosimilar").

FDA Looks to Multiple Sources, Including EMA Guidelines, in Developing Biosimilar Approval Standards

By James DeGiulio --

In an article published in the New England Journal of Medicine on August 4, U.S. Food and Drug Administration (FDA) executives presented a sneak preview of what to expect when the FDA issues its biosimilar standards under the Biologics Price Competition and Innovation Act (BPCIA) later this year.  The article, entitled "Developing the Nation's Biosimilars Program," was authored by Dr. Steven Kozlowski (Director, Office of Biotechnology Products), Dr. Janet Woodcock (Director, Center for Drug Evaluation and Research), Dr. Karen Midthun (Director, Center for Biologics Evaluation and Research), and Dr. Rachel Behrman Sherman (Associate Director for Medical Policy).

If the article was intended to indicate how far the FDA has progressed in formulating biosimilar standards, it appears we may be waiting a while longer, as the article provides minimal substantive guidance.  However, if a preview of substantive biosimilarity standards is desired, the article does indicate that the FDA is evaluating the adoption of some of the guidelines previously developed by the European Medicines Agency (EMA).  The article makes several references to the EMA's Guideline on Similar Biological Medicinal Products, published in 2005, as well as the EMA's 2010 Guideline on Similar Biological Medicinal Products containing Monoclonal Antibodies (see "EMA Publishes Guidelines for Biosimilar Antibodies - Part I" and "Part II"), answering the question of how much the FDA would seek to harmonize its biosimilar guidelines with those of the EMA, and suggesting that the EMA Guideline documents could provide a substantive sneak preview of the FDA's biosimilar standards.

Rather than provide any details on the actual scientific standards, the authors instead categorize the FDA's tentative approach to formulating these standards using a series of buzzwords:  (1) "totality of the evidence," including sponsor input on whether further clinical studies are needed; (2) no chance of a "one size fits all" standard akin to bioequivalence/bioavailability under the Hatch-Waxman ANDA scheme; and (3) depending on how well the mechanism of the biologics are characterized, "fingerprint identification" studies, rather than full scale clinical trials, may be permitted to establish biosimilarity with a reference product.

Biologics vary in complexity from cellular therapies to small, highly purified proteins, although even the simplest biologics typically are more structurally complex than the small-molecule drugs in today's market.  Partly due to this complexity, new biologics require a substantially greater investment from BLA filers (or "sponsors") for their development and regulatory approval.  As a result, biologics tend to be more expensive than small-molecule drugs for patients, and the article notes that these cost obstacles currently limit patient access to these biological products.  The Hatch-Waxman framework has proved very successful in overcoming cost barriers and improving patient access to small-molecule drugs.  In 2009, almost 75% of small-molecule prescriptions dispensed in the United States were for generics, and the approval of a generic drug resulted in average savings of 77% of the product's cost within 1 year.  The article acknowledges that cost reductions for biosimilars probably won't be as large, at least in the early going, but points to the Federal Trade Commission report ("Emerging Health Care Issues: Follow-on Biologic Drug Competition"; see "No One Seems Happy with Follow-on Biologics According to the FTC"), which predicts that the availability of biosimilar products will significantly reduce the cost of biologics and increase their accessibility.

The article outlines the familiar challenges facing the FDA in formulating the standards that an applicant must meet to secure approval for a follow-on biologic product.  The agency must establish scientific criteria that address the key question:  how similar is similar enough when it comes to the substitution of complex biologic drug products in clinical practice?  The complex structures of biologic products are not as easily characterized as small-molecule drugs, with biologics generally requiring more advanced and expensive technology.  Further, therapeutic proteins must have a specific set of structural features, such as glycosylation and protein folding, essential to their intended effect, and slight modifications in these features can affect the performance of these drugs in humans.  This additional secondary structural layer is required to fully characterize biologics, and this layer is more difficult to detect using conventional technological means.  This secondary structural layer, often represented by chemical modifications of the amino acid sequence of the protein, has proven to be just as important as the primary amino acid sequence and structure, for changes in the chemical modifications of biologics affect their immunogenicity and safety profiles.

The authors quickly turn to reassuring the reader that the FDA is fully equipped to deal with these challenges, discussing the agency's expertise in this area.  The article notes that the FDA has worked with biologics since the mid-1990s, evaluating the physiochemical and functional assays used to characterize biologics and test changes in manufacturing processes.  The FDA has made decisions on when animal or clinical studies are required to resolve any remaining uncertainties about the comparability of the products created before and after such changes, these decisions being extremely relevant in setting the biosimilar standards.  The FDA must consider the following balance:  the biosimilar applicant must be required to establish with sufficient confidence that safety and efficacy are not diminished with their product.  However, requiring the biosimilar applicant to repeat all of the clinical trials conducted by the BLA holder would defeat the purpose of the regulatory framework.  The FDA acknowledges that simply repeating all of the sponsor's trials is not feasible and is too costly.  Utilizing knowledge from the reference products, the abbreviated pathway must eliminate unnecessary (and therefore unethical) testing of biosimilars in animals and humans.

Despite the FDA's experience in deciding when additional clinical trials are required to establish similarity between two products, the authors prudently acknowledge that the EMA has even more experience in this area.  The EMA biosimilar guidelines have been in place since 2005, and the EMA first approved a biosimilar in 2006.  The FDA seems to be fashioning its approach after the EMA, relying on the EMA's more than five years of experience in implementing a biosimilar framework, and latching onto the EMA's standards and ideas for determining exactly how many studies will be required.

Continuing with the theme of acknowledging others with more experience than the FDA, the article suggests that BLA holders should expect to be heavily involved with setting biosimilar standards and approving biosimilar products than under the Hatch-Waxman framework.  Sponsor input will be more extensive and will carry more weight, and extensive product review will be required early on.  The new pathway will require a new paradigm for sponsor–FDA interactions.  Although the agency frequently meets with sponsors before they submit investigational new drug (IND) applications, a more extensive product review will be required to determine how much additional data and studies are needed for a biosimilar.  The first step will be taken by the FDA, which will conduct an in-depth review of the biosimilar applicant's comparative analytic characterization and in vitro data.  Once the review of this data is completed, the FDA will work with the BLA holder/sponsor to determine the scope of any required animal and human studies.  Since the BLA holder/sponsor has an interest in keeping the biosimilar product off of the market, the agency is currently considering how to structure this interaction so that neutral and more reliable input can be acquired.

The FDA has traditionally relied on integrating various kinds of evidence in making regulatory decisions, and drafting the biosimilar guidelines will be no exception, as seen by importing the EMA and BLA holder standards.  The FDA authors prefer a flexible "totality of the evidence" approach for assessing biosimilars, since multiple assay technologies are currently used to characterize the structural attributes of biosimilars, and more likely to be developed going forward.  For small molecules, a generic's structure is readily determined by nuclear magnetic resonance, mass spectrometry, infrared spectrometry, X-ray crystallography, or other well-known physical methods.  However, accepted methods such as these do not yet exist for biosimilar products.  Developers of biosimilars who intend to match reference products more closely will need to select appropriate assays and source materials, and tune their processes carefully.  Current approaches to manufacturing process design and improvements in process analytics will become more useful as the technology continues to progress.

Even if certain technological assays become recognized as the gold-standard for determining a biological structure, given the complex nature of biologics, it's unlikely that a "one size fits all" systematic assessment of biosimilarity will ever be developed.  Indeed, the EMA biosimilar guidelines are highly product-specific, with the EMA guidance providing structural, animal, and clinical study requirements for each biosimilar product.  This is in sharp contrast to the Hatch-Waxman small molecule scheme, where often an ANDA filer must show only bioavailability and bioequivalence for approval.  In the biosimilar setting, FDA scientists will need to integrate multiple types of information from multiple assays to provide an overall assessment that a biologic is biosimilar to an approved reference product.  The authors also suggest that implementing a more rigorous pharmacovigilance program will also be significant information source, with an emphasis on tracking adverse events and even the smallest change in manufacturing.  This will inform future decisions not only on that particular product, but also on products that can be grouped in the same class, such as monoclonal antibodies.

Importantly, the development of the mechanism of the biologic's activity will also factor in determining the product-specific standards for the particular biosimilar.  If the mechanism is well known, there might be more flexibility to deviate from the structure of the approved reference product.  For example, if the literature shows that all known glycosylation patterns of a biologic molecule show comparable activity and immunogenicity, a glycosylation pattern identical to the reference product may not be required for a finding of biosimilarity.  Understanding the mechanism of biologic activity, including any clinical information available, will help evaluate the risks of changes in manufacturing by the applicant and the resulting potential to introduce harmful impurities.  This factor is significant to the basic science research community, including university research labs, which could be in a position to secure funding from biosimilar applicant companies that need to establish the safety profile of new manufacturing protocols.

If the mechanism of a biosimilar product is well-characterized, the FDA may accept a "fingerprint"-like identification of similar patterns in two different products.  The EMA monoclonal antibody guidelines introduce an outline to consider when designing biosimilarity studies, including the use of populations, pharmacodynamic markers, and end points that are sensitive to the potential differences between products.  The EMA guidelines allow a biosimilar monoclonal antibody to differ structurally from the reference product, providing a specific set of "fingerprint" metrics are satisfied.  These "fingerprint" strategies were used to secure the approval of the generic low-molecular-weight heparin product enoxaparin, which is structurally different from the reference product.  The authors admit that although animal and clinical studies will generally be needed for protein biosimilars for the foreseeable future, the scope and extent of such studies may be reduced further if more extensive "fingerprint"-like characterization is used.  Therefore, it is conceivable that at some future date, there may be a set of minimum "fingerprint" biosimilar characteristics, akin to the familiar bioequivalence and bioavailability minimum requirements seen in Hatch-Waxman ANDA filings.  Of course, that future date is likely decades away.

Finally, the authors seemingly feel obligated to address the "interchangeability" standard of the BPCIA, which provides for when a biosimilar may be substituted for the reference product without requiring the prescriber's intervention (as in the classic generic drug scenario).  The language in the BPCIA focuses on alternating or switching between the two products, requiring the biosimilar to provide the same risk and clinical result as using the reference product throughout.  The article presents little reason for optimism in meeting such a heightened standard, instead focusing on the FDA's dedication to policing the marketplace to ensure that merely biosimilar products are not substituted for a reference product without the prescriber's consent.  Even equipped with the EMA guidelines as a template, the FDA has its hands full in determining what should be the standards for biosimilarity.  Until the FDA's guidelines are established, the standard for interchangeability is likely to be left to statutory interpretation according to the language in the BPCIA.  This (perhaps purposefully) vague standard is extremely difficult to meet as it reads textually, and it would be surprising if the FDA approves any biosimilar as interchangeable before the year 2020.

FDA Drug Approvals for 2011 on Pace to Surpass 2010 Despite New Safety Standards

    By James DeGiulio --

The Food and Drug Administration has been the subject of recent criticism from drugmaker advocates who allege that the FDA's tougher safety standards have slowed down the pace of drug approvals and have hurt the drug industry.  However, despite these allegedly repressive safety standards, the head of the FDA's drug division, Dr. Janet Woodcock, speculated in May that the FDA would approve more drugs in 2011 than the number of new drugs approved in 2010 ("FDA official sees drug approvals rising").  Barring some unforeseen event, it appears likely that this year, the FDA will easily surpass the number drug approvals for 2010. The FDA has already approved 20 new drugs so far, excluding approvals granted for vaccines or new formulations or uses of existing drugs, almost matching the 21 drugs approved in 2010, according to a recent article in the Wall Street Journal ("FDA's Drug-Approval Rate for 2011 on Pace to Exceed 2010"; subscription required for full access).

These numbers should quiet critics of the safety standards for the time being.  Industry advocates and some lawmakers have criticized the FDA for instituting higher burdens on drugmakers to win approval.  The FDA has tightened safety regulations since the 2004 market withdrawal of the painkiller Vioxx.  After the Vioxx withdrawal, the FDA was criticized by the public for lack of vigilance, and the agency responded by re-evaluating its practices.

Last week, The House Energy and Commerce's health subcommittee held a panel hearing to discuss the reauthorization of legislation that allows the FDA to charge drug companies user fees (which is expected to be renewed, as it is supported by both parties).  However, during the panel, Jonathan Leff, a managing director at Warburg Pincus LLC, a private-equity and venture-capital firm, provided written testimony asserting that the FDA's tougher focus on drug safety has hurt the drug industry and is a major contributor to the rising cost and length of drug development.  Mr. Leff stated that despite potential for producing a marketable and beneficial therapeutic, many promising scientific discoveries are not being developed into new treatments for disease due to lack of investment capital.  He cited figures showing venture investment in the U.S. life sciences industry declined by $2 billion from 2008 to 2010.

In response, Dr. Woodcock (at left) defended the FDA, insisting that the FDA has changed its requirements only because the new science required it.  She pointed instead to the high failure rates of drugs in the development stage, rather than the FDA approval stage, as presenting the main contributor to the rising cost and length of drug development.  Dr. Woodcock explained the agency meets more than 90 percent of deadlines that are part of the drug-review process.  She also said first cycle approvals are at a 20-year high, and more than two-thirds of new drugs are approved within the 6-to-10-month time frame given to new drug applications.  Dr. Woodcock admitted that there are certain cases where companies are asked to submit more information, which prompts additional reviews, and in other cases drugs are rejected.  She did note that expert advisory panels, which generally make determinations on new drugs, have been more difficult to assemble.  In 2007, the FDA tightened guidelines to minimize drugmaker industry ties that could sway a panelist's view.  Since many of the individuals with the most expertise are affiliated with drugmakers, they are ineligible to sit on these advisory panels due to conflicts.  Rather than relying on advisory panels for specific experimental drugs, Dr. Woodcock said she would prefer to see more panel discussions of general policy issues, such as approval standards for a specific area.

FDA Officials Hint at Provisions of Biosimilar Guidances

By Kevin E. Noonan --

Under the biologics pathway provisions of the Patient Protection and Affordable Care Act (P.L. 111-148), § 351(k) of the Public Health Service Act, codified at 42 U.S.C. § 262(k)), the FDA is given the authority to develop procedures for approving biosimilar applications.  Recognizing the complexities of the issues involved, Congress granted the agency broad authority to impose, or dispense with, explicit requirements under the broad umbrella that a biosimilar have comparable safety and efficacy of the reference biologic drug product:

§ 351(k)(2)(A):

(i) REQUIRED INFORMATION.—An application submitted under this subsection shall include information demonstrating that—

(I) the biological product is biosimilar to a reference product based upon data derived from—

(aa) analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically in- active components;

(bb) animal studies (including the assessment of toxicity); and

(cc) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product;

(II) the biological product and reference product utilize the same mechanism or mechanisms of action for the condition or conditions of use prescribed, recommended, or suggested in the proposed labeling, but only to the extent the mechanism or mechanisms of action are known for the reference product;

(III) the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product have been previously approved for the reference product;

(IV) the route of administration, the dosage form, and the strength of the biological product are the same as those of the reference product; and

(V) the facility in which the biological product is manufactured, proessed, packed, or held meets standards designed to assure that the biological product continues to be safe, pure, and potent.

(ii) DETERMINATION BY SECRETARY.—The Secretary may determine, in the Secretary's discretion, that an element described in clause (i)(I) is unnecessary in an application submitted under this subsection.

The devil being particularly resident in the details of how FDA will make these decisions, there is great interest in the standards the agency will set on for fulfilling these requirements, from both innovator biologic drug companies and potential biosimilar drug applicants (who some, like the FTC, believe will be the same companies in many instances).

This month there were hints from FDA officials on the general contours of these requirements.  The most significant of these came from Janet Woodcock, Head of the FDA's Center for Drug Evaluation and Research, who was quoted by Reuters on May 9th as saying that human clinical trials may not be required in every case to obtain biosimilar approval.  She described there being a "spectrum," where "some [biologic drugs] will get much closer than others in your ability to characterize them," for example on analytical grounds.  Dr. Woodcock also said that if a company were to develop a longer-lasting version of a drug (for example, a PEGylated version), or increased its safety or efficacy, such a drug would be considered a "new molecule" that would be entitled to 12 years of data exclusivity, thus raising the possibility of "evergreening" biologic drugs in ways that many in the debate over the pathway thought (or intended) would be precluded.  Dr. Woodcock further indicated that the experience of biosimilar drug applicants in Europe would be considered by the agency.

Similar statements were made by Dr. Rachel Behrman, Associate Director of Medical Policy at CDER in an interview broadcast on the May 1st edition of BioCentury This Week.  In her responses, Dr. Behrman stated that the standard generally was whether the agency "has confidence" that the biosimilar will have the same safety and efficacy as the innovator biologic drug.  Conceding that biologic drugs could not have the same degree of "sameness" as conventional generics, she said that the agency had made an "extraordinary amount of progress" since the Act was passed, including gathering resources for implementation and meeting with manufacturers, including a "significant outreach to the [biosimilar] community."  She also affirmed that the "biosimilar industry" will be broader than small molecule generics and will include traditional innovator companies.

What all these companies want to know is the standards that will be required for biosimilar applicants, and she echoed remarks by Dr. Woodcock that the agency expects to issue guidances -- "not just one" -- by the end of 2011.  She said that analytical comparisons would be "fundamental" in establishing that approved biosimilar drugs will have "the same [biological] effect without any clinically meaningful differences" with regard to safety and efficacy.  The focus will be on analytics regarding, for example, chemical structure of molecule prior to any clinical data, and her remarks suggested that the quality of the analytical data will be relevant to the extent of the biological/clinical testing required.  In this regard, she said that a basic tenet of the agencies thinking is that "duplicative testing is unethical," and that data and other information from biosimilar drugs licensed in Europe will be considered.  She noted however that the law requires a single reference drug product approved by the FDA (i.e., a licensed "American" biologic reference product), which precludes wholesale reliance on European products.  With regard to interchangeability, Dr. Behrman called that a "high hurdle" where the "safety of patients is paramount."  While not enunciating a formal standard, Dr. Behrman said that a patient would have to be able to go "back and forth and back and forth . . . without any compromise in safety or efficacy" for a biosimilar drug to be declared interchangeable.  She also emphasized that each biosimilar drug would be evaluated on a "case-by-case" basis with regard to extrapolation of different indications based, inter alia, on common mechanisms of action.

These considerations will be important, particularly in view of the many biologic drugs that will be "eligible" for biosimilar competition in the next five years, where the market is estimated to increase from $243 million to $3.7 billion, according to a report by Datamonitor.

Fabry Patients Request Rehearing of NIH March-In Request for Genzyme's Fabrazyme Patents

By James DeGiulio --

Last year, following Genzyme's inability to supply patient needs for the enzyme replacement drug Fabrazyme, concerned Fabry patients petitioned the Department for Health and Human Services (HHS) to exercise the government's "march-in" rights under the Bayh-Dole Act and force Genzyme to license the patents covering the drug to other manufacturers who can produce the needed Fabrazyme quantities (see "Genzyme's Manufacturing Issues with Fabrazyme Prompt Patients to Petition HHS Secretary to Exercise Bayh-Dole 'March-in' Rights").  That petition was denied on December 1, 2010, and Fabry patients resorted to bringing a civil suit against the Food and Drug Administration for damages caused by the shortage (see "Fabry Patients Sue Genyzme for Damages Caused By Fabrazyme Rationing").  Genzyme has since reported additional manufacturing errors at its Massachusetts plant that will further delay U.S. Fabry patients access to the drug.  Fearful that Genzyme will continue to delay restoring production of Fabrazyme indefinitely, Fabry patients on April 5 once again asked for relief from the NIH by filing a petition for rehearing of their 2010 march-in request.

On March 23, Genzyme announced that due to vial contamination issues, it had changed the predicted date of restoration of Fabrazyme supply from early 2011 to late 2011.  Additionally, Genzyme announced that due to the loss, it would re-allocate drug away from American patients to overseas markets.  According to the petition for rehearing, this is the ninth consecutive time that Genzyme has pushed back the projected deadline.  The NIH kept the request for march-in open upon receiving information that "progress toward restoring the supply of Fabrazyme to meet patient demand was not proceeding as represented," and that it would revisit the petition upon receiving such information.  Fabry patients have requested rehearing because the latest information from Genzyme contradicts Genzyme's original representations to the NIH.  Genzyme's assurance to the NIH was that it expected to restore full access to patients in the first half of 2011, a deadline which the company appears to be unable to meet based on the latest manufacturing problems.  According to the petition for rehearing, the NIH must now presume, for the protection of Fabry patients, that Genzyme will de facto never be able to reliably supply Fabrazyme to meet patient needs.  Fabry patients ask that another manufacturer be provided with a license to the Fabrazyme patents in order to provide a second source of drug production should Genzyme fail once again.  The petition also cites a conflict of interest, asking for (among others) NIH director Francis Collins to recuse himself from reviewing their petition because they maintain he has a financial interest in at least nineteen federally-funded inventions, which creates "at least the appearance of a conflict of interest."

For additional information regarding this topic, please see:

• "Fabry Patients Sue Genyzme for Damages Caused By Fabrazyme Rationing," March 10, 2011
• "U.S. Patients Petition FDA to Regulate Genzyme Export of Fabrazyme," January 25, 2011
• "HHS Denies Request to Exercise Bayh-Dole 'March-in' Rights for Fabrazyme," December 9, 2010
• "Genzyme's Manufacturing Issues with Fabrazyme Prompt Patients to Petition HHS Secretary to Exercise Bayh-Dole 'March-in' Rights," August 15, 2010

U.S. Patients Petition FDA to Regulate Genzyme Export of Fabrazyme

By James DeGiulio --

In December 2009, the Department of Health and Human Services denied a petition filed by U.S. Fabry patients to secure higher quantities of drug Fabrazyme, exercise Bayh-Dole march-in rights against Genzyme, and issue an open license to U.S. patents needed to manufacture the drug (see "HHS Denies Request to Exercise Bayh-Dole "March-in" Rights for Fabrazyme").  Instead, the FDA entered a consent decree with Genzyme, which gave the FDA authority to regulate distribution of drugs during a shortage, which is the current status of Fabrazyme.  Still faced with the prospect of inadequate treatment options, according to a press release, U.S. Fabry disease patients have now petitioned the FDA to force Genzyme to keep more Fabrazyme for United States patients, rather than shipping it to Europe and other countries.  The initial production of Fabrazyme was sufficient to meet the needs of all patients in the United States.  However, in June 2009, Genzyme decreased production as a result of a viral infection at its manufacturing plant.  As a result of Genzyme's inability to meet the market need, doctors have been prescribing Fabrazyme in doses that are far below the indicated therapeutic use, current patients have been unable to obtain dosage increases, and newly diagnosed patients have been unable to receive therapy.

The petition filed with the FDA requests that Fabrazyme be allocated first to U.S. patients and, if it is not, that U.S. patients be allowed to present their case for medical need before the drug is sent overseas.  At present, only 38% of the total current drug production is actually allocated to U.S. citizens, with the majority of the drug being sold overseas, even though such patients have access to the alternative drug, Replagal, which is manufactured by Shire Pharmaceuticals.  There is no drug shortage in Europe, as the European Medicines Agency has recommended that patients either receive a full dose of Fabrazyme or be switched to Replagal.  The FDA has allowed some Fabry patients to import Replagal from Europe for emergency medical use in the U.S.  However, patients must petition the FDA and then show a critical medical need.

In the U.S., Replagal is not an FDA approved drug, and Shire has withdrawn its application for FDA approval, so no alternatives exist.  Citing the Bayh-Dole Act, the petition argues the public has a right of access to publicly funded inventions, and that depriving the public from this invention is a violation of Constitutional rights, specifically the Fifth Amendment.  According to the petition, by sending most of its Fabrazyme overseas, the current allocation system de facto denigrates the rights of U.S. citizens in favor of non-citizens.

In denying the petition to exercise Bayh-Dole march-in rights, the HHS relied on Genzyme reports indicating that they are very close to renewing and meeting the supply of Fabrazyme.  According to Genzyme, Fabrazyme engineering runs at the company's new Framingham manufacturing facility are nearly completed, and the material created there will become commercial product inventory upon regulatory approval of Fabrazyme production at this facility.  This approval is expected during the second half of this year and will enable the company to provide full, sustainable product supply.

The Medicines Company Clearing Last Hurdles to Patent Term Extension for Angiomax®

By Kevin E. Noonan --

Last week, Judge Claude M. Hilton, District Court Judge for the Eastern District of Virginia, denied APP Pharmaceuticals request to intervene in The Medicines Company's lawsuit against the U.S. Patent and Trademark Office over the timeliness vel non of its Patent Term Extension Request for its patent on the blockbuster drug Angiomax® (bivalirudin).  Coupled with indications from the Solicitor General (cited in APP's briefs) that the government is not inclined to appeal Judge Hilton's order that the Office accept as timely MDCO's Request, there seems to be few remaining obstacles that could prevent the term of MDCO's patent from being extended.  Thus, in due course MDCO's U.S. Patent No. 5,196,404 (which nominally expired on March 23, 2010), will have its term extended by 1773 days, having a new expiration date of January 30, 2015.

APP argued in its brief that it was entitled to intervene as of right, or in the alternative that the District Court should permit the company to intervene using its discretion, because it was injured by the Court's "retrospective changes" in the law mandating extension of the '404 patent.  Specifically, APP argued that it had relied on the expiration dates for patents listed in Orange Book and the U.S. Patent and Trademark Office's "final determination" that the '404 patent was not entitled to extension because MDCO had not timely filed its Request.  Accordingly, APP's ANDA for generic Angiomax® was filed with a Paragraph III certification (21 U.S.C. § 505(j)(2)(A)(vii)(III)), that is the company certified that it would not request regulatory approval until expiration of the '404 patent.  Accordingly, the Court's order mandating an extension of the term of the '404 patent will delay APP receiving regulatory approval for 1773 days.  As a consequence, APP argued, it had a "substantial investment" in developing generic Angiomax®, including lost expenditures of "time, money and people."  Recovery of this investment is now being substantially delayed as a result of the Court's order extending the patent term.  APP also argued that in addition to its investment, it had suffered from lost opportunity costs (in pursuing generic Angiomax® instead of other drugs).  The company also raised the harm to the public due to lack of generic drugs, as well as its own interest (and reliance upon) "promulgation, maintenance, and enforcement of consistent rules and procedures by the PTO and FDA."

APP addressed the standards for intervention as of right under 4th Circuit law based on:  (1) timely motion; (2) an interest in the subject matter; (3) protection of the interest impaired because of the action; and (4) interest not adequately represented by the parties to the litigation.  Its request was timely, according to APP's brief, because it occasions no prejudice to the other parties:  APP requests permission to intervene solely to pursue an appeal of the Court's order.  Its interest in the subject matter was the alleged one million dollars per day of Angiomax® revenues to MDCO to which APP is denied a portion thereof due to the Court's order.  Impairment of this interest is "indisputable," APP argues, since without regulatory approval it cannot enter the Angiomax® market.  Finally, APP argued that its interests are not adequately represented by the government in view of the Solicitor General's disinclination to appeal.  (Even the potential that the government may not appeal, or may not pursue the appeal adequately, is sufficient interest according to APP's brief.)  APP argued that these facts support intervention by right, but further argued that the equities (specifically, that without an appeal from the government it has no remedy) demand that the Court exercise its discretion to permit APP to intervene for the limited purpose of pursuing an appeal of the Court's order.

MDCO opposed APP's motion, arguing that APP has neither Constitutional nor prudential standing to intervene.  There is no basis for the Court to permit APP to "stand in the government's shoes," because inter alia the statutory regime of patent term extension is exclusively ex parte, with no 3rd party rights to challenge.  MDCO's brief cites Federal Circuit precedent -- Syntex (U.S.A.) Inc. v. U.S. Patent and Trademark Office, 882 F.2d 1570, 1575 (Fed. Cir. 1989), affirming No. 08-527-A (E.D. Va. July 22, 1988) (Hilton, J.), and Boeing Co. v. Commissioner of Patents & Trademarks, 853 F.2d 878, 882 (Fed. Cir. 1988) -- that a 3rd party must have an independent right to challenge agency action.  APP's "remedies," insofar as it is entitled to them, are limited to the provisions of the Hatch-Waxman Act (specifically, by refiling its ANDA with a Paragraph IV certification) and § 282 remedies under the Patent Act (regarding invalidity and unenforceability defenses to an infringement action).  In addition, MDCO argued that APP had no Article III standing, if only because the FDA has not yet approved APP's ANDA and thus any injury was speculative at best.  "[APP] is just a third party hoping to obtain a financial windfall if MDCO's patent rights are prematurely cut short," MDCO argued in its brief, saying that this was not enough to confer jurisdiction.  Its brief also argued that there was no jurisdictional basis for APP to intervene under either the Patent Act or the Administrative Procedures Act, and that the right of a third party to challenge agency action is limited to defenses in infringement suits (as set forth in the statute), citing Syntex:

[E]very perceived injury caused by improper agency action does not carry a right to immediate judicial redress.  A right to immediate judicial review must be granted or reasonably inferred from a particular statute.  For example, a potential infringer may not sue the PTO seeking retraction of a patent issued to another by reason of its improper allowance by the PTO.  A remedy must await confrontation with the patent owner [in an infringement suit].

Syntex, 882 F.2d at 1576 (emphasis added).

Turning to APP's arguments, MDCO asserted that APP has not satisfied the requirements to intervene as of right, because at best it had a  "contingent economic interest -- depending on FDA approval of its ANDA -- but not a legally-cognizable interest."  MDCO also argued that APP's motion was untimely, since the government had not definitively stated that it would not appeal (although the Court would be creating a Catch 22 for APP should it base its decision on this aspect of MDCO's argument).

In rebuttal, APP argued that MDCO had applied the wrong law to the issue, since the standards for permitting a party to intervene were governed by 4th Circuit law (not falling under the Federal Circuit's exclusive jurisdiction).  Substantively APP argued that it was not challenging agency action but rather the Court's decision that "retroactively" changed the PTE timing requirements, which was the proximate cause of APP's injury.  Accordingly, MDCO's prudential arguments were irrelevant according to APP's brief.  The company argued that it satisfied the 4th Circuit's requirements for intervening as of right, or alternatively that it deserved the exercise of the Court's discretion to permit it to intervene.

The Court did not agree, denying APP's motion from the bench in a hearing held last Friday.  The Court has not rendered (and may not render) a formal opinion, but the transcript of the hearing will become available 90 calendar days after the hearing, or on December 13, 2010.

For additional information regarding this and other related topics, please see:

• "The Medicines Company Prevails in Patent Term Extension Dispute," August 4, 2010
• "House Passes Patent Term Extension Bill," June 27, 2008