Taking the First Step: Reporting ADEs

As discussed earlier, ADEs are a significant patient safety and public health problem. However, it is possible to use these incidents to improve patient care; the key is reporting them. Reporting is critical not only for postmarket surveillance of drugs, but also for developing a pharmacoepidemiologic surveillance program, at both the institutional and national levels.

It is important to keep in mind that although clinical trials have highly regulated methodologies, they also have significant limitations in defining a drug's safety profile. Because of the sample size used in clinical trials, the only adverse reactions that are usually discovered are those that occur frequently.

For example, if a study enrolls 10,000 patients and not a single patient has a particular serious reaction, one can still only be 95% confident that the likelihood of that reaction occurring in that sample size is less than 1 in 3333.^[16] In order to raise the threshold of safety to a confidence level of 99%, the study would need to involve 46,000 patients^16]; however, clinical trials generally do not enroll that many patients, and even some of the largest clinical trials enroll only 5000-10,000 patients.

An example of how serious drug reactions were not detected in clinical trials can be seen with the drug bromfenac. Bromfenac is an NSAID that was marketed for acute pain and inflammation. During the postmarketing experience, however, a number of adverse events were reported involving the use of this drug, including reports of fatal liver toxicity. Unfortunately, serious liver damage occurred in about 1 in 20,000 patients who used bromfenac for more than 10 days. However, the incidence of death due to hepatotoxicity was below the practical detection limit of most clinical trials. In order to have reliably detected serious liver toxicity at the clinical trial level, the researchers would have had to expose 10,000 patients to the drug.^[17] After weighing the postmarketing reports of hepatotoxicity, the FDA decided only to issue a recommendation that bromfenac be used for less than 10 days. This labeling change, however, did not stop prescribers or patients from using this drug for longer periods of time. Eventually, the FDA concluded that the risk for hepatotoxicity outweighed any benefit of bromfenac, given the availability of other drugs in the class that were not associated with such serious adverse effects. As a result, the FDA and the manufacturer (Wyeth-Ayerst) agreed to withdraw the product from the market -- after it had been used by 2.5 million patients.

The effectiveness of postmarketing surveillance and ADE reporting can also be seen in the cases of several other drugs that were removed from the market after unexpected adverse reactions were reported (see Table 2). None of these reactions had been evident during clinical trials of these drugs.^[17]

Table 2. Scope of Patient Exposure to Drugs Removed From Market

For healthcare professionals, it can be a challenge to know what, when, and where to report an ADE. The FDA's MedWatch program^[18] was created to collect reports of serious adverse events. The agency has defined an ADE as "serious" when one or more of the following patient outcomes occur as a result of the ADE:

• Death;
• Life-threatening condition;
• New hospitalization;
• Prolonged hospitalization;
• Permanent disability or damage; and
• Congenital anomaly or birth defect.

The FDA's definition also includes ADEs that required some type of intervention to prevent permanent impairment or damage to the patient.

Most individuals prefer to report an ADE to the FDA's MedWatch program, which provides a convenient online form with directions on how to file the report.^[19] Some clinicians may feel more comfortable reporting the event directly to the drug manufacturer by contacting the company's adverse event department, usually by phone. Regardless of how these "serious" events are reported, the FDA and the pharmaceutical companies are required to share these reports with each other. This allows them to determine whether further action needs to be taken, such as updating the drug safety information for the drug involved. The key is for healthcare providers to use whatever mechanism is most comfortable for them to report the adverse events that they see in their practices.

In addition to reporting ADRs to the FDA and drug manufacturers, internal reporting systems within medical institutions can also have a significant impact on improving patient care. Although filing institutional reports is usually voluntary, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) does require that hospitals have procedures and methods in place so that employees can report ADEs. In fact, the establishment of such a reporting system is a key element in hospital accreditation evaluations. The JCAHO medication management standard MM.6.20 also requires that the hospital respond appropriately to actual or potential ADEs that are reported.^[20]

The key to producing effective ADE reports is knowing which incidents to report and what information to include. Many times, healthcare workers believe that ADRs are limited to events such as rashes and hives caused by antibiotics, or other characteristic events that involve the immune system. As mentioned earlier, these "type B" reactions are unpredictable because they are specific to individual patients, and the mechanism of what causes these reactions is not clearly elucidated. Therefore, due to their idiosyncratic nature, there is little that can be learned from these events that will improve patient outcomes, other than identifying a given patient as allergic to that specific drug, to prevent future occurrences.

In fact, type B reactions comprise only about 10% to 20% of all ADRs, so why do they tend to be reported more than type A events? One reason is that many healthcare professionals view type A events -- those related to a drug's pharmacologic effects -- as merely "side effects." However, these types of ADRs make up the most frequently occurring adverse reactions, and they are, by definition, generally predictable and dose dependent.^[21] Due to these factors, they represent the most preventable ADRs.

The following scenario illustrates how certain "side effects" can be classified as adverse reactions:

Mrs. M. is a 70-year-old woman admitted to the hospital with dehydration and anorexia. She has a history of diabetes mellitus and osteoporosis. Her medications prior to admission included insulin glargine 50 units at bedtime, glyburide 2.5 mg twice per day, and alendronate 70 mg once per week. She is believed to have a gastrointestinal viral syndrome and has a poor oral intake of food, yet her oral insulin glargine and glyburide are still being administered. She is found at 6 am to be diaphoretic with an acute change in mental status, and her glucose level is found to be 10 mg/dL. She is treated with dextrose 50% and administered an infusion of dextrose 10%. Her diet is advanced because she will require a continuous intake of carbohydrates to prevent repeat events of hypoglycemia throughout the day. Meanwhile, insulin glargine and glyburide are temporarily discontinued.

Should this case be reported as an ADE? Is the patient's hypoglycemia "just a side effect" or potentially more serious? According to the WHO definition, this is indeed an ADR. Criteria established by the American Society of Health-System Pharmacists (ASHP) also confirm that this patient has experienced an adverse event. These criteria^[22] state that an ADR is a reaction that is potentially life-threatening, causes permanent damage or even death, or requires intensive medical intervention (similar to the FDA MedWatch definition of a serious ADR). The ASHP definition also includes reactions to drugs that require a change in drug therapy (usually discontinuation or a dose reduction) and/or initiation of a specific treatment to prevent further harm to the patient.