Washington Report

Generic Drug Battles Heat Up

Jill Wechsler

It seems that everyone wants to hop on the generic drug manufacturing bandwagon. Novartis recently moved to become a lead player in the sector, and other major brand-name firms may follow (see sidebar, “Brands move in on generics”). Biotech companies as well as generics makers are eyeing opportunities to develop follow-on protein products. The Bush administration is promising to approve more generic AIDS therapies for distribution to third-world nations. With Medicare poised to greatly expand government purchases of prescription drugs, pressure is mounting for regulators and legislators to remove obstacles that block low-cost generic products from the market. Generic drug makers are challenging the sale of “authorized generics” by innovators and are opposing legislation that would grant patent extensions to brand-name firms that conduct research on counterterrorism agents. The US Food and Drug Administration is examining ways to process citizen petitions more efficiently along with other steps to streamline its system for approving new generics for market. Slow but steady After more than a year of discussion and delay, FDA now seems poised to develop formal guidance on how drug manufacturers should tackle the tricky task of developing and testing “comparable,” “equivalent,” or “follow-on” protein products (FOPPs). The last term reflects general agreement that FOPPs may be similar and comparable but not necessarily therapeutically equivalent to an innovator product and thus require a different testing and approval process from that for conventional generic drugs. Innovator firms insist that biopharmaceuticals made from living organisms seldom have manufacturing processes and product formulations that are exactly the same; generics firms, therefore, should be required to conduct animal tests and clinical trials to document comparable safety and efficacy. Generics makers agree in part but claim that improved analytical technology makes it possible to produce very similar products that require much less clinical and preclinical testing to come to market, particularly for less-complex products such as insulin, human growth hormone, and erythropoietin. FDA has accepted abbreviated testing approaches by permitting biotech firms to make significant changes to manufacturing processes without conducting new clinical trials to prove that the changes do not alter product safety, efficacy, or quality. At a hearing before the Senate Judiciary Committee in June 2004 on key issues related to follow-on biotherapies, then-chairman Orrin Hatch (R-UT) said that legislation authorizing FDA to move forward with FOPPs was “inevitable.” He urged biotech firms to stop stonewalling and engage in a constructive dialogue on legitimate scientific concerns. Because generic drugs promise to expand patient access to less costly medicines and to make the Medicare prescription drug benefit more affordable in coming decades, FDA officials are under pressure to articulate a clear pathway for manufacturers to test and ensure the quality and equivalence of FOPPs. Biopharmaceuticals are proliferating and becoming more important for patient treatment, especially for serious and rare diseases, a trend likely to accelerate with the anticipated shift toward more personalized medicines. Increased competition among biotech manufacturers promises not only to reduce product prices, but also to limit the risk of shortages, to encourage product refinement and improvement, and to limit human and animal testing. Current FDA policies make it difficult and costly to develop generic versions of biologics. The laws that govern drugs and biologics are confusing in how they define product “sameness” and “difference,” which are critical parameters for determining drug equivalence and comparability. In light of the current criticism of FDA for being too lax about drug safety, officials are leery of taking any action that might smack of lowering quality standards. Scientists and manufacturers acknowledge that biologics can produce immune system responses, opening the door to a debate over how much preclinical and clinical testing is needed to detect any problems with immunogenicity, toxicity, and carcinogenicity. To ensure that all parties have ample opportunity to air their views on these controversial issues, FDA is proceeding at a very deliberate pace in developing new policies for marketing FOPPs. To this end, FDA cosponsored a workshop with the Drug Information Association (DIA) in February to examine the scientific and technological issues related to FOPP development and marketing. This discussion further detailed  an initial FDA open meeting on follow-on biologics held this past September. FDA next will issue a background document recapitulating agency regulation of proteins and the scientific basis for past and current policies, including immunogenicity, characterization, impurities, pharmacology-toxicology studies, clinical safety, and efficacy. The plan is to lay out the scientific underpinnings for draft guidance on policy changes needed to approve FOPPs, which may appear as a set of “interlocking guidances” that address key scientific issues, explained Janet Woodcock, FDA acting deputy commissioner of operations. After issuing the draft guidance, the agency will hold another public forum to discuss the proposal before finalizing any regulatory approach. (continued)