GAO criticizes FDA's management of postmarketing commitments for drug efficacy

At the request of the Senate Finance Committee, the Government Accountability Office (GAO) has looked into FDA’s management of postmarketing commitment (PMC) trials, specifically those under which a drug was approved using surrogate endpoints to define efficacy, rather than full-blown clinical trials. GAO doesn’t like what it found: out of a universe of 319 requested or required PMCs, over a span of time reaching back to 1992, 42% were still “open,” meaning that the drug sponsor hadn’t completed a study that met FDA’s requirements.

The poster child for slow response is ProAmatine (midodrine hydrochloride), a drug for which Shire Pharmaceuticals was granted approval in 1996, sold through 2003 when it went generic (and is now sold by five generic manufacturers). Despite a requirement (rather than a request) for the PMC, the drug’s efficacy is still unresolved, after 13 years.

GAO says that FDA has “not fully utilized its authority” to regulate drugs lacking the PMCs, even though has the authority to withdraw the drugs’ approval. Moreover, it lacks a consistent method for evaluating how long to wait for studies’ completion. And its own recordkeeping systems for tracking PMC is lax, with start dates or milestones unrecorded.

FDA counters that the use of the surrogates (which began in 1992, under an accelerated NDA process intended to get needed drugs out to market faster) has been effective in getting many lifesaving drugs approved and in use, and that at the very least, the drugs lacking certain efficacy have been shown not to be unsafe for patients. Even ProAmatine can be defended: The drug, a treatment for low blood pressure called orthostatic hypotension, remains the only approved treatment; some clinical data shows a “trend” for efficacy; and in the final analysis, “FDA must carefully balance exercising its regulatory authority versus considering the best interests of patients.”

Under the 2007 FDA Amendments Act (FDAAA), FDA’s authority to require PMCs—and specifically risk evaluation and mitigation strategies (REMS) was expanded. FDA also asserts that its DARRTS (document archiving and records retention system) program will improve overall program management. And Booz & Co. has been retained since 2006 under a contract (recently renewed) to evaluate and make recommendations for its PMC programs.

The report, "New Drug Approval: FDA Needs to Improve Its Oversight of Drugs Approved on the Basis of Surrogate Endpoints," is available at GAO's website.