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FDA’s New Drug Safety Plan Under the Microscope
In an effort to restore the public’s confidence in the nation’s prescription drug supply, the Food and Drug Administration recently announced plans to create the Drug Safety Oversight Board. Despite the FDA’s planned new system, many are still questioning the overall safety of the current drugs on the market as well as whether the pace at which drugs are being approved may potentially compromise patient safety.
Drug Safety Oversight Board (DSB)
On February 16, 2005 the FDA released a statement announcing their decision to establish an independent Drug Safety Oversight Board (DSB), as well as an informational Web site. The DSB will, for the first time, take the officials who approve new drugs largely out of the process of assessing whether side effects that appear later are serious enough to require quick regulatory action. According to the FDA, the DSB will be comprised of members from the FDA and medical experts from other Health and Human Services agencies and government departments who will be appointed by the FDA Commissioner. In addition, the board will also consult with other medical experts and representatives of patient and consumer groups. The DSB plans to inform the public more frequently and directly about established and emerging drug safety data.
While stating that the DSB is a step in the right direction, critics are uncertain how effective this new system will really be. If the FDA does notify the public of all suspicions pertaining to drugs people might prematurely decide to stop taking a medication that could in fact be more helpful than harmful. “There may be a need for graduated levels of concern, as is done with the yellow, orange and red security alerts,” said Joyce Cramer, Associate Research Scientist, Yale University. “This process could explain the degree of risk to the public so people who need a medication do not stop taking it without first asking their doctor.”
Striking a Balance
“The FDA faces a difficult challenge—establishing a system of drug approval and monitoring that maintains a balance between the benefits of bringing a new, potentially life-saving drug to market quickly, and the risks associated with widespread use of a new drug,” said the American Society of Health-System Pharmacists (ASHP) in a statement submitted to the Senate Health, Education, Labor and Pensions committee. ASHP further qualified this statement by touching upon FDA clinical trial design issues, “The short duration and small number of participants in the clinical drug trials required for FDA approval dictates that the toxicity of new products cannot be fully understood when a drug is approved and initially marketed.”
“If the FDA were to require larger numbers of participants in clinical trials before approving a drug for market, then the study could go on indefinitely, thus prolonging the actual use of a drug that could potentially benefit patients,” said Barry Gidal, PharmD, Professor of Pharmacy & Neurology, University of Wisconsin-Madison. “For example, patients with epilepsy who may have tried all available FDA-approved anti-epileptic drugs could potentially benefit from a new anti-epileptic drug that could stay in the premarket clinical trial phase indefinitely and therefore not be accessible to those patients. So if we extend the process of drug approval then we also may extend the process of patients obtaining seizure control.”
Anne Trontell, M.D, M.P.H., Deputy Director, Office of Drug and Safety at the FDA agreed with Gidal, saying “Larger clinical trials could add time and expense in bringing drugs to market, which could also be detrimental to public health in the long-term by delaying access to important new therapies. It’s a difficult balancing act. People want and deserve the best possible information about their drug products and the side effects associated with them.” She further emphasizes the need for people to know that all drugs have some risk of safety problems that must be balanced against their potential benefit. “When allowing any drug on the marketplace, the FDA has to ensure that its benefits outweigh its risks,” she said.
“However, some drugs are approved and used in Europe and other areas before they are reviewed by the FDA,” noted Cramer. “This provides extra data about the drug’s safety in a general, non-research population. For example, after several years of general use in Europe, vigabatrin (Sabril) treatment was associated with visual field defects. Therefore, although prolonged assessment by FDA prevented many Americans from using this effective drug, it saved them from potential visual damage. This experience, like the thalidomide case, demonstrated the need to expose many “typical” patients to a drug before uncommon adverse events were observed. This cannot be accomplished in clinical trials because patients enrolled in clinical trials are carefully selected.”
How does Postmarketing Safety Surveillance Work?
Postmarketing surveillance, as the name implies, is a monitoring system used to track any and all possible adverse effects associated with a drug or medical device after it has been FDA approved and put on the market. Many pharmaceutical companies have their own postmarketing surveillance system, but are still required to report any adverse events regarding a drug or medical device to the FDA.
Through the FDA’s MedWatch program, healthcare professionals and consumers can send adverse event reports on a voluntary basis directly to the FDA. If healthcare professionals or consumers notify a pharmaceutical company of an adverse event, that company is mandated to pass along that adverse event to the FDA.
Adverse Event Reporting System (AERS)
Each time an adverse event report is completed and sent to the FDA, the FDA inputs the information into the Adverse Event Reporting System (AERS). The reports in AERS are evaluated by clinical reviewers in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). They form the basis for epidemiological studies when appropriate. “Surveillance happens once a product starts being used and is conducted on an ongoing, often daily, basis. All reports are input into AERS, which is now a very large database. We are always on the lookout for a safety signal, which is an excess of adverse events compared to what might normally be expected. We look at the reports very carefully in terms of the number of events versus the number of people taking the drug. How we respond is contextual to the disease being treated, the particular drug, and to the rate of drug use,” said Trontell.
Inherent Weaknesses of Adverse Event Reporting
Due to the voluntary nature of adverse event reporting, many adverse events may in fact be underreported,” Trontell said. “The FDA only sees a fraction of cases. Some estimates are that only 1 to 10% of adverse events are actually reported.” From her own clinical experience Trontell believes the reason for underreporting is that adverse event reporting is outside the normal routine for most physicians. “Physicians have to fit adverse event reporting into what is often a full professional day. The time commitment is potentially burdensome,” she said. Another reason for lack of reporting, according to Cramer, “is that doctors often do not associate an event with a specific medication. If they do report something, they have to consider the liability of describing an adverse event for which they were responsible.”
Gidal believes that in order to reduce the problem of underreporting, clinicians in both community and organized healthcare systems need to be strongly encouraged to utilize the adverse event reporting system. He advises hospitals to incorporate training and active participation in adverse event reporting systems such as Medwatch into their own quality assurance programs.
Recommendations for Improvement of Medwatch
ASHP contends that “the MedWatch program must be strengthened to encourage more reporting. The information gathered from the MedWatch program must be acted upon in a timely manner, by someone separate from the team that initially approved the drug for marketing. Information must also be made available to patients and providers in a timely manner. This may require the FDA being granted additional authority to make labeling changes.” They further contend that “the FDA's ability to measure the ultimate safety of a drug once it has entered the market is limited by the fact that the FDA cannot conduct independent clinical trials, and it is unclear whether the FDA can require manufacturers to conduct such studies. In order for the FDA to fully understand side effects of an approved drug that may not have surfaced in the limited premarket test group, it is essential that the FDA be able to require these studies under certain circumstances.”
ASHP also recommends that more funding is needed by the FDA especially in the area of postmarketing surveillance. Given that manufacturers are required to pay a user fee when they submit a drug approval application; more financial resources are available for drug approval review than for postmarketing surveillance. “This is an area where pharmaceutical companies could support the cost of reporting adverse events because it is in their best interest to know what types of problems are occurring with general use of their drug,” suggested Cramer.
For more information regarding drug safety and surveillance please visit: www.fda.gov/medwatch.index.html
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