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FDA: This Agency Can Be Dangerous

James T. and Karla L. Murray
Lexington Avenue at East 79th Street, New York City, 2008; photograph by James T. and Karla L. Murray from their book Store Front: The Disappearing Face of New York, published last year by Gingko Press

The US Food and Drug Administration (FDA) is a vital public agency. It is responsible for ensuring the safety of the foods we eat and many of the medical treatments we receive, and thereby regulates about a quarter of the nation’s domestic economy. I strongly believe in the FDA’s mission, and respect the many FDA employees who are dedicated to carrying it out.

But there is growing evidence that the Center for Drug Evaluation and Research (CDER, pronounced “cedar”), the part of the agency that regulates prescription drugs, has become the servant of the industry it regulates. This has resulted in the sale of drugs of uncertain benefits, some with serious side effects, and in the agency’s failure to respond promptly to evidence that a drug is dangerous. There is no better example than the agency’s decision to allow the diabetes drug Avandia to remain on the market after having determined three years ago that it increases the risk of heart problems and despite the existence of a similar drug that appeared safer. Even after revelations that the drug’s maker, the British company GlaxoSmithKline, suppressed indications of problems and biased its research in Avandia’s favor, the FDA remained reluctant to pull the drug. By the end of August it was still unclear whether the agency would remove Avandia from the market.1

CDER also does not fulfill its obligation to oversee the marketing of prescription drugs, thus permitting misleading drug ads and illegal practices such as drug companies inducing doctors to prescribe drugs for uses that have not been approved by the FDA. Although nearly every major drug company has paid enormous fines to settle charges of illegal marketing (Pfizer’s recent $2.3 billion fine—for illegally promoting its painkiller Bextra and three other drugs—is the current record), they evidently consider the fines the cost of doing business, since the same practices keep recurring with little interference from CDER.

Americans use enormous amounts of prescription drugs. According to the Kaiser Family Foundation, 3.9 billion drug prescriptions were filled in the US in 2009, an average of 12.6 per person. Most people over age sixty-five take at least three prescription medications daily. Since the FDA is what stands between the public and an aggressive, profit-driven industry, its independence from the industry it regulates is of fundamental importance.

This is not an issue that receives much attention from Daniel Carpenter in his imposing new book, Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA, nor does the related question of whether CDER is doing its job of ensuring that the drugs we take in such huge quantities are really safe and effective. Instead, Carpenter, a professor of government at Harvard, spends 752 dense, exhaustively documented pages telling the reader virtually everything else about the FDA—its history, procedures, personalities, and politics. Like much academic work on public and social policy, it strives to be impartial. But it sees complexity even when it is not there (some things about the FDA are quite simple), and it remains oddly aloof from the issues that most matter.2 Its main value is as a reference work.

Here I’ll discuss the problem that Carpenter largely neglects—how to ensure that CDER, free of industry influence, protects the public from unsafe and useless drugs.

CDER consists of several sections, the largest of which is the Office of New Drugs (OND), which has responsibility for approving new drugs and deciding what action to take when a drug already on the market is found unsafe. Other sections monitor drugs for safety, approve generic drugs, oversee marketing, and ensure quality in manufacturing plants.

By law, before a drug company can sell a drug, it must sponsor clinical trials to prove to CDER that the drug is reasonably safe and effective. CDER usually requires only that the trials compare the new drug with a placebo, not with existing drugs. (This minimal standard means that most new drugs merely have to be better than nothing, which makes it possible for companies to turn out trivial variations of top-selling drugs, called “me-too” drugs, instead of innovative ones.) Before these “pre-marketing” trials begin, a drug company must file an “investigational new drug” application (IND), which describes the proposed research, including measures to protect the welfare of human subjects.

After the trials are completed, which usually takes a few years, the company must file another application, called a new drug application (NDA), to get approval to go to market. With the help of advisory committees of outside experts, CDER staff reviews the NDA, including the results of the clinical trials. The review process is relatively fast, usually taking about a year and sometimes as little as a few months.

Only if the drug passes this scrutiny is it allowed to be sold, and it is then given exclusive marketing rights for a specified time, usually five years (twelve years for biotech drugs, which are large molecules, usually made from living biological systems). Sometimes, drug companies may be asked to conduct “post-marketing” studies to make sure a drug is safe after it comes into widespread use. Generic drugs are copies of brand-name drugs whose exclusive rights have expired. They, too, need CDER approval, which requires their manufacturers to show that they are essentially the same as the brand-name drugs they copy. Companies are permitted to promote drugs only for the uses for which they were approved, although once on the market, doctors may prescribe them for any reason they choose.

Industry influence on the FDA is exerted in two major ways—first, through congressional legislation largely dictated by industry lobbyists, and second, through administrations that are beholden to industry, and sometimes, as in the case of the George W. Bush administration, openly hostile to the very idea of regulation. The result is a climate in which CDER employees are inhibited from acting against drug company interests even when the agency has legal authority to do so. In addition, drug companies spend millions of dollars to directly lobby the FDA, even though it seems improper to permit a lobbyist to walk in the door of a regulatory agency.

The Obama administration is friendlier to regulation than was the Bush administration. The new FDA leadership has taken steps to make the agency’s actions more transparent, and has set up a program for doctors to report misleading drug ads. But to my knowledge, there has been little substantive change in CDER’s organization or procedures, and it retains the same director.

The following are nine reforms that I believe would greatly strengthen CDER, protect it from industry influence, and enable it to do its job better.3 Although Carpenter describes many of the conditions that make reform necessary, he does not adequately examine the underlying issues, nor does he recommend solutions. Some of the reforms I suggest would require congressional legislation, some would not, and others might.

First, the Prescription Drug User Fee Act (PDUFA) should be repealed. This legislation, which Congress enacted in 1992 and must be renewed every five years, authorizes drug companies to pay CDER for reviewing their drugs. But the payments are made under terms largely set by the industry. PDUFA greatly extended the industry’s influence. Even the name of the act suggests that CDER’s “users” are drug companies, not the public, and sadly that seems to be the case. The drug companies pay fees for each drug reviewed, so it is in the agency’s interest to review as many drugs as possible as quickly as possible. Approval is faster than disapproval, since it produces no argument from the company. Originally, the act stipulated that the money could be used only to speed review of drugs to meet industry-approved goals. Since 2002, a small fraction may be used for safety monitoring, but most is still directed toward drug approval. Fees paid by private companies now account for more than half of CDER’s budget.

Immediately after PDUFA was enacted, CDER began to hire large numbers of new drug reviewers. As staffing for drug approval grew, staffing languished for equally important functions—such as ensuring drug safety, approving generic drugs, reviewing advertising for accuracy and balance, and inspecting manufacturing plants. As of the first of the year, the Office of New Drugs, which approves brand-name drugs, had 930 employees, while the Office of Surveillance and Epidemiology (OSE), which monitors the safety of drugs on the market, had only 206. The Office of Generic Drugs (OGD) had 268, the Division of Drug Marketing, Advertising, and Communication had fifty-one, and the Division of Manufacturing and Product Quality (DMPQ) had eighty-three.4

This staffing is manifestly unbalanced. How, for example, can only fifty-one people ensure that tens of thousands of ads and promotional campaigns accurately convey the balance between risks and benefits of prescription drugs? Similarly, how can a staff of only eighty-three possibly ensure that the thousands of foreign manufacturing plants under its purview follow good manufacturing practices?

The FDA should be much better funded by Congress, and the balance of functions within CDER should be restored, so that the Office of New Drugs is no longer the tail wagging the dog. Four former FDA commissioners have agreed that the agency should be entirely publicly funded, and they are right. Under PDUFA, private companies pay CDER about $400 million a year, but I strongly doubt that taxpayers come out ahead. If we want better, safer, and cheaper drugs, Congress should appropriate that additional amount, and more. Carpenter discusses PDUFA, but with little apparent concern for its pernicious effect on the agency’s independence and effectiveness.

Second, the Office of Surveillance and Epidemiology (OSE) should have more authority and independence from the Office of New Drugs (OND). This office, which is concerned with drug safety, has no direct regulatory authority, but serves only to advise the OND. Decisions to withdraw drugs or restrict their marketing or labeling are the responsibility of the OND. That is plainly a conflict of interest, since the same office that approves drugs is then responsible for revising and possibly overturning its own decisions.

Carpenter describes this problem at length, but makes no recommendation for solving it. Some critics have advocated a new agency to oversee post-marketing drug safety. I don’t think that is necessary, but I do believe the OSE should be given final authority for monitoring and regulating the safety of drugs after they come on the market, with the OND serving in an advisory capacity. The post-marketing relationship between the OND and the OSE would then be the reverse of their relationship before drugs reach the market.

Third, members of CDER’s standing advisory committees should have no financial ties to drug companies (except for research support provided under carefully restricted conditions). According to the reporter Merrill Goozner, in 2006 some 30 percent of all advisers disclosed conflicts of interest, and in 75 percent of committee meetings at least one voting member did so.5 Although advisers are not supposed to vote on matters involving companies with which they are financially associated, waivers are granted so frequently as to be almost routine.

  1. 1

    For an overview of the Avandia story, see Clifford J. Rosen, “Revisiting the Rosiglitazone Story—Lessons Learned,” The New England Journal of Medicine, August 26, 2010. Rosen was chairman of the FDA advisory committee that concluded in 2007 that Avandia increased the risk of heart problems. See also Gardiner Harris, “Diabetes Drug Maker Hid Test Data, Files Indicate,” The New York Times, July 12, 2010; and the Senate Finance Committee’s “Staff Report on GlaxoSmithKline and the Diabetes Drug Avandia,” January 2010.

  2. 2

    An earlier book, Philip J. Hilts’s Protecting America’s Health: The FDA, Business, and One Hundred Years of Regulation (Knopf, 2003; University of North Carolina Press, 2004), managed to be both less comprehensive and more informative about the central issues.

  3. 3

    I suggested most of these reforms in a short Op-Ed piece in the Boston Globe, “Charting a New Course at the FDA,” April 6, 2009, and in a talk I gave at the FDA on January 27, 2010.

  4. 4

    These figures were provided to me by CDER in January 2010.

  5. 5

    Goozner is author of the 2004 book, The $800 Million Pill: The Truth Behind the Cost of New Drugs (University of California Press, 2004) and is one of the best observers of the American health system now writing.

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