Nearly all of the company representatives and experts interviewed commented on what they perceived as a particularly risk-averse regulatory climate of recent years. Many framed the problem as a disproportionate weighting of risk in the risk-benefit equation, with FDA now appearing hesitant to take on even small amounts of risk, regardless of the potential benefit to patients. Those with several years of experience in the industry observed that this conservatism is part of a cyclical pattern governed by political, Congressional, and media pressure following adverse outcomes.
In describing this perceived regulatory conservatism, many company representatives expressed frustration with FDA’s safety data demands for certain indications. For example, multiple interviewees said that many companies can no longer afford to develop drugs for diabetes because of new cardiovascular risk guidelines. In 2008, in light of published findings that the approved drug Avandia increased the risk of heart attacks, FDA issued guidance requiring that all diabetes drugs undergo a cardiovascular risk assessment lasting at least two years (Harris, 2010). Similar requirements are being considered for obesity drugs in the United States (Pollack, 2012).
While interviewees supported the goal of improving patient safety, they also encouraged consideration of the disincentives created by the new rule. They explained that it takes months to test whether a diabetes drug works to help control blood sugar levels, but it takes years and thousands of patients to determine cardiovascular risk, making clinical trials in this therapeutic class prohibitively expensive. Such barriers discourage investment by venture capitalists, and can drive sponsors to other (non-U.S.) markets or lead them to stop pursuing drugs in these classes altogether, thereby drying up the pipeline at a time when high obesity rates in the United States necessitate more treatment options (Pollack, 2012).
Drug company representatives also warn that safety requirements calling for large programs and large volumes of data can produce unexpected safety signals as a result of multiple comparisons and detection bias. Some feel that FDA is requiring too much investigation of safety pre-approval and could instead allow for more of this work to be shifted to post-marketing studies, while reserving the authority to pull the drugs off the market if these are not completed satisfactorily. Sponsors further argue that at the time of approval, FDA could simply make all information available to clinicians and their patients so that they can make their own decisions.
FDA’s exploratory IND guidance was offered by a CRO representative as another example of regulatory risk aversion. Often, in the early stages of research, there are many potential molecules a sponsor is interested in, and some human data is needed before the sponsor can decide which to pursue. FDA’s exploratory IND rule says that sponsors do not have to have all the toxicity data that they would normally need before getting started, but they can only use 1/100th of a dose in human patients (U.S. Food and Drug Administration, 2006a). The interviewee argued that 1/100th of a dose is not informative, and therefore the rule was of little practical use.