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FDA has to address multiple technical and legal issues to bring similar versions of biotech therapies to market.
While Americans were going to the polls on November 2, executives from biopharmaceutical and generic drug companies, research organizations, and patient groups were advising Food and Drug Administration officials on establishing an abbreviated framework for approving “highly similar” versions of licensed biological products. Despite the anti-health reform rhetoric raging all around, there is broad support for the Biologics Price Competition and Innovation Act (BPCI), which was included in the Affordable Care Act (ACA) enacted last March. The 50-some presenters at the meeting agreed that biosimilars have to be safe and effective, and of high quality, and that some clinical trials may be needed to document comparability of these more complex large molecules. Patient advocates urged speedy FDA action to make needed therapies available to patients at affordable prices, but also backed thorough product assessment to ensure comparability to the reference product.
Innovator firms, as expected, proposed a high bar for biosimilars, with extensive product characterization, comparative clinical trials, required post-marketing studies and pharmacovigilance plans, and little chance for product interchangeability. Pharmaceutical and biotech manufacturers also want biosimilars to be very distinct from innovator drugs, with unique names and codes, and labeling that admittedly will limit prescribing. “Biosimilars will be similar, but not the same,” stated Marie Vodicka, associate vice president of the Pharmaceutical Research and Manufacturers of America.
Biosimilar advocates agreed that some preclinical and clinical testing may be necessary, but that study requests should not be excessive or arbitrary. Interchangeability should be possible, although it may require additional testing, and biosimilars should be able to adopt the same names and codes as innovators to ease prescribing and dispensing. Scientists noted that advanced mass spectroscopy and other technology can better characterize biologics, making some in vivo testing unnecessary—and thus avoiding the ethical issues raised by requiring sponsors to conduct redundant animal and human studies.
Fees and exclusivity
FDA has to set user fees for biosimilar applications, and pharma companies want sponsors to fully cover the agency’s advisory and review activities, including postmarketing surveillance. Generics makers are looking for moderate fees linked to metrics that will expedite approvals and not “create a barrier for entry for biogenerics,” stated Mylan Vice President Rasmus Rojkjaer, representing the Generic Pharmaceutical Association (GPhA).
Generics makers are unhappy that the BPCI provides 12 years data exclusivity for innovator biologics, and they’re livid over the prospect of an additional exclusivity period—or patent “evergreening”—for next generation therapies. The substantial exclusivity period is a key feature of the law for brand-name firms, and BIO Executive Vice President Sara Radcliffe claimed that additional exclusivity for structurally modified products is critical to preserving incentives for innovation. The FDA has the difficult task of determining when changes in a product’s safety, purity, or potency make it sufficiently distinct to warrant additional exclusivity.
The new law broadened the definition of biologic to include certain proteins such as insulin and human growth hormone that have been regulated for years as drugs. Now, generic versions of these products may require more extensive testing to come to market, after the FDA sorts out which proteins and polypeptides should be considered biologics, and which are chemically synthesized and thus remain drugs.
Another contentious topic is whether sponsors of biosimilars can reduce the scope of clinical testing by extrapolating data from one study to additional populations or indications. Extrapolation of results across indications may be appropriate when the product’s mechanism of action is well understood, explained Parexel Principal Consultant Bruce Babbitt. But Jim Shehan, vice president of Novo Nordisk, urged caution is using this approach unless “scientifically justified.” The use of foreign clinical data also came up, along with discussion of whether a biotech therapy approved in Europe, but not in the US, can serve as the reference product for FDA approval of a biosimilar.
Rachel Behrman, director of the Office of Medical Policy in the Center for Drug Evaluation and Research (CDER), chaired the meeting and will be weighing these statements and additional comments filed with the agency through December 31, 2010 in developing agency proposals. John Jenkins, director of CDER’s Office of New Drugs (OND), chairs the FDA’s Biosimilars Review Committee that will coordinate advice to sponsors on developing biosimilars and the review of resulting applications. Jenkins has appointed Leah Christl as acting OND associate director for biosimilars to oversee policy implementation and relevant training of OND reviewers.
The FDA is expected to issue guidance on many of the key issues discussed, even though sponsors can submit market applications for biosimilars before that occurs. Many experts urged agency flexibility, while supporting more formal guidance to ensure transparency and predictability for biosimilar development; innovator firms promoted a case-by-case approach to weighing test requirements for these products, which could slow product development. The challenge for the FDA will be to find a middle ground that will bring needed products to market.