The Obama administration’s FDA has proposed a relaxing of the rules for pre-approval drug trials, and new research published in the New England Journal of Medicine indicates that the rules may already be insufficient. According to an analysis of drugs approved in 2008 — the last year of the George W. Bush administration — the bulk of the required post-marketing studies had not been performed by 2013, drugs that received expedited review were tested for efficacy less rigorously than drugs that received standard review, and five of the 20 drugs approved — 25% — ended up receiving a “Black Box” warning label by 2013.
In a companion “invited commentary” piece, Daniel Carpenter, PhD, warns that “In the absence of sound, independent evidence and underlying trust, just about everything can go wrong.” He points to previous research to bolster his claims, noting that “new molecular entities approved just before the deadline to complete the drug reviews were three to five times more likely to be subsequently withdrawn from the market for safety reasons or to be subject to an FDA safety alert or a new Black Box warning than drugs approved well in advance of a review deadline.” Boxed warnings, also known as “Black Box” warnings, are described thus by the FDA: “Drugs that have special problems, particularly ones that may lead to death or serious injury, may have this warning information displayed within a box in the prescribing information.”
An example of a drug approved in 2008 that received a Black Box warning is Cimzia, a tumor necrosis factor alpha (TNF-a) inhibitor made by UCB and approved in April 2008 for the treatment of Crohn’s disease, a potentially autoimmune inflammatory bowel disorder. Not even one year later — in January 2009 — Cimzia received a Black Box warning about the risk of serious infections, and in November 2009, Cimzia received another Black Box warning, this time about the risk of lymphoma and other malignancies posed by the drug and others in the TNF-a inhibitor class. Two Black Box warnings within two years of approval — it’s enough to cause “alert fatigue” among prescribing physicians, who may distrust the warnings and disregard them.
In addition to drugs approved in 2008 that subsequently received Black Box warnings, at least one drug approved in 2008 that already had a Black Box warning. Tysabri, the marketing name given by Biogen Idec and Elan to the monoclonal antibody natalizumab, was approved in January 2008 for Crohn’s disease — despite already having a Black Box warning (issued in 2006) stating that Tysabri “increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability.” (Tysabri was previously approved for the treatment of multiple sclerosis (MS). As Dr. Carpenter notes, “the report by Moore and Furberg points to emerging troubles in the regulation of pharmaceuticals in applying the standards used for drugs for AIDS, cancer, and other life-threatening diseases to a wide variety of disorders that are either less severe or already have established, well-tolerated treatments.” Indeed.