Regulatory Beat: FDA Under Pressure to Address Drug Safety Issues

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BioPharm International, BioPharm International-02-01-2005, Volume 18, Issue 2

The growing alarm over harmful side effects from a number of popular prescription drugs is affecting a range of issues of critical importance for pharmaceutical and biotech manufacturers. Safety concerns may slow down efforts to expand drug importation from foreign nations. The National Institutes of Health (NIH) has halted important clinical trials due to fear that the painkillers under study increase risk for cardiovascular events.

The growing alarm over harmful side effects from a number of popular prescription drugs is affecting a range of issues of critical importance for pharmaceutical and biotech manufacturers. Safety concerns may slow down efforts to expand drug importation from foreign nations. The National Institutes of Health (NIH) has halted important clinical trials due to fear that the painkillers under study increase risk for cardiovascular events. Congress is supporting more comparative studies of drugs and medical treatments and may take action to expand requirements for hospitals and physicians to report adverse drug events. The Food and Drug Administration (FDA) is on the defensive, as policymakers propose to revise how the agency evaluates pre- and post-approval drug safety data.


The Department of Health and Human Services (HHS) task force on drug importation issued a final report in December that lived up to expectations by opposing any broad opening of US borders to prescription drugs from other countries. The 13-member panel headed by US Surgeon General Richard Carmona ruled out legalizing individual importation for personal use, insisting that such a program would cost up to $3 billion to regulate and would open the door to a flood of unapproved and unsafe products entering the US.

The panel acknowledged, however, that it is feasible for the US to establish a large-scale commercial system to re-import low-cost prescription drugs from Canada, but that such a system would be very expensive to oversee and would not save consumers much money in the end. The report [available at] notes that Congress would have to authorize legal importation and should limit it to certain high-volume, high-cost drugs that would enter the US through a limited number of distribution centers. Such an initiative would require a system for product tracking, pedigree maintenance, and frequent import sampling by FDA, and probably would cost hundreds of millions of dollars to establish and maintain. These costs, combined with price hikes by wholesalers and other intermediaries to cover added regulatory requirements, would further erode any healthcare savings. In the end, manufacturers would lose revenues that ultimately could limit the development of new drugs.

These conclusions were roundly criticized by Congressional Democrats for presenting the same old scare tactics largely to protect US manufacturers from foreign competition. Import opponents claimed that opening up the nation's borders to drugs of unknown origin and questionable quality could aggravate concerns about the safety of the US drug supply. Advocates countered that current policies were not keeping unsafe drugs off the market anyway.



An even more alarming result of recent drug safety disclosures is the research community's growing nervousness about conducting clinical studies that involve pain medications or other high-risk treatments. In December, researchers stopped an important NIH-sponsored cancer study that was testing whether anti-inflammatory drugs might help prevent colon cancer. The data showed some evidence associating Pfizer's Celebrex (celecoxib) with cardiovascular events. However, Pfizer executives decided to keep the COX-2 on the market pending further review of the data — data which the manufacturer believes is fairly inconclusive on the safety front and still may reveal beneficial anti-cancer effects.

A few days later, NIH halted another prominent study due to surprising evidence that patients taking naproxen — but not Celebrex — might experience 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 2400 elderly patients to see if the medicines might help delay the onset of Alzheimer's disease. 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 put on hold additional NIH cancer trials seeking evidence of additional uses for these commonly prescribed painkillers, and some 40 studies testing Celebrex for various purposes are 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. The unexpected naproxen adverse event data cast a shadow over chronic use of other non-steroidal anti-inflammatory (NSAID) drugs. 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 on its drug safety study and plans to address COX-2 issues at a meeting of its drug safety advisory committee in February.


While some research may be cancelled, drug safety concerns may generate more support for studies to compare the effectiveness and safety of similar medicines. Although the usual aim of such analysis is to reduce the use of more costly drugs and biologics that lack clear benefits over older therapies, experts also consider comparative data requirements useful in pressuring manufacturers to study product safety and efficacy more thoroughly.

The 2003 Medicare bill 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 assess the scientific literature on 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 of certain interventions. The aim is to help physicians and patients make informed treatment choices by making the results available to Medicare, Medicaid, health plans, prescription drug plans, and the public.

Manufacturers stress 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. A main concern is that comparative studies could block access to products deemed less effective and keep new products off the market, even when those therapies offer benefits for certain patient populations.

Manufacturers also oppose any move by FDA to require comparative clinical studies of new vs. existing drugs to bring a new drug to market, but some members of Congress consider such analysis useful. 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. The Center 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. While 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.


These developments are raising a clamor about revamping the FDA regulatory system, and Congress now may be willing to provide more money for post-approval monitoring and other proposals under discussion:

  • Require clinical trial registration and study disclosure by manufacturers.

  • Give FDA authority to limit product distribution, curb marketing, and enforce safety requirements without having to pull a drug off the market completely.

  • Enhance the authority of FDA drug safety reviewers by establishing a separate safety office that would have veto authority over new drug applications (a move opposed by manufacturers and FDA officials who believe it is important to review safety and efficacy data together).

  • Give FDA authority to compel manufacturers to complete post-approval safety studies after a drug goes to market.

  • Improve FDA's adverse event reporting system to capture and analyze adverse event data more quickly and to conduct more proactive safety analysis.

Jill Wechsler is BioPharm International’s Washington editor, 7715 Rocton Avenue, Chevy Chase, MD 20815, 301.656.4634,