The heavier emphasis on post-marketing studies in drug development is causing a good deal of disgruntlement among pharmaceutical companies, judging by the results of a US survey.

In the survey by the Tufts Center for the Study of Drug Development (CSDD), 68% of clinical study sponsors and 79% of non-clinical study sponsors said the results of post-marketing or Phase IV studies contributed marginally or not at all to their understanding of the safety, efficacy or quality of their product. Just 32% of respondents felt the studies significantly or very significantly increased understanding of their products.

Tensions over post-marketing studies have been building since a US regulation requiring sponsors to provide annual reports on the status of Phase IV trials took effect in 2001. One moot point is that the US Food and Drug Administration (FDA) does not have real authority to require Phase IV studies as a condition of approval. However, the Food and Drug Administration Revitalization Act (S 1082), the bill to re-authorise the Prescription Drug User Fee Act (PDUFA) that was passed overwhelmingly by the US Senate earlier this month, includes provisions for mandatory post-marketing studies.

FDA under fire

The FDA has come under fire over its hefty backlog of post-marketing commitments. Last July, a report by the Department of Health and Human Services’ Office of the Inspector General (OIG) concluded that the agency was unable to monitor effectively the progress or completion of post-marketing studies, did not consider the issue a top priority and had limited powers to fall back on if drug applicants failed to comply with Phase IV commitments.

Among its findings were that 35% of the annual status reports on post-marketing studies due from pharmaceutical manufacturers in fiscal 2004 were either missing completely or contained no information on outstanding commitments.

The report came hard on the heels of one from the US Government Accountability Office, which also questioned the FDA’s ability to track the safety of medicines once they were on the market. More recently, the agency itself reported that, as of 20 September 2006, prescription drug manufacturers had failed to begin 71% of the post-marketing studies they had promised as a condition of getting treatments approved. Among the 360 out of 1,259 pledged studies that had started, 184 were on or ahead of schedule, 144 had been submitted to the FDA for review and 31 were delayed.

Antidote to public concern

In the meantime, the onus on post-approval monitoring as an antidote to public concern over drug safety and a corollary to efforts to streamline drug development under the FDA’s Critical Path initiative continues to grow. Of the $37.9 million increase for programme enhancements proposed by the FDA in its recommendations to Congress for PDUFA IV, which would cover the fiscal years 2008 to 2012, $29.3 million was directed towards tightening up the agency’s post-marketing surveillance programme.

The Tufts CSDD survey also indicated that completing post-marketing studies on time was a stiff challenge for the pharmaceutical industry. It found that 45% of studies were delayed due to enrolment problems, technical difficulties, additional FDA requirements or sponsors expanding the scope of their own studies.

Moreover, Phase IV trials were expensive and time-consuming, the Tufts Center noted. According to the survey responses, clinical post-marketing studies on average took 10 months longer to complete and cost almost nine times as much as non-clinical studies. Between 1998 and 2005, the Center reported, sponsors spent on average $5.3 million per clinical post-marketing study compared with $610,000 per non-clinical study.

A recent report on Phase IV studies by Cutting Edge Information showed that pharmaceutical companies on average had 1.8 active Phase IV trials running per marketed product. Of these studies, 61% were initiated voluntarily and only 24% were required by the FDA as a condition of approval. The remaining 15% were requested by the FDA or another regulatory body but were not required as a condition of approval.