Approving new drugs is a risky business. Despite best efforts (and frankly, some less than best efforts), newly approved drugs frequently turn out to have unexpected toxicities. One example is unexpected heart toxicity associated with the use of the common pain-killers like rofecoxib (i.e. Vioxx). Another is the surprising heart toxicity associated with the wonder drug for AML (a type of leukemia), imatinib mesylate (i.e. Gleevec).
According to a 2002 paper in JAMA, 8% of new drugs approved by FDA receive “black box” labels warning of toxicities that were not originally detected in drug trials. Another 3% are withdrawn from the market because of safety concerns.
But what about biologics- vaccines, monoclonal antibodies, recombinant protein products, cell derived agents, etc.? There are a number of reasons why one might anticipate even higher rates of “unexpected” toxicities with this class of therapeutics. For one, they frequently cause immune reactions that are exceedingly difficult to anticipate in animal studies. For another, small alterations in production can dramatically change the composition and properties of a biologic product. For still another, biologics often have a very high degree of species specificity, limiting the predictive value of animal studies.
According to a recent report in JAMA led by Thijs Giezen (October 22/29, 2008), 24% of biologics approved for marketing in Europe received “black box” warnings. For first-in-class agents, five of eight compounds were subject to regulatory action following approval. A story in the January 2009 issue of Nature Biotechnology (Jim Kling) provides some perspective on these findings: most biologics are used to treat life threatening illnesses, which may make people more susceptible to toxic reactions (on the other hand, toxicity might be difficult to detect amidst the noise of disease course).
Bottom line: as translational researchers pursue biologics, uncertainty will continue to present a major challenges, necessitating new approaches to pharmacovigilence and trial design. (photo credit: teotwawki 2005)