By Kevin E. Noonan —

The Subcommittee on Health of the House of Representatives’ Committee on Energy and Commerce recently solicited comments and information on so-called "follow-on biologics" (FOBs) from stakeholders and other interested parties.  The Subcommittee on Health’s letter, signed by Subcommittee chairman Frank Pallone, Jr. (D-NJ, 6th Dist.) and ranking member Nathan Deal (R-GA, 9th Dist.), elicited dozens of responses, from innovator and generic pharmaceutical companies (including Amgen and Biogen Idec on one hand and Teva Pharmaceutical and Mylan Labs on the other); industry groups like the Biotechnology Industrial Organization (BIO) and the Generic Pharmaceutical Association (GPhA); benefits providers (including General Motors Corp., the AFL-CIO, and UAW) and special interest groups, like AARP and the National MS Society.  Here, we set forth the Subcommittee’s questions, broken out (as they are in the letter) in subcategories of related questions:

Science/Safety:

1.  What is immunogenicity?  Why is immunogenicity a special concern for biologics and what are the risks to patients?  Do immunogenicity risks vary depending on the type of biologic?
2.  To what degree, if any, is immunogenicity testing necessary?  Should immunogenicity testing be mandated by statute for all follow-on biologics (FOBs) or should the Food and  Drug Administration (FDA) be given discretion to determine whether such studies, and what types of studies, are needed on a case- by-case basis?
3.  Has FDA exercised appropriately its discretion whether to require immunogenicity testing for manufacturing changes?  Should immunogenicity testing for manufacturing changes be mandated by statute, or should FDA be given discretion to determine whether such testing is necessary?
4.  Should FOB applicants have to provide evidence of similarity, safety, and effectiveness of each indication separately or can evidence for one indication be extrapolated to another?
5.  Under the Food and Drug Administration Amendments Act of 2007, Congress established new authorities for FDA to enforce drug safety.  How should the new postmarket authorities enacted in this legislation be applied to FOBs?  Are post-market studies always needed for FOBs?  Are there situations in which FOB applicants will need to conduct post-market studies that are different from those that have been required and/or requested for the reference product?
6.  Should non-interchangeable FOBs be required by statute to have different non-proprietary names from the reference product?  What should the standard be for interchangeable FOBs?  What are the advantages and disadvantages of requiring different non-proprietary names, including any affect on patient safety?  What alternatives are available?
7.  Is it important that an innovator and an FOB have the same mechanism of action?  Why or why not?  If the mechanism of action of the reference product is unknown, should the FOB applicant be required to determine the mechanism of action and ensure that both products share the same one?  Why or why not?
8.  How much variability in chemical structure is there in individual brand biologics:  (1) batch-to-batch, and (2) as a result of manufacturing changes?  What are the implications, if any, for FOBs testing requirements, naming, and interchangeability?
9.  Should human clinical trials be mandated by statute for all FOBs or should FDA be given discretion whether such trials are needed on a case-by-case basis?  Would not requiring human clinical studies of FOBs result in these products having a more difficult time reaching market acceptance?  Why or why not?
10.  What studies have been required for past approvals of protein products under section 505 of the Federal Food, Drug, and Cosmetic Act (FFDCA)?  Have any been approved without clinical trials?
11.  Omnitrope is approved in the U.S. and in Europe (as the first biosimilar).
    a.  Have patients experienced any problems?
    b.  Have patients been switched to Omnitrope from other recombinant human growth hormone products?
    c.  If the answer to part b is yes, how are payers handling the availability of this comparable product?

Regulatory/Administrative:

1.  Some believe Section 505 of the FFDCA provides a regulatory pathway for approval of biosimilars for reference products approved under Section 505.  Should a newly created biosimilar regulatory approval process include all biologics approved under the FFDCA as well as those regulated under the Public Health Service Act?
2.  The current statute gives FDA discretion to decide whether a change in an approved biologic requires assessment through a clinical trial.  Do you think this statutory discretion has been appropriate or adequate?  What has been its effect on patient safety?
3.  What FDA office should review FOBs?
4.  What standards are required to assure sufficient similarity between the FOB and the reference product?  Is the requirement that the FOB be "highly similar" to the reference adequate or should an applicant be required to establish that the FOB is "as similar as scientifically as possible"?  How would FDA assess these requirements?
5.  Should FDA be required to promulgate regulations and guidance before reviewing applications?  Why or why not?  Furthermore, should FDA be required to issue and permit public comment on product-specific guidance before submission of applications?  What are the advantages and disadvantages?  How long will it take to put a regulatory framework in place, including new regulations and guidances for FOBs?
6.  How much in additional appropriations or user fees would FDA need to implement a generic biologics program?  What proportion of resources should come from user fees?  How would that relate to the user fees that are assessed for traditional drugs and/or biologics?

Interchangeability:

1.  Does current science permit an assessment of interchangeability (substitutability) for any biologics at this time?  What is the likelihood that interchangeability assessments for some or all biologics will be possible in the future, and in what period?
2.  In general terns, what types of testing or data would be necessary to establish that two biologics are interchangeable?
3.  How should product-specific requirements for demonstrating interchangeability be established?  Should the statute prohibit interchangeability assessments or give FDA the authority to determine interchangeability as science permits?  Please explain your answer.
4.  Should there be product specific guidances, with opportunity for public comment, on establishing interchangeability before submission of applications?  What are the advantages and disadvantages?
5.  What are the potential risks to patients from interchangeability of one biologic for another?  If FDA finds two biologics interchangeable, should physicians, pharmacists, and patients feel comfortable with substitution by pharmacists?  Why or why not?  How would interchangeability affect patient access to biologics?
6.  How would interchangeability affect competition in the market place, and/or reimbursement by health plans?  Will it affect the costs of biopharmaceuticals?

Patents:

1.  In your view, how long is the current effective patent term for pharmaceuticals?  Specifically, how long on average are drugs marketed under patent protection following FDA approval?
2.  The Hatch/Waxman Act restored innovator patents up to 14 years, and further provided manufacturers with 5 years of data exclusivity.  Is this a good model for biologic manufacturers?  What lessons can we learn from the Hatch-Waxman Act, and apply towards Congress’s discussion about FOBs?
3.  Please explain if patents on biotech medicines will provide meaningful protection of intellectual property if a pathway is created to allow for the regulatory approval of FOBs?  How do patents on biotechnological medicines compare or differ in the value they offer to traditional small-molecule drugs, if an FOB’S pathway requires only that the FOB be highly similar to the reference product?
4.  What procedures, if any, should be included in legislation to enable reference product companies or third parties to identify potential patent infringement claims by a biosimilar company and to ensure timely resolution of legal disputes?
5.  If patent issues are to be addressed in a statute, how should we balance the interests of third-party patent holders and the reference product sponsor?
6.  Should an FOB statute require FDA to administer patent listing and notification provisions as Hatch-Waxman does?  Has this process been an appropriate and efficient use of FDA’s resources and expertise?  Why or why not?  Can appropriate notification be accomplished through an alternative process that does not enlist FDA resources?

Incentives/Exclusivity/Investment:

1.  Should reference product manufacturers be given a period of exclusive marketing in addition to the patent-term restoration already provided to them under Hatch-Waxman?  If yes, how much is necessary to provide adequate incentives for innovation without unnecessarily delaying competition?
2.  What types of assessments have been conducted to determine the minimum term of exclusivity that will enable a robust industry for discovery and development of biologics?
3.  How should exclusivity for modifications to approved products be addressed?
4.  What benefits do innovator firms obtain from data exclusivity, and how is this protection different from patent protection?
5.  Do you think biologics should receive a different period of data exclusivity than drugs?  Why or why not?
6.  What policy considerations justify that patent protections be the principal form of intellectual property protection for biologics and drugs?
7.  If a follow-on biologics pathway was created without additional incentives — beyond existing patent protections — for continued innovation, how would innovation be affected either positively or negatively?  What additional incentives, if any, would be necessary to support continued research and innovation, including at American universities?

Economic Impact:

1.  How much savings would a generic biologics pathway create and in what period (taking into account the time it will take to implement any new law, and the time needed by manufacturers to develop products and submit applications)?  Please describe the evidence on which you base your answer.
2.  Can you provide an estimate of the amount of money your agency/company will spend on biological products over the next 10 years, in absolute dollars, and as a percentage of total program/plan spending?  If FOBs, approved by FDA as comparable to the brand name product, were available, what is your estimate for the cost of the reference product and the follow-on product?
3.  What implications would a follow-on biologics pathway have on U.S. economic competitiveness and leadership in protection of intellectual property rights?
4.  What implications does the treatment of patents in the context of a follow-on biologics approval pathway have for the future of biotechnological innovation?
5.  If a follow-on biologics pathway was created without ample incentives for innovators to continue to innovate, what would the effect be for future research, current clinical programs, and universities?

European Model (abbreviated approval pathway):

1.  The European Union (EU) regulatory system for biosimilars requires the development of product-specific guidances which detail the standard for approval that would need to be met by a biosimilar in a defined product class.  Do you think these guidances would provide similar benefits to industry, healthcare providers, and patients in the U.S.?
2.  Legislation passed by the European Parliament encourages innovation by providing 10 years of market exclusivity, extendable to 11 years for select new indications of use, for innovator biologics, thereby preventing the introduction of FOBs during that period.  Should the U.S. be guided by treatment of drugs and biologics in the EU with respect to exclusivity periods?
3.  If the U.S. adopts incentives for innovation in biologics that are substantially less than those afforded in Europe, what could the potential effect be on U.S. competitiveness?
4.  To what extent do you agree or disagree with the EU’s current model when it comes to access to needed biologics, patent protection, patient safety considerations (including interchangeability), and the length of time needed for the approval of a new product?  What are the advantages and disadvantages of the EU’s model?  Are there other models that the U.S. can examine?  What are the strengths and weaknesses of their models?
5.  FOBs are now approved in Europe, and FDA has approved a number of follow-on protein products under the FFDCA.  Have these shown any problems with respect to safety or efficacy?  In what ways are these different from any safety problems seen with brand products?

Patent Docs will provide summaries and commentaries on some of the answers to the Subcommittee’s questions in future posts.

    By Donald Zuhn —

Earlier this year, we reported on the campaign undertaken by Insmed Inc., a biopharmaceutical company based in Richmond, VA, to raise national awareness about the importance of establishing a regulatory pathway in the U.S. for follow-on biologics.  As part of that campaign, Insmed commissioned an economic study of the cost benefits to patients and healthcare providers from the establishment of a follow-on biologics market in the U.S.  The study, which was prepared by economist Dr. Robert J. Shapiro, former Under Secretary of Commerce in the Clinton Administration, concluded that "generic versions of the top 12 categories of biologic treatments with patent protections that have expired or that are due to expire in the near future could save Americans $67 billion to $108 billion over 10 years and $236 billion to $378 billion over 20 years."

Last month, we reported that Insmed had retained Bill Thomas, a former Representative from California who headed the House Ways and Means Committee from 2001-2007, to help the company promote a follow-on biologics regulatory pathway.  At the time, we noted that Insmed – itself a developer of follow-on biologics – had more than a passing interest in the passage of a follow-on biologics bill.  In fact, Insmed released data in July demonstrating the bioequivalence of its INS-19 biologic and Neupogen® in Phase I clinical trials (see Patent Docs report).

Today, The Washington Post reported on Insmed’s continuing efforts to teach Congress about biologic drugs and about the benefits of follow-on biologics (see "Biotech Campaigns for Easier Access to Generic Drug Market").  In the article, author Kendra Marr discusses the ultimate objective of Insmed’s national awareness campaign:  securing quick approval for generic biotech drugs (otherwise known as follow-on biologics or biosimilars).

Ms. Karr notes that two follow-on biologics bills are currently pending in the House and that one bill is pending in the Senate.  She also notes that the main point of contention among the various groups lobbying for or against the three bills is the length of an innovator company’s data exclusivity.  According to Ms. Karr, Insmed, AARP, and the National Organization for Rare Disorders have been pushing for a 5-year period of data exclusivity, while innovator (or brand) companies and the Biotechnology Industry Organization support a 14-year period.  While Ms. Karr correctly observes that the longer period of data exclusivity would "allow companies to recoup their investment and conduct further clinical trials to improve the product," she incorrectly notes that the longer period is needed "[b]ecause biosimilars aren’t exact duplicates of the original drugs," and therefore "they don’t violate the original drug’s patent, enabling legal distribution before patent expiration."

With respect to Insmed’s generic version of Amgen’s Neupogen®, the article quotes Amgen’s director of regulatory affairs, Andrew Fox, as stating that "Insmed’s limited data appeared to be good data," but also noting that "bioequivalence testing in healthy volunteers does not provide the necessary data on how the biologic actually works in the body, which can only be determined through more extensive clinical testing in patients where safety and efficacy are evaluated."  In response, Insmed CEO Dr. Geoffrey Allan observed that "[biologics] make an enormous amount of money," and argued that innovator companies were seeking longer exclusivity periods simply to protect their drug monopolies.  The debate regarding follow-on biologics legislation, and the appropriate period of data exclusivity, is expected to pick up steam early next year.

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

• "Insmed Announces Partnership With Former House Ways and Means Chairman," July 17, 2008
• "Insmed Announces Bioequivalent G-CSF Biologic," July 10, 2008
• "Dr. Robert Shapiro Discusses Follow-on Biologics Report," February 19, 2008
• "Insmed Announces National Awareness Campaign Regarding Follow-on Biologics," February 13, 2008