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FDA: This Agency Can Be Dangerous

Conflicts of interest matter. Consider the case of Vioxx,6 the arthritis drug that was removed from the market in 2004 because it was associated with an increased risk of heart attacks and strokes. In 2005, a special FDA panel, consisting of two of the standing advisory committees, held public hearings to consider whether Vioxx and two other drugs in the same class, Bextra and Celebrex, were safe enough to stay on the market. After three days, the panel recommended that all three drugs be allowed on the market, perhaps with strong warnings on the labels and a moratorium on advertising directly to consumers.

About a week later, however, The New York Times revealed that ten of the thirty-two members of the panel had financial ties to the makers of the drugs. If their votes had been discounted, the panel would have recommended that only Celebrex stay on the market. In a departure from its usual practice, CDER, no doubt embarrassed, rejected the advice of the full panel and allowed only Celebrex to stay on the market. If not for the revelations in The New York Times, the decision would probably have gone the other way.

The story of how Vioxx came to market in the first place is even more damning. It was approved in 1999, after the approval of Celebrex. Even though it was the second drug in the class, neither of which had been shown to be better or safer than over-the-counter drugs for pain relief, Vioxx was given a rapid review (called a “priority review”) by CDER. The FDA’s minutes of the advisory committee meeting that led to its approval revealed that four of the six members, including the chairman, were given waivers, because they had “a potential for a conflict of interest.” Although Carpenter discusses Vioxx in some detail, he inexplicably omits mention of these conflicts of interest.

The new FDA guidelines concerning conflicts of interest, issued in 2007, are hardly reassuring. They allow up to a $50,000 interest in relevant companies—for example in consulting fees or stock ownership—and call for limitations on the number of waivers granted. That’s a very weak reform. Some of our best medical schools now have much tighter restrictions on investigators’ financial ties to the sponsors of their research beyond support for the research itself. The position of FDA advisers should be analogous. In both cases, a drug is being evaluated by experts who should have no financial interest in the outcome of their recommendations.

Members of advisory committees should be permitted to accept research grant support from industry. But when they do, they should be barred from any FDA meetings involving that company, and of course, they should have no other financial associations with industry. There should be no waivers; no one is indispensable. Apologists often claim that it is impossible to find experts who don’t have financial conflicts of interest. When I was editor of The New England Journal of Medicine, I often had to find such experts to write editorials for the journal, because our policy prohibited authors of editorials from having conflicts of interest. Finding them was sometimes difficult, but not impossible. If the FDA insisted that its advisers not have conflicts of interest, it would probably have a salutary effect on the larger medical community, since serving on FDA advisory committees is considered to be prestigious.

Fourth, the FDA should see that the post-marketing studies it requires as a condition of approval are carried out in a reasonable time. Some drugs are now approved on the basis of only one or two short clinical trials, or trials that use “surrogate endpoints.” (A surrogate endpoint is an outcome, like cholesterol level, that is probably correlated with a clinical outcome, like heart attack, but isn’t itself a clinical outcome.) When drugs receive such fast-track approval, sponsors agree to conduct post-marketing studies to ensure that the drugs are safe and effective after they are in widespread use. However, drug companies regularly disregard this commitment. As of 2008, there was reportedly a backlog of more than 1,200 required post-marketing studies, of which 900 hadn’t even been started.7

CDER often asserts that it does not have the legal authority to enforce the completion of these studies. But it does have the authority to withdraw drugs from the market, and that threat ought to persuade drug companies to honor their commitments. Carpenter devotes a long chapter to post-marketing regulation, and seems to agree that the FDA could force the completion of these studies but is constrained from doing so by fear of the political reaction. He’s probably right about that.

CDER has never pulled a drug off the market because of a company’s recalcitrance in conducting a post-marketing study. It should. If drug companies know the FDA will never use its authority in this way, they have no incentive to meet their commitments. In the case of me-too drugs, which by definition do not fill unmet needs, failure to meet a commitment to do a post-marketing study should result in withdrawal of the drug from the market. In the case of innovative drugs, of which there are relatively few, there should be heavy and escalating fines for noncompliance.

Fifth, approval of new drugs should be limited to three years, and during that time advertising aimed directly at consumers should be prohibited. A similar reform was recommended in the Institute of Medicine’s 2006 report “The Future of Drug Safety: Promoting and Protecting the Health of the Public.”8 During those three years, the OSE would collect information on safety, using databases such as those maintained by large health facilities like Kaiser Permanente. Continued approval after three years would be contingent on a favorable balance between risks and benefits. During this probationary period, direct-to-consumer ads should be banned. Too often, these ads aim to convince people that they have medical conditions requiring drug treatment they would not otherwise seek, thus unnecessarily risking side effects not yet identified.9 Carpenter does not discuss the issues raised by ads aimed directly at consumers.

Sixth, the FDA should review generic drugs as rapidly as brand-name drugs, and be adequately staffed to do so. It currently takes more than twice as long to review generic drugs as brand-name drugs, and there is a backlog of some 1,900 of them waiting to be reviewed. This disparity between the leisurely pace of getting generic drugs on the market and the rush to approve brand-name drugs is indefensible. It merely protects brand-name profits. The excuse that it is more important to get brand-name drugs on the market because they offer innovative treatments is not persuasive. About 80 percent of newly approved brand-name drugs are classified by CDER as appearing “to have therapeutic qualities similar to those of one or more already marketed drugs”—that is, they do not fill unmet needs and most often are me-too drugs.10 Given the staggering costs of brand-name drugs to consumers, it’s at least as urgent to get generic drugs on the market. Carpenter does not discuss the FDA’s responsibility for the approval of generic drugs, much less discuss the disparity in approval times.

Seventh, in pre-marketing trials, me-too drugs should be compared with an existing drug to treat the same condition, not just with a placebo. Me-too drugs are now the major output of the pharmaceutical industry. It is too late to wait until they are on the market to compare them with existing drugs. Once drugs are aggressively promoted, it is very difficult to counter sales pitches with data from comparative studies. Sometimes, a pre-marketing trial should compare a new drug with both a placebo and an existing drug, because there may be doubts about the effectiveness of the older drug or the whole class of drugs. The agency should have considerable discretion in deciding whether to approve another me-too drug. If, for example, it is no more effective than its predecessors, but substantially more convenient or has fewer side effects, then it should be approved. But if it is no better in any way, and there are already several similar drugs on the market, it should be rejected.

If me-too drugs were limited, there would be more pressure to develop innovative drugs, fewer clinical trials of no medical importance, and far fewer expensive and misleading promotional campaigns. Over the past three decades, the industry has shifted its focus from trying to discover innovative drugs to producing me-too drugs, many for vague or minor conditions. Companies use their marketing muscle to expand sales, and often sales grow not just for the advertised drug, but for the others in the same class made by other companies. Carpenter does not see this as a problem, but he is wrong. Not only are people taking more and more drugs of marginal benefit, but we are seeing less and less innovation from the industry.

The eighth reform concerns the “surrogate endpoints” I mentioned earlier. As I noted, these are measurements that are thought to predict clinical results in drug tests. For example, in a trial of a drug to prevent heart attacks, the outcome measured might be cholesterol levels instead of actual heart attacks. Or in a trial of a cancer drug, the outcome measured might be the size of a tumor, not length of survival. But surrogate endpoints do not always have the expected predictive value. It makes sense to rely on them in clinical trials of drugs to treat serious conditions for which there are no existing treatments, because such trials are faster, even if sometimes misleading. (Even then, post-marketing studies should always be required to check clinical outcomes.) But for me-too drugs or drugs for less serious conditions, there is no rush and the FDA should insist on clinical endpoints. Although Carpenter discusses surrogate endpoints at length, he does not say whether their use should be curtailed.

Ninth, as a condition for enrolling human subjects, all clinical trials, without exception, should be registered at inception in a public database and the results shown when the research is completed. If drug companies or their agents ask members of the public to participate in research, they have an obligation to make the design and outcome of the work publicly accessible, along with disclosure of investigators’ conflicts of interest. The industry contends that registering all clinical trials would harm companies’ proprietary interests. But by the time clinical trials begin, drugs are already patented; further secrecy is unjustified and may run counter to the public interest. Suppose, for example, a competitor learns something from a company’s experience that would enable it to avoid pitfalls in its own research. While that might be detrimental to the first company’s competitive position, it might also speed the process of getting a good drug to market. The FDA should not put proprietary claims ahead of the public welfare, as I believe it sometimes does. Carpenter does not address the issue of registration of clinical trials.

There is a widespread belief within CDER that the pharmaceutical industry and the FDA are engaged in a common endeavor—that they’re “partners.” I’ve even heard a senior FDA official refer to drug companies as the agency’s “clients,” and another assert that the agency’s job is to “facilitate drug development,” which is different from regulating it. This confusion is probably greatest at the upper levels of the agency, which are most vulnerable to industry pressures. In 2003, the Health and Human Services inspector general found that 18 percent of CDER reviewers felt pressured by their superiors to recommend approval of drugs against their better judgment.

The pharmaceutical industry and the FDA are not engaged in a common endeavor, and they shouldn’t be. Drug companies, of course, want to sell safe and effective drugs, but their primary purpose, like that of other investor-owned businesses, is to enhance the value of their shareholders’ stock by maximizing profits. If they did not do that, their top executives would risk being fired. The job of regulators, on the other hand, is to enforce legal constraints that often moderate the profit incentive. Thus, the basic missions of industry and regulators are different, and inherently somewhat adversarial, no matter how pleasant the relationship. No business likes having its profit-seeking activities curbed by external rules, and industries almost always resist government regulation. But self-regulation is an illusion, as we learned from the collapse of the financial industry and the oil spill in the Gulf of Mexico. There must be some tension between the pharmaceutical industry and the FDA. If there is not, the FDA is not doing its job.

A book on the FDA’s regulation of prescription drugs cannot be complete without confronting the extent to which the agency’s responsibilities have been distorted by the pharmaceutical industry. Carpenter provides a vast store of information about the FDA, its history, and its politics, but he avoids taking positions on important issues or suggesting remedies. Instead, he seems determined to maintain a detached neutrality. That is a great pity, because the FDA’s failures are of immense public importance and deserve full exploration in a work as ambitious as this one.

—September 1, 2010


How Dangerous is the FDA?: An Exchange October 28, 2010

  1. 6

    I wrote about Vioxx in these pages, “Your Dangerous Drugstore,” June 8, 2006.

  2. 7

    These figures come from Associated Press reporter Matthew Perone, in his March 4, 2008, report on Sen. Charles Grassley’s letter asking the US GAO to assess the adequacy of FDA follow-up of drugs approved on the basis of surrogate endpoints.

  3. 8

    This report, while it highlighted many of the problems at the FDA and offered some constructive recommendations, stopped short of recommending the major overhaul of the FDA that is needed.

  4. 9

    Many authors have commented on the pharmaceutical industry’s new strategy of promoting medical conditions first, then drugs. Among the earliest were Ray Moynihan and Alan Cassels, in their 2005 book, Selling Sickness: How the World’s Biggest Pharmaceutical Companies Are Turning Us All into Patients (Nation Books, 2005). I discussed the practice in my “Drug Companies and Doctors: A Story of Corruption,” The New York Review, January 15, 2009.

  5. 10

    CDER’s classification of new drugs is available on the FDA website. Over the past decade, only about 20 percent have been classified by the FDA as likely to represent a “significant improvement compared to marketed products, in the treatment, diagnosis, or prevention of a disease.”

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