Safety concerns at the FDA

The US Food and Drug Administration is in crisis. Under fire for its record on drug safety, brought to a head when Merck voluntarily withdrew rofecoxib in September, 2004, and suffering from prolonged lack of leadership, the FDA is in a sorry state.

Three decisions in the past few weeks were heralded as cause for optimism. On Feb 14, President Bush nominated Lester Crawford, the acting commissioner of the FDA, to become its permanent commissioner. An advisory panel spent 3 days last week hearing evidence on the efficacy and safety of the COX-2 inhibitors rofecoxib (Vioxx), valdecoxib (Bextra), and celecoxib (Celebrex). And on Feb 15, the FDA announced that it was creating a Drug Safety Oversight Board.

Lester Crawford has been acting commissioner or deputy commissioner to the FDA for almost 3 years under the Bush administration. The permanent post has been vacant since March, 2004, when the previous chief, Mark McClellan, left after only 17 months. Crawford is a veterinarian with a PhD in pharmacology. It is during his reign as acting commissioner that concern over drug safety has reached a head. Sidney Wolfe, a long-time critic of the FDA and a director at Public Citizen, a consumer advocacy group, told The Lancet that Crawford had done a “terrible job”, with a poor record on drug safety issues, failing to warn adequately about the cardiovascular risks of rofecoxib. “Crawford won, so the American public loses”, said Wolfe on Crawford's nomination as FDA chief. Crawford has shown repeatedly that he lacks the determination to strengthen the weak regulatory culture within the FDA. He has failed to protect agency scientists who try to speak openly about drug safety concerns. And he has refused to recognise that his primary duty is to protect the public, not to facilitate the entry of inadequately tested medicines onto the market.

The FDA took the unusual step of holding a joint public meeting of its Arthritis Advisory Committee and its Drug Safety Risk Management Advisory Committee between Feb 16 and 18. The aim was to discuss the overall benefit to risk considerations for the three COX-2 selective non-steroidal anti-inflammatory drugs currently approved in the USA. The conclusion of the panel was that the potential benefits outweighed the risks. Support for marketing was stronger for celecoxib (with 31 panellists in favour, and one against) than for valdecoxib (17 in favour, 13 against) or rofecoxib (17 for, 15 against). All three drugs should, said the panel, be marketed as painkillers accompanied by strong warnings of the risks, including the cardiovascular risks, which the panel concluded were likely to be a class effect and not unique to rofecoxib. The FDA usually follows its committees' advice. When the FDA does issue its conclusions, which may not be for a few weeks, clear guidance on which patients are most likely to benefit, and least likely to be harmed, and on dose and duration is needed, assuming the data are available.

Announcing the creation of the Drug Safety Oversight Board, Crawford and Health and Human Services Secretary Mike Leavitt said that the board would consist of scientists drawn from throughout the federal government. The board will advise on the management of drug safety issues within the Center for Drug Evaluation and Research. It will not have the independent power to force the withdrawal or relabelling of drugs, but can only advise the FDA. The board will make its conclusions public via a new Drug Watch internet site, which will allow discussion of emerging or potential safety issues before the FDA has reached conclusions that would prompt regulatory action. In addition, changes at the FDA will allow information about adverse effects of drugs to be collated from databases, including those at Medicaid and other government or private health plans, and will increase the number of FDA-approved fact sheets that patients receive with their prescriptions. However, analysing adverse event data held on large databases will cost millions of dollars each year, yet no additional funding has been provided.

Until now, it has been the remit of the Office of Drug Safety at the FDA to monitor adverse events. But with a staff of around 100 to analyse the miscellaneous reports sent in by doctors and drug companies, and a reporting structure submerged within the FDA's drug review division, the Office of Drug Safety has neither the power nor the independence needed to reliably detect drug side-effects and to take action to protect patients.

This solution to the problem of monitoring drug safety is flawed. The new Drug Safety Oversight Board is a hurriedly put together substitute to fundamental change in the structure and power of the Office of Drug Safety. What is needed is an Office of Drug Safety with increased staff, and the same power and political clout as the Office for New Drugs. Monitoring drug safety can be done within the FDA if there are no ties with the division that is responsible for approving new drugs, and if enough money is given to fund database analyses. In addition, the Bush administration must grant the FDA greater legal authority to demand that manufacturers conduct postmarketing surveillance or give the FDA the resources to fund its own drug-surveillance studies. Creating a board with only advisory powers on an issue as important as drug safety is unacceptable.

“The FDA is an icon of trust, a certifier of safety, an enabler of innovation and a repository of information”, said Leavitt when announcing the new Drug Safety Oversight Board. If only all that were the case. He continued, “We will keep the promise of the FDA brand by putting in place more rigorous oversight and collecting and sharing important and emerging information about drug safety and effectiveness”. What is in place or being created so far is, unfortunately for the US public, inadequate to monitor drug safety. What is needed is an FDA chief with the foresight and ability to change a lumbering organisation, armed with the legal framework to achieve an effective drug safety monitoring system, and the power to then act promptly when safety concerns arise.