Drug Safety Fears Threaten Research

Concerns over risky medicines are shutting down clinical studies and boosting demand for comparative drug analysis.

The growing alarm over harmful side effects related to a number of popular prescription drugs is affecting a range of issues of critical importance for clinical trial sponsors and investigators. The National Institutes of Health (NIH) recently halted important clinical trials due to fear that the painkillers under study increased risk for cardiovascular events, and more studies are under review. At the same time, support is growing for more comparative analysis of drugs and medical treatments, as well as expanded postmarket surveillance.

Congress may take action to stiffen requirements for hospitals and physicians to report adverse drug events. Safety concerns also may slow down the campaign to legalize drug importing from foreign nations. Import advocates maintain that the Food and Drug Administration's failure to keep unsafe products off the market illustrates how foreign drugs really are not the problem. Amidst all these developments, FDA has been put on the defensive as policymakers propose to revise how the agency evaluates pre- and postapproval drug safety data.

Raising the bar
An alarming result of recent drug safety disclosures is the growing nervousness of the research community about conducting clinical studies that involve pain medications or other high-risk treatments.

In December, researchers halted an important NIH-sponsored cancer study designed to test whether anti-inflammatory drugs might help prevent colon cancer. The data from more than 2,000 patients in the APC (Adenoma Prevention with Celecoxib) study showed some evidence associating Pfizer's Celebrex with cardiovascular events. Pfizer executives decided to keep Celebrex on the market pending further review of the data, which the manufacturer believes is fairly inconclusive on the safety front and still may reveal beneficial anticancer effects. But Pfizer did comply with an FDA request to halt all its direct-to-consumer advertising and to provide more risk information to doctors pending further analysis of safety evidence.

A few days later, NIH halted another prominent study due to surprising evidence that another anti-inflammatory might have harmful cardiovascular effects. The three-year-old Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) had been testing naproxen (Bayer's Aleve) and Celebrex on 2,400 elderly patients to see if the medicines might help delay the onset of Alzheimer's disease in individuals with a family history indicating increased risk for the condition. NIH officials and study leaders put the trial on hold after detecting signs of increased risk of cardiovascular and cerebrovascular events in patients taking naproxen--but not Celebrex. Because the study participants were healthy, the sponsors decided it was unethical to expose them to an added risk without clear evidence of an offsetting benefit. Investigators also stopped enrollment in a number of NIH cancer trials seeking evidence of additional uses for commonly prescribed painkillers. Some 40 studies testing Celebrex for various purposes are now under review.

The analysts acknowledged that they examined the adverse event data from these trials earlier than planned due to all the bad news about COX-2 safety problems. In the APC cancer study, the data is particularly confusing because the same group of cardiology experts reviewed both the NCI trial and a similar study conducted by Pfizer, which failed to exhibit the same heart attack risk evidence for patients taking Celebrex. It may be that additional side effects have surfaced in some cancer trials because they use much higher doses than what is recommended for arthritis patients. The reviewers felt, though, that even very slight risks could be dangerous because more than 20 million people have been taking these painkillers.

The unexpected bad news about naproxen cast a shadow over chronic use of other nonsteroidal anti-inflammatory (NSAID) drugs. FDA issued a statement advising patients using nonprescription naproxen to follow the label carefully and to stay within recommended doses. Some doctors believe that aspirin is the only painkiller with clear cardiovascular benefits, but note the higher risk of stomach bleeding. Everyone acknowledged that they were being ultra-cautious, and that a much broader review of the long-term impact of all anti-inflammatory painkillers is needed. FDA is working with the Institute of Medicine (IOM) on its drug safety study and plans to address COX-2 issues at a meeting of its drug safety advisory committee at the end of February.

More comparisonsAnother drug safety response is increased interest in research to compare the effectiveness and safety of similar medicines. The usual objective of such analysis is to reduce the use of more costly drugs that lack clear benefits over older therapies. But experts also consider comparative data requirements a way to pressure sponsors to conduct the studies needed to prove superiority.

The Medicare Modernization Act of 2003 authorized the HHS Agency for Healthcare Research & Quality (AHRQ) to support more research on comparative effectiveness of medical interventions (including prescription drugs) for the 10 top conditions affecting the elderly. AHRQ's 2005 budget includes $15 million for this program--much less than the $50 million initially proposed, but enough to get the program started.

With that funding in hand, in December AHRQ issued a long-awaited list of priority conditions that warrant comparative review: ischemic heart disease, cancer, asthma, stroke, arthritis, diabetes, dementia, pneumonia, stomach ulcers, and depression.AHRQ will fund projects to survey and assess the scientific literature on the outcomes from various treatments for these conditions. AHRQ is not supposed to set national standards of care, but such analysis is likely to lead to more common agreement on the effectiveness and risks of certain interventions. The aim is to help physicians and patients make informed treatment choices by communicating the results to Medicare, Medicaid, health plans, prescription drug plans, and the public.

Pharmaceutical companies maintain that any comparative drug analysis should focus on effectiveness more than costs, include drugs among a full range of treatment options, and recognize that patients respond differently to various treatments and products. PhRMA (Pharmaceutical Research and Manufacturers of America) made these points in a white paper on government-supported outcomes research issued in January 2004 in anticipation of increased involvement in this area by AHRQ, NIH, and FDA. Industry's main concern is that comparative studies could block access to products deemed less effective and keep new products off the market, even when those drugs offer benefits for certain patient populations.

Sponsors have long opposed any move by FDA to require comparative clinical studies of new versus existing drugs to bring a new drug to market. But charges of insufficient safety testing may build Congressional interest in such policies. Private insurers and payers are supporting more comparative studies of similar drugs, as seen in the growth of the Drug Effectiveness Review Project operated by Oregon's Center for Evidence-based Policy Support. It now is providing 11 states and other organizations with head-to-head comparisons of drugs that treat common health problems such as diabetes, migraine, and cholesterol. The prime objective of the research is to help public and private health plans select the most effective and cost-effective drugs for formularies. Such analysis is likely to pay more attention to the comparative safety of similar drugs in the wake of current concerns.