Inside Washington: Debate Escalates Over Follow-On Biologics

Hoping to establish an affordable Medicare prescription drug benefit, Congress, the White House, and the Food and Drug Administration are taking steps to increase the use of less expensive generic therapies by reducing protracted patent disputes between brand-name and generics manufacturers.

Generic versions of major medications — such as those for diabetes and heart disease — accounted for 45% of all prescriptions in the United States last year, up 5% over 2001. The generic market is expected to rise even more as blockbuster treatments lose their patent protection, and as health plans, insurers, and large employers offer consumers financial incentives to accept generic therapies. These prescription drug payers, along with generics firms, are also looking for strategies to develop “follow-on” versions of the biologics slated to lose patent protection in the near future.

Currently, there are 350 biotech drug products and vaccines in clinical trials. By 2010, biologics are expected to create a $60 billion market. It may also be important to have multiple sources of important biologics to avoid product shortages, particularly in a national emergency. Consequently, both generics manufacturers and policy makers are looking for legal and technical strategies for developing therapeutically equivalent biologics. Although new legislation before Congress avoids addressing FDA policies to facilitate approval of therapeutically equivalent biotech therapies, generics makers will continue to press for clarification of these issues.

Battle over Biologics

Biotech companies claim that interferons, growth hormones, and proteins do not lend themselves to generic production because live cell cultures yield considerable variation among batches and require much more testing than conventional drugs. Generics makers acknowledge that biologics are more complex but believe that more sophisticated production and testing methods can address product quality concerns.

According to Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research (CDER), agency policy on biotechnology equivalence is “evolving.” The consolidation of oversight for Center for Biologics Evaluation and Research (CBER) therapeutics in CDER provides an opportunity for “coherent policy development,” she says (see “CDER Shifts Personnel to Oversee Biotech Therapies,” below).

FDA will begin examining data requirements for generic biologics in coming months, Woodcock explains, noting that evaluation of equivalence for biotech products usually requires full chemistry, manufacturing, and controls (CMC) information — including comparative characterization data — for the listed drug and the follow-on product. That information is key to determining the need for preclinical safety tests, comparative pharmacokinetic studies, and possibly full comparative clinical studies. Experts on both sides agree that considerable analytical testing — and probably some preclinical and clinical studies — are needed to document the comparability of biotech products. But they also point to advances in bioinformatics, microarray, and pharmacogenomics technologies that yield more reliable testing of comparable therapies.

Hybrid Route

One controversial idea is for FDA to use the 505(b)(2) provision in the Hatch–Waxman Act to approve a biotech therapy that differs from the innovator product but relies on the innovator’s data. Manufacturers have used this hybrid approach only occasionally over the past 15 years to bring some drugs to market, but it is gaining attention as mature generics companies — and some biotechs — see it as a way to develop equivalent versions of complex therapies.

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