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This idea is evaluated and rejected by Roth-Cline in the this issue of Circulation. A better solution will have to be based on a more comprehensive understanding of how the risks of new drugs are detected, evaluated, and addressed. Article p The thalidomide tragedy of the early s led to important reforms in the regulatory authority of the Food and Drug Administration FDA , including giving it the power to require that a manufacturer demonstrate efficacy before a new drug can be marketed.
We take this expectation for granted today, but it was seen as revolutionary, and bitterly opposed by many, at that time. Unfortunately, many of the lessons drawn from such case studies by regulators, clinicians, companies, and the public, including the proposal rightly condemned by Roth-Cline, have led to the wrong conclusions.
It is false because a well-functioning system of postmarketing safety surveillance could make it possible to detect important adverse effects of a drug, even rare ones, soon after it comes into routine use. If analyzed correctly, use of a new product by hundreds of thousands or millions of typical patients can readily address the power considerations that would otherwise bedevil a modest-sized preapproval trial. On the other hand, the draconian probability value proposal has been advanced in part because the United States does not have such a system of safety surveillance. Other trends in risk detection at the FDA also help to explain the appeal of this extreme plan.
In the early s, an implicit social contract was proposed in which the FDA would approve new products more quickly and concurrently develop a better system of monitoring for adverse events once the drugs were in routine use to detect problems that the new speedier approval process may have overlooked.
The first part of the plan was implemented with the help of the Prescription Drug User Fee Act, allowing pharmaceutical companies to pay the FDA to cover the cost of the additional agency staff required to review new drug applications rapidly. Recent evidence published in the Federal Register might also seem to lend credence to the tempting idea that extending preapproval studies is the only sure means we have of identifying adverse events. Each year, the FDA reports to Congress on the progress made by pharmaceutical companies in conducting postmarketing studies mandated by the agency.
How could this be?
Powerful Medicines: The Benefits, Risks, and Costs of Prescription Drugs
After the FDA has approved a product, it has few regulatory tools available to compel companies to conduct follow-up studies. Ironically, even that remedy can be delayed if the safety studies needed to document a serious risk were never performed. This dismal record makes it easier to understand why some might favor forcing companies to measure risks more thoroughly during the only period when the government has any real influence: before approval. In the case of rofecoxib, however, this was not the issue.
There were already ample signals in preapproval studies of possibly increased cardiovascular risk and even a documented and statistically significant 5-fold increase in myocardial infarction rates in a trial published soon after marketing began. A more sensible policy would be to ensure that needed safety studies are required as promptly as possible, either as part of the approval process or immediately thereafter.
These might be rigorous observational studies of drug use and adverse events in large, well-defined populations, or new clinical trials that target specific clinical questions. This could be accomplished if the FDA were able to compel companies to conduct such research or if there were other funding streams available to support these studies. Defenders of this view argue that improving the capacity of preapproval studies to detect risks will inevitably delay the availability of new products and drive up their costs.
In using this argument to reject the extreme efficacy evidence proposal, Roth-Cline arrives at the right conclusion for the wrong reason. Drug evaluation is not a zero-sum game requiring impossible tradeoffs among numbers of subjects, probability values, and time, as Roth-Cline suggests. At present, the design of many preapproval trials is more of a problem than the probability values used to evaluate them.
In response to decades of pressure to make the FDA more industry-friendly, we have drifted toward a lowest-possible-standard approach. Often, a manufacturer must show merely that its new product works better than a comparator often placebo in achieving a surrogate outcome eg, improvement in a laboratory test in a modestly sized sample of atypically younger and healthier patients compared with expected users of the marketed drug who are observed over a brief period of time weeks or a few months, even for medications designed to be used chronically.
There are several ways these standards could be made more relevant to practice without dramatically increasing the duration or cost of drug evaluation and without recalibrating the level of statistical certainty required for approval. For toxicities that do not depend on the duration of drug exposure, risk detection can be enhanced without extending trial length simply by enrolling more adequate numbers of patients.
An even better way to identify potential safety problems would be to correct the present maldistribution of age and comorbidity among study subjects. More than a decade ago, our group reported on the systematic exclusion of older patients in pivotal drug trials in cardiovascular disease. A third and relatively inexpensive means of improving the detection of adverse effects is the study design itself. The rofecoxib example cited by Roth-Cline offers a veritable museum of such problematic strategies.
Despite evidence that selective cyclooxygenase-2 inhibition might be prothrombotic compared with traditional nonsteroidal antiinflammatory drugs, the Vioxx Gastrointestinal Outcomes Research VIGOR trial prohibited use of cardioprotective doses of aspirin, even in a population of rheumatoid arthritis patients at increased risk of cardiac disease.
There is also much promise in better use of pharmacogenetics, biomarkers, and other basic science approaches to provide earlier warnings about drug toxicities, a strategy the FDA has begun to embrace.
Jerry Avorn, MD
Ample data are available to refute this nihilistic view, with numerous examples from the cardiovascular literature alone. Evidence of the potential thrombotic effects of cyclooxygenase-2 inhibitors was present even in the early stages of development of these drugs but was not used to develop trials designed to elucidate this problem. The same applied to rofecoxib, which was never a more powerful analgesic than older nonsteroidal antiinflammatory drugs. The modest gastroprotection afforded by selective cyclooxygenase-2 inhibitors is probably about the same as that afforded by a proton pump inhibitor 16 and is largely negated by concurrent use of low-dose aspirin.
As for cost, the United States almost certainly spends more on medications because of the current flawed system than it would with a better approach to drug evaluation. The public-communications correlate of using an unreasonably high threshold for efficacy is using an unreasonably low threshold for warning about possible risks.
Similar calls were made recently for warnings about the cardiac risks of attention deficit disorder drugs, again without compelling data. Even if I had the time and acumen to do so — and what busy practitioner has hundreds of hours to assess each new medication? The agency then assessed thousands of drugs then on the market to weed out the many that were ineffective, dangerous, or both.
The summer of could mark the beginning of a step back to the pres era for prescription drugs. The proposals under discussion fly in the face of much of what we know about rigorously evaluating clinical interventions. Yet all these measures would become fair game for companies seeking to promote their products to us.
Language in the bill is adding pressure on the agency to relax its guidelines. Patients and physicians would not benefit from legislation that instead of catapulting us into the future, could actually bring back some of the problems we thought we had left behind in the 20th century. Please note , comments are no longer published through this website. All previously made comments are still archived and available for viewing through select posts.
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