A Failure to Ask the Right Question

The Center for Science in the Public Interest's Integrity in Science project (my day job) released the following report today to coincide with the opening of FDA hearings into the safety of COX-2 inhibitors:

In November 2000, the New England Journal of Medicine published the Merck-funded VIGOR trial, which compared Merck’s Vioxx (rofecoxib) to generic naproxen, a typical non-steroidal anti-inflammatory painkiller sold over-the-counter as Aleve, in patients with rheumatoid arthritis. While the primary results showed the drugs were comparable for pain and the new COX-2 inhibitor caused fewer gastrointestinal side effects, the Vioxx users had more than twice as many cardiovascular problems and five times as many heart attacks. To minimize those risks, the study authors suggested that the increase in heart attacks may have been due to naproxen having heart protective attributes similar to low-dose aspirin.

Over the next several months, prominent cardiovascular researchers associated with the Cleveland Clinic revisited the data not just in the VIGOR trial but in three other trials involving Pfizer’s COX-2 inhibitor Celebrex (celecoxib). In August 2001, they published a Special Communication in the Journal of the American Medical Association warning about the risk of cardiovascular events with the new class of drugs. The called for further trials to “characterize and determine the magnitude of the risk.”

This week, a Food and Drug Administration Advisory Committee is holding a three-day hearing to evaluate the magnitude of that risk. They will be presented with meta-analyses of existing trials; post-hoc epidemiology studies of large populations that took the drug; and re-analyses of data in trials whose primary outcomes had nothing to do with measuring heart disease. What they won’t see is a well designed, placebo-controlled clinical trial that asked what the Cleveland Clinic researchers in August 2001 said should be asked.

The Center for Science in the Public Interest conducted a systematic review of the studies that have appeared in the academic literature since the JAMA article questioned the safety of COX-2 inhibitors. CSPI looked at all published trials for Vioxx, Celebrex and Bextra. The study found that no researchers funded by either the public or private sector published a study specifically designed to measure the risk of heart attacks or strokes from COX-2s.

“The failure of researchers in both the private and public sectors to follow up on the critical safety questions raised in one of the earliest large trials for these drugs points out the need for an independent safety arm at the Food and Drug Administration to require such trials and independent researchers to conduct them,” said Merrill Goozner, director of the Integrity in Science project at the Center for Science in the Public Interest. “Industry managed to enroll tens of thousands of patients in clinical trials aimed at selling more of these drugs, but none in a trial designed to measure the risk of heart attacks or strokes.”

The findings:
Since August 2001, the three approved COX-2 inhibitors have been tested in at least 237 clinical trials involving over 75,000 patients. The funding source was not disclosed or could not be determined for 93 of those trials. But in 103 of those trials, the companies behind the drugs – Merck and Pfizer – either funded the trial itself or provided financial support to the researchers. The other 41 trials were funded either by government or non-profit institutions.

Just 16 (15.5 percent) of the industry-funded trials evaluated any type of health risk associated with the drugs and only five (4.9 percent) of those had anything to do with cardiovascular risk. Four of those five (one by Merck and three by Pfizer) were very short term and designed to measure narrow questions like drug-drug interactions among patients with other cardiovascular problems. One Merck-funded French study of nearly 3,000 patients over 24 weeks suggested Vioxx did not cause an excess of thrombotic events, but the authors warned “this should be confirmed by large controlled clinical trials with a longer follow-up.”

Among the trials whose funding could not be determined, four trials dealt with cardiovascular risk. There was one reanalysis of data in the original trial used to gain FDA approval for Celebrex. The reanalysis claimed the drug did not cause cardiovascular side effects. But it’s important to note that the original study was not designed to detect such risk. The three other trials were short-term trials looking at specific issues like drug-drug interactions and not long-term trials designed to measure the overall cardiovascular impact of taking COX-2 inhibitors.

Public and non-profit institutions were no better at putting safety and heart health at the top of their agendas. Of the 41 trials not funded by industry, just eight (19.5 percent) asked questions related to potential side effects of COX-2 inhibitors and none of those involved cardiovascular risk.

So if it didn’t ask the big question, what did industry use its research-and-development budgets to study? The vast majority of the industry-funded trials in the literature were “seeding” trials: clinical trials for common but off-label uses of drugs that have already been approved for narrower indications. The idea is to get results published in a wide range of journals so that salespersons can deliver reprints to physicians in those specialties.

Nearly 85 percent (87 of 103) of industry-funded trials that have appeared in the academic literature since 2001 involved testing the pain relief afforded by COX-2 inhibitors for off-label uses. A typical example: Merck funded 12 physicians associated with the Altoona Center for Clinical Research to test Vioxx against a traditional non-steroidal anti-inflammatory drug made by one of its rivals for arthritis of the knee. The results, published last year in the Journal of the American Geriatric Society, showed both worked, both were well tolerated and Vioxx offered slightly faster pain relief.

It is interesting to note that among the 93 trials whose funding was undisclosed or could not be determined, seeding trials accounted for nearly 90 percent of the total (83 of 93). This suggests that a high proportion of the trials whose funding couldn’t be determined were also industry-funded.

Staid NEJM gets political on eve of COX-2 hearings

The New England Journal of Medicine in this week's edition will publish three studies questioning the safety of all COX-2 inhibitors, not just Merck's Vioxx. It also early released a hard-hitting editorial. The Food and Drug Administration advisory committee considering the safety of COX-2 painkillers like Vioxx opens hearings Wednesday morning, and the nation's leading medical journal left no doubt where it stands.

"When (early) clinical trials showed an increased risk of myocardial infarction (that's the medical terminology for a heart attack), rather than consider this finding a major danger signal, the manufacturers designed trials to show efficacy for other indications and enhanced the cardiovascular safety monitoring in these subsequent trials. . . Had trials designed to test the question of cardiovascular toxicity directly been launched in 1999 and executed with urgency, substantial morbidity and perhaps a substantial number of deaths could have been prevented."

The NEJM might have pointed out that though the Merck trial that showed an increased risk of heart attacks was eventually published in its own pages in November 2000, it wasn't until nearly a year later and in the pages of the rival Journal of the American Medical Association that cardiologists at the Cleveland Clinic raised the alarm bells. The FDA wasn't the only institution slow to react to the mounting evidence against the COX-2s.

Protecting the View from Mt. NIH

A little over a decade ago, a senior scientist at the National Institutes of Health came up with an accurate 3-D model for an enzyme inside the HIV/AIDS virus. It was a time when nearly 40,000 Americans were dying a year from AIDS and the three existing drugs were ineffective. This scientist believed his model held the key to developing a new class of drugs that would finally control the disease.

So what did he do? Did he patent his insight? No.

Did NIH sign an exclusive research agreement with a firm that wanted to use his model? No.

Did the scientist sign lucrative consulting contracts with every company that wanted access to his knowledge? No, not that either.

This was in the days before former NIH director Harold Varmus relaxed the rules prohibiting such consulting gigs. So this scientist did what NIH scientists had always done: he made unpaid visits to any drug company or academic lab that would have him. He made unpaid presentations about his discovery. He showed slides of the enzyme’s chemical structure and encouraged everyone to work on the project. And a few years later, the first drugs that inhibited the enzyme – the HIV protease – came on the market and became the third and final leg of the triple cocktail that finally reduced the deadly toll from AIDS.

I thought about that story last week after reading some of the inane commentary about NIH director Elias Zerhouni’s decision to ban agency scientists from having outside financial ties with drug, biotechnology and medical device companies. In announcing the new directive, which was actually rammed down the agency’s throat by the Office of Government Ethics and the determined reporting of David Willman in the Los Angeles Times, Zerhouni sounded the right notes. NIH must “preserv(e) the public trust,” eliminate “conflict of interest or the appearance of conflict of interest” and maintain “at least one source of public health information in the country that can be completely trusted.”

But many press accounts, including on National Public Radio and in the Washington Post (where this was a very big hometown story – the majority of NIH’s 17,500 employees work just outside the nation’s capital), predicted nothing but negative effects. This will set back the commercialization of NIH knowledge, they said, drive the best and brightest into the private sector and hamper industry by cutting off access to NIH’s cutting-edge science. “What great public purpose is served by preventing (NIH scientists) from making a buck by sharing that informal knowledge with profit-making companies,” Post business columnist Steven Pearlstein asked in a typical comment.

Here’s the answer: The total ban will prevent NIH scientists from engaging in what has become a misguided biomedical industrial policy. Financial entanglements with private firms are, in effect, an effort (biased by personal financial gain) to pick winners and losers among different approaches to curing disease, which is, after all, the agency’s mission.

Congressional hearings and Willman’s articles focused attention on the sheer greed of some of the NIH scientists who’d parlayed their taxpayer-funded knowledge into lucrative consulting careers. It’s not a pretty picture when a senior heart disease researcher pens an article for a drug-industry funded journal supplement whose sole purpose is to sell more statin drugs, or a mental health researcher takes in more than a half million dollars in fees from Pfizer, a maker of antidepressants.

But these flagrant abuses don’t get at the heart of the problems caused by senior NIH scientists taking money from private firms. Real medical innovation, the kind of breakthrough science that NIH is supposed to develop, takes a long time. It inevitably involves many twists and turns, blind alleys and serendipitous events. The bottom line is that breakthroughs or even a major advance in the war against a disease are rare.

If scientists sign on with a particular firm with a promising approach, they tie their personal financial fortunes to the success of that approach. Will they give the same service to other firms that have alternative approaches but may not have won financial backing (and hence the ability to pay the fee) from Wall Street? Will academic labs with promising approaches (many of the best new treatments begin in academia and then get transferred to industry) get short shrift? Will the desire to keep the money rolling in blind NIH scientists to new information that suggests their client’s approach may no longer be valid?

A total ban on outside consulting, honoraria and the like is the right solution. This isn’t about purity or appearances. One of the great privileges of working for the nation’s premier biomedical research institution is that it gives its scientists a panoramic view of developments in their fields. It enables them to focus on the most promising developments. That’s why over the years so many critical breakthroughs in the directed research programs aimed at combating AIDS, cancer or rare diseases have come from the 27 institutes and centers that make up the agency. Taking money from a player in a field is like being allowed to climb to the top of Mt. Everest and then looking in just one direction.

Will prohibiting financial ties with industry stop NIH scientists from talking to industry scientists? The summary of the new guidelines posted on the NIH website refers to any “compensated or uncompensated employment.” But the detailed Federal Register notice suggests that while uncompensated “employment” is prohibited (serving on a company’s scientific advisory board is a typical uncompensated arrangement), there is nothing to stop scientists from engaging in normal scientific exchanges with their peers in either the private or public sectors. That AIDS researcher would not have been stopped by the new rules.

Will the ban drive the best and brightest away from careers in the public health service? NIH has always been seen as a way station by many medical researchers. They come for a few years to get that panoramic view and engage in pioneering research without teaching responsibilities. Many then leave for either academia or industry. But some devote their lives to public service.

I hope our culture hasn’t become so crassly commercial that there are no longer young scientists who want to climb to the top of the mountain, or veteran scientists who won’t stick around to enjoy the view.