H.R. 5629, the bipartisan Pathway for Biosimilars Act introduced in the House by Representatives Anna Eshoo (Democrat, California) and Representative Joe Barton (Republican, Texas) on 13 March, "is a pathway to the wrong destination for patients in need of safe and affordable biogenerics", said the Generic Pharmaceutical Association (GPhA). The bill is, at best, "a disappointing distraction that does nothing to advance legislation", commented GPhA president and chief executive officer (CEO) Kathleen Jaeger. "At worst, it's a step backwards that puts brand company profits before patient needs. For a pathway to work, it must ensure patient access. Unfortunately, this new proposal creates a pathway filled with needless roadblocks to access." What particularly bugs the GPhA is the 12 years of data exclusivity offered for reference biological products in the bill, a term that could be extended by two years for a "medically significant" new indication and by an extra six months if the product were approved for paediatric use. Unsurprisingly, this makes H.R. 5629 a good deal more palatable to the research-based industry. The Biotechnology Industry Organization (BIO) commended Representatives Eshoo and Barton for "taking a strong, bipartisan step forward toward developing a pathway for the approval of follow-on biologics". In particular, noted BIO president and CEO Jim Greenwood, the new bill "includes essential elements to ensure that any such pathway follows two critical principles: namely, protecting patient safety and ensuring continued innovation" - although the association feels the minimum 12 years of exclusivity on offer "falls short of the base 14 years that has been demonstrated to be the needed period required to strike the right balance between providing incentives for innovation and follow-on product entry". The Pathway for Biosimilars Act addresses a number of issues around approving biosimilars, including data requirements for applications, guidance documents, interchangeability, exclusivity provisions for both first interchangeable biosimilars and reference products, and measures to ensure transparency in patent disputes. Applications would have to include demonstrated proof of biosimilarity to a reference product, based on analytical studies showing the follow-on product were "highly similar to the reference product notwithstanding minor differences in clinically inactive components", as well as animal studies and a clinical trial or trials that included assessments of immunogenicity and pharmacokinetics or pharmacodynamics. The US secretary of health and human services would have discretion to waive these requirements, although in the crucial area of immunogenicity the secretary would need to have first issued guidance "that the current state of scientific evidence allows for a determination of immunogenicity safety without the need for a study". Interchangeability is another touchstone of the biogenerics debate, not only in the US but in the far more developed European market. Under US state law, a designation of therapeutic equivalence - and therefore interchangeability - means a pharmacist may substitute a generic for the reference product on his/her own initiative. The Food and Drug Administration (FDA) has expressed qualms about the interchangeability of biosimilars. Health and human services secretary Michael Leavitt made the position clear in a letter sent last June to the Senate Committee on Health, Education, Labor and Pensions, in response to proposed legislation on biosimilars. Arguing that the complexity and frequent immunogenicity of protein-based products would in most cases preclude substitution, Leavitt said the "Administration believes that patients should not be switched from the innovator biological product to a follow-on biological product (or vice versa) without the express consent and advice of the patient's physician, and legislation should not allow for determinations of interchangeability at this time". The Pathway for Biosimilars Act does provide a mechanism for determining interchangeability. Specifically, the data filed in support of an approval application would have to show that: The follow-on biological were biosimilar to the reference product and to "any biological product licensed under this subsection that has been determined to be interchangeable with the reference product". The follow-on product could be "expected to produce the same clinical result as the reference product in any given patient for each condition of use prescribed, recommended, or suggested in the labelling of the reference product". For a product that needed to be administered more than once to the patient, the "risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch". Before any such determination could be made, though, the health secretary would need to have issued guidance "advising that it is feasible in the current state of scientific knowledge to make a determination of interchangeability for that product class". To encourage R&D investment in the development of truly interchangeable biosimilars, the proposed legislation includes two years of market exclusivity for the first biosimilar determined to be interchangeable with the reference product. This exclusivity period would apply either from the date the first interchangeable biosimilar hit the market or, if the follow-on product were launched before being designated interchangeable, from the date on which the biosimilar was assigned interchangeable status. As has already been mentioned, reference biologicals would get 12 years' data exclusivity under the proposals. This would apply from the date of first approval - in other words, it would run parallel to any remaining patent life, as would any subsequent extensions for medically significant new indications or paediatric use. The GPhA blurs this distinction somewhat by complaining that the bill includes "an unjustifiable 14.5 years of market exclusivity beyond the years companies already have under their existing patents". The Wall Street Journal swallowed this ambiguity whole, declaring that the Pathway for Biosimilars Act would "give brand-name biotech drugs an extra 14.5 years of patent protection". Of course, data exclusivity represents a far more intractable barrier to generic contenders than patent coverage, which can always be challenged. The bill also stipulates that the FDA must issue final guidance for a product or product class before it can approve any relevant biosimilars. Given the agency's past record on issuing guidance documents for biosimilars, this process - which would have to include an opportunity for public comment - could delay the introduction of a formal approval structure even further. There would, however, be an opportunity to petition for guidance on a particular product class in cases where reference products in that class had less than five years' data exclusivity left to run. In these instances, the health secretary would be obliged to issue guidance within two years of the request. The provisions in the bill on transparency in patent disputes relate to creating a mechanism for information exchange between the innovator company, the generic (or rather biosimilar) challenger and any third-party patent holder. For example, the FDA would have to publish a notice identifying the reference product named in a biosimilar application and notify the reference product sponsor within 30 days of accepting the application, "thereby initiating a timely process that enables biosimilar applicant and patent holders to identify relevant patents". How far this legislation will advance in the current climate remains to be seen. In February, the Bush administration sought to inject some momentum into the long haul towards a biosimilars pathway by proposing in its budget for fiscal year 2009 "new FDA authorities to approve follow-on protein products through a new regulatory pathway that protects patient safety, promotes innovation, and includes a financing structure to cover the costs of this activity through user fees". Despite this mandate, though, the Food and Drug Administration appears once again to have passed the buck to Congress. Last year there were several attempts to push through legislation creating an approvals framework for biosimilars, the most promising of which was The Biologics Price Competition and Innovation Act (S. 1695), a compromise package passed by the Senate Health, Education, Labor and Pensions Committee in June 2007. This bill was not that dissimilar to the proposed legislation now in hand. It offered innovator companies 12 years of data exclusivity for new biologicals while permitting the FDA to approve follow-on products shown to be biosimilar to the reference drug. The agency would also be able to approve a follow-on biological as interchangeable, and the first such biosimilar would benefit from one year of market exclusivity. The bill permitted, but did not require, the FDA to issue guidance documents on the criteria it would use to approve biosimilar and interchangeable products. But the congressional compromise did not carry through to the research-based and generic industries. BIO objected to the interchangeability provisions and insisted that 14 years was the only appropriate exclusivity term, while GPhA described the 12-year protection on offer as arbitrary, excessive, unprecedented and unwarranted. Eventually, hopes of attaching the bill to the massive Food and Drug Administration Revitalization Act were dashed and the year ended once again without an approval pathway for biosimilars on the statute books. This year may be different, though, with the prospect of the US presidential election in November 2008 ushering in a more generics-friendly Democrat administration. It has been suggested the generics industry may have been happy to let last year's proposals slide in the hope of getting a better deal under the Democrats. BIO appears to acknowledge this factor, commenting in its response to the Pathway for Biosimilars Act: "Some special interests publicly say they want to delay follow-ons legislation until next year or beyond. We urge Congress to pass the right bill as soon as possible." It was time all parties worked together "to place patient needs before political gamesmanship", the association added. "The time is now to pass a pro-patient, pro-innovation, pro-science follow-on biologics bill."