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Adverse Drug Event Monitoring at the Food and Drug AdministrationYour Report Can Make a DifferenceSyed Rizwanuddin Ahmad, MD, MPH The Food and Drug Administration (FDA) is responsible not not be representative of the real world where the drug is only for approving drugs but also for monitoring their safety eventually used.1 An analysis of 192 randomized drug after they reach the market. The complete adverse event trials found that the quality and quantity of safety profile of a drug is not known at the time of approval because of reporting may sometimes be presented erratically or may the small sample size, short duration, and limited general- izability of pre-approval clinical trials. This report describes The FDA is responsible not only for approving drugs for the FDA's postmarketing surveillance system, to which manyclinicians submit reports of adverse drug events encountered marketing but also for monitoring their safety after they while treating their patients. Despite its limitations, the reach the market. This function is carried out by the FDA's spontaneous reporting system is an extremely valuable mech- Office of Drug Safety, which maintains a spontaneous anism by which hazards with drugs that were not observed or reporting database called the Adverse Event Reporting recognized at the time of approval are identified. Physicians System (AERS). AERS receives adverse events information are strongly encouraged to submit reports of adverse outcomes from 2 principal sources: mandatory reports from phar- with suspect drugs to the FDA, and their reports make a maceutical companies on adverse events that had been difference. The FDA is strengthening its postmarketing sur- spontaneously communicated to the firms, primarily by veillance with access to new data sources that have the physicians and pharmacists;and adverse event reports potential to further improve the identification, quantification, that physicians, pharmacists, nurses, dentists, and con- and subsequent management of drug risk.
sumers submit directly to the FDA's MedWatch program.3,4 KEY WORDS: Food and Drug Administration (FDA); adverse Since 1969, more than 2 million adverse event reports have drug events; postmarketing surveillance; MedWatch; drug been submitted to the FDA. Currently, the agency receives approximately 250,000 of these reports per year. In the United States, the estimated cost of morbidity and mortal-ity related to adverse drug reactions (ADRs) is more than $75 billion annually, and ADRs are among the top 10 hen the Food and Drug Administration (FDA) approves a new drug for marketing, its complete The majority of reports that are submitted to the FDA adverse event profile may not be known because of the come from pharmaceutical companies. However, late or limitations of pre-approval clinical trials. Typically, clinical non-reporting of case reports by drug companies, or failure trials for new drugs are of short duration and are to report any adverse event at all, are major problems. The conducted in populations that number from a few makers of the arthritis medication benoxaprofen (Oraflex), hundred to several thousand;therefore, the most common the antihypertensive drug ticrynafen (Selacryn), and the dose-related adverse drug reactions are usually detected antidepressant drug nomifensine (Merital) have been in the premarketing phase. Since most trials exclude the criminally prosecuted for delay in reporting or failure to elderly, children, pregnant women, patients with multiple report serious adverse drug events. In recent years, the FDA diseases, and those on medications suspected of inter- has issued several warning letters to companies, primarily action with the study drug, the studies' participants may as a result of the late reporting of adverse drug events.
Timely reporting of adverse events is fundamental to the success of the FDA's postmarketing surveillance (PMS) Received from the Division of Drug Risk Evaluation, Office of program, especially in the case of newly marketed drugs.
Drug Safety, Food and Drug Administration, Center for Drug Physicians are on the frontline of FDA's PMS program, and Evaluation and Research, Rockville, Md.
their reports make a difference. Inadequate reporting of Address correspondence and requests for reprints to Dr.
adverse events by physicians may delay detection of Ahmad: Division of Drug Risk Evaluation, Office of Drug Safety,Food and Drug Administration, Center for Drug Evaluation and postmarketing adverse drug events.7 There is no program Research HFD-430, Room 15B-08, 5600 Fishers Lane, Rock- of testing prior to the marketing of a drug that will find all ville, MD 20857 (e-mail: [email protected]).
its risks in real-world situations, and no drug is completely Ahmad, Adverse Drug Event Monitoring at the FDA safe. The objective of this paper is to describe the FDA's incidence of adverse events, the FDA's epidemiologists PMS program and to highlight the important role of frequently estimate the reporting rate (number of case physicians and other health care professionals in this task reports of adverse outcome of interest divided by estimated with the hope that this will stimulate and encourage total number of prescriptions) of adverse events with a increased reporting of serious adverse events associated suspect drug, and compare it with the background rate at with drugs. It is only with the help of alert and vigilant which the same event occurs in a population not treated by physicians and other health care professionals that new the suspect drug. A reporting rate that is higher than the background rate is an indication of a possible causalrelationship between the adverse event and the drug.
Spontaneous reporting systems such as AERS are the As the next step, the FDA may attempt to confirm most common, effective, and relatively inexpensive meth- potential signals by conducting studies in one of several ods used in pharmacovigilance to identify new or rare large claims databases that link prescriptions with adverse adverse events. Data from AERS are first scrutinized by the outcomes. The FDA has funded extramural investigators FDA's postmarketing safety evaluators for previously through a system of cooperative agreement for more than a unrecognized (unlabeled) serious adverse events, which decade. These investigators, who have access to large may represent potential ``signals.'' Most helpful in this population-based databases, are affiliated with depart- process are ``good'' adverse event reports that contain ments of pharmacoepidemiology and/or pharmacy in information such as: a complete description of the adverse universities and/or managed care organizations/HMOs.
outcome;baseline status of the individual;laboratory Over the years, the FDA has been able to utilize the values and biopsy report, where applicable;temporal resources of these investigators to answer a number of drug relationship with the suspect drug;information about safety questions. The FDA may also query foreign regula- dechallenge (event abates when drug is discontinued) and tory agencies, mainly those in Europe, Canada, and rechallenge (event recurs when drug is restarted);and Australia, regarding whether similar adverse events may information about confounding drugs or conditions. Even a have been reported with the suspect drug. In addition, the single ``good'' adverse event report can qualify as a potential FDA may query the World Health Organization (WHO) ``signal'' that requires further research.
Uppsala Monitoring Center database, which collects When a ``signal'' is noted, the safety evaluators, who adverse drug reactions data from over 60 countries are specially trained clinical pharmacists, routinely try to participating in the WHO International Drug Monitoring find additional cases in AERS and medical literature or from foreign regulatory agencies. A case definition may bedeveloped and repeatedly refined as new cases are col- lected. After assembling a series of cases, the safety evaluators search for any common trend, causal relation-ship, or pattern of events to identify potential risk factors or The confirmation of a ``signal'' may be followed by one any other peculiarities. Usually, they look for signs such or more FDA regulatory actions, the extent and rigor of as: temporal association (the suspect drug was taken which depend on the seriousness of the adverse events, the before the occurrence of adverse outcome);coherence with availability, safety, and acceptability of alternative therapy, existing information or biological plausibility;similar effect and the outcome of previous regulatory intervention. The in drugs of the same class;dose-response relationship; agency may require the drug manufacturer to inform consistency of the association (replicability of results);and prescribers about the identified hazard in a ``Dear Health Care Professional'' letter, and to add to or strengthen new One of the limitations of spontaneous reports is that, in or boxed warning information in the product's professional general, they are poorly documented, and the safety labeling. Boxed warning may be required when special evaluator may need to contact the event reporter, either problems, particularly those that may lead to death or directly or through the manufacturer, in order to secure serious injury, may be associated with a drug. If a boxed warning is required, its location is specified by the agency.
Another limitation of spontaneous reporting is that it The FDA may also require that the drug company enhance captures only a small fraction of the adverse events that patient information materials such as medication guides.
actually take place. The extent of under-reporting is Recent examples of FDA regulatory actions stimulated unknown, and depends on the severity of the adverse by ADR reports include postmarketing reports of myocar- event, among other factors. One group of researchers ditis in association with clozapine (Clozaril), which led to estimated that the FDA receives reports of less than 1% of strengthening of the boxed warning and warnings section serious adverse events, whereas another group gave this of the drug's labeling;and reports of liver failure leading to estimate as between 8% and 13%.8,9 Since it is not possible transplants and/or death in association with the use of the to calculate from the available information the actual antidepressant nefazodone (Serzone), which led to the Table 1. Recent Safety-based Drug Withdrawals Drug interactions/arrhythmias (torsades de pointes) Drug interactions/arrhythmias (torsades de pointes) * Cisapride is available only through an investigational limited-access program.
y Phenylpropanolamine or PPA was an ingredient in many cough/cold and diet pills.
z In June 2002, the FDA approved restricted remarketing of alosetron.
Detailed information on all the above drugs can be accessed by visiting the FDA's website (www.fda.gov/medwatch/safety.htm).
addition of a black box warning in the labeling. A boxed addition, the agency regularly disseminates new drug warning was added following spontaneous reports of safety information on its website (www.fda.gov/medwatch/ serious cardiac arrhythmias in association with the use of safety.htm), through articles in professional journals,13±26 levomethadyl acetate (Orlaam), a drug for opiate addiction and at scientific forums where FDA scientists give treatment. The warnings, precautions, and adverse reac- tions section of labeling for the two antidiabetic drugspioglitazone (Actos) and rosiglitazone (Avandia) were strengthened, and physicians and patients with diabetes The FDA is strengthening its postmarketing surveil- were alerted to the possibility of fluid retention that could lance system with new staff and resources in order to meet lead to or exacerbate congestive heart failure when either the challenges of the changing world of therapeutics.
drug was used as monotherapy or in combination with Ensuring the safety and effectiveness of drugs on the insulin. The FDA issued a public health advisory concern- market, however, is a responsibility that the FDA shares ing the systemic use of two antifungals itraconazole with industry, all health care professionals, including (Sporanox) and terbinafine (Lamisil) and the association physicians and pharmacists, and patients. The FDA's of serious hepatic events with both drugs and possible success in reducing drug-related adverse events depends association of serious cardiac adverse events with the to a large extent on the adverse event reports it receives from health care professionals, either directly or through The FDA can also restrict distribution of a drug, and on the manufacturers. Health care practitioners are on the rare occasions, it may request a drug's withdrawal from the front line of the FDA's postmarketing program, and their market, or the manufacturer may voluntarily withdraw the reports are vital to the FDA's ability to protect consumers drug. The cholesterol-lowering drug cerivastatin (Baycol) and patients. Physicians are strongly encouraged to submit was voluntarily withdrawn from the market by the drug's reports of adverse outcomes with suspect drugs to the manufacturer following serious reports of rhabdomyolysis FDA's MedWatch program by phone (1-800-FDA-1088), fax in association with its use. The irritable bowel syndrome (1-800-FDA-0178), or via the MedWatch website at http:// drug alosetron (Lotronex) was withdrawn from the market by the company following postmarketing reports ofischemic colitis a few months after the drug was launchedin the market. In June 2002, the FDA approved restricted The author thanks Julie Beitz, MD, of the Division of Drug Risk marketing of alosetron. The diabetes drug troglitazone and Evaluation, FDA for her helpful comments and suggestions the heartburn drug cisapride are recent examples of drugs during preparation of this manuscript.
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