Summary*

Adverse reactions to prescription drugs (adverse drug events, or ADEs) are quite common and usually do little harm to patients. But in a small percentage of cases, they can have serious consequences and can cause serious injury or death. All drugs must undergo extensive studies to examine their safety and efficacy before they receive FDA approval. As a result, the risk of adverse drug events is often well known in advance. However, these studies are conducted on a limited number of subjects, making it difficult to identify adverse reactions that are rare but potentially serious. Furthermore, because these studies are limited in duration, they may not identify reactions that occur over long periods of time.

In order to identify adverse drug events after a drug has been released, the Food and Drug Administration (FDA) relies on a postmarketing surveillance program known as MedWatch. Information collected through MedWatch is placed in a large database known as the Adverse Event Reporting System (AERS). There are significant concerns about the effectiveness of this system. Furthermore, the FDA has limited options for conducting follow-up safety assessment once a drug has been approved. As a result, serious adverse drug reactions may be fully appreciated only after a drug has been on the market for many years.

*

The Forum’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop.



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Adverse Drug Event Reporting: The Roles of Consumers and Health-Care Professionals - Workshop Summary Summary* Adverse reactions to prescription drugs (adverse drug events, or ADEs) are quite common and usually do little harm to patients. But in a small percentage of cases, they can have serious consequences and can cause serious injury or death. All drugs must undergo extensive studies to examine their safety and efficacy before they receive FDA approval. As a result, the risk of adverse drug events is often well known in advance. However, these studies are conducted on a limited number of subjects, making it difficult to identify adverse reactions that are rare but potentially serious. Furthermore, because these studies are limited in duration, they may not identify reactions that occur over long periods of time. In order to identify adverse drug events after a drug has been released, the Food and Drug Administration (FDA) relies on a postmarketing surveillance program known as MedWatch. Information collected through MedWatch is placed in a large database known as the Adverse Event Reporting System (AERS). There are significant concerns about the effectiveness of this system. Furthermore, the FDA has limited options for conducting follow-up safety assessment once a drug has been approved. As a result, serious adverse drug reactions may be fully appreciated only after a drug has been on the market for many years. * The Forum’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop.

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Adverse Drug Event Reporting: The Roles of Consumers and Health-Care Professionals - Workshop Summary In November 2005, the Institute of Medicine’s Forum on Drug Discovery, Development, and Translation convened a workshop to explore issues associated with the reporting of ADEs. The workshop addressed the following questions: How can ADEs be effectively identified, particularly when the adverse effects are rare? How can the direct, causal effects of drugs be distinguished from simple associations? How can health-care professionals and their patients aid in the identification of drug-related adverse events? How can knowledge of ADEs be more effectively used in clinical practice? IDENTIFYING ADVERSE DRUG EVENTS Since the FDA has limited options for addressing safety questions about drugs after premarketing research has occurred, identifying ADEs requires the participation of health-care providers, consumers, and others. MedWatch, the FDA’s program for postmarket surveillance, collects clinical information involving drugs from health-care professionals and consumers through a variety of channels, including mail, Internet, and telephone. The largest source of postmarket information on ADEs is drug companies themselves. Companies typically submit large numbers of reports at a time in batch form to the FDA. Data on adverse events are placed in the AERS, and are evaluated by FDA staff to detect safety signals and monitor drug safety. Potential adverse events are also identified through case reports in the medical literature and through epidemiologic surveillance of electronic claims and other data. Surveillance systems screen claims data for adverse events and notify health-care providers who then determine if follow-up reporting is required. The Centers for Medicare and Medicaid Services captures data on drug use and clinical services for individual subscribers. And institutional review boards of individual health systems capture many adverse events in clinical trials. Challenges associated with current systems for reporting ADEs were discussed by workshop participants. Underreporting and incomplete reporting and poor quality of data are concerns about all reporting systems. There have been suggestions that streamlining these systems and ensuring anonymity may motivate health-care providers to file adverse event reports with greater frequency and accuracy. Participants discussed the need for incentives to encourage the development of long-term safety studies. Furthermore, it was suggested that informing consumers about known drug risks and benefits may encourage consumer reporting of ADEs and participation in follow-up studies.

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Adverse Drug Event Reporting: The Roles of Consumers and Health-Care Professionals - Workshop Summary ESTABLISHING CAUSE AND EFFECT Once a possible association between a drug and an adverse event is detected and reported, it is important to confirm whether the ADE is actually caused by the drug rather than due to the influence of some other confounding variable. In order to answer this question, studies must obtain adequate information about confounding factors, such as comorbidities, patient risk factors, and concurrent treatments. Furthermore, studies must be of sufficient duration to detect problems over time. Unfortunately, many postmarketing studies lack these basic characteristics. Participants suggested that researchers and clinicians discuss safety and efficacy in the early stages of protocol development in order to improve the subsequent postmarketing study design. DRUG-DRUG INTERACTIONS When attempting to understand cause and effect in ADEs, it is important to tease out single drug effects from effects due to the interaction of two or more drugs (drug-drug interactions, or DDIs). DDIs can make a medication less effective, cause unexpected side effects, or increase the action of a particular drug. There are multiple systems in place for capturing DDIs. However, these systems often disagree about which interactions have the greatest clinical importance. Participants discussed the need to establish uniform criteria for interactions and ADEs, and a standardized terminology to evaluate interactions for their clinical importance. Several strategies for reducing DDIs were discussed, including a more active role for pharmacists and pharmacy benefit managers (PBM). PBMs electronically share information about drugs with health-care providers, manufacturers, and heath plan sponsors. These linked databases could potentially provide valuable information about reducing harm from inefficacy, drug interactions, and adverse drug reactions. Patient education is also an important step in the reduction of DDIs. The formation of a cross-disciplinary DDI working group that would create improved tools for communicating interactions and consequences was discussed. This group could identify and prioritize DDIs, develop a public database capable of receiving all new labeling information on drug interactions, perform an ongoing review of data from the FDA and the published literature, and possibly recommend specific interaction studies. LABELING Information on known ADEs and DDIs is not effectively communicated to clinicians and pharmacists. The drug label is the principal means of communication, and there are concerns about the presentation

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Adverse Drug Event Reporting: The Roles of Consumers and Health-Care Professionals - Workshop Summary and usefulness of the information it contains. One concern identified by participants is that all reported adverse reactions are included on labels, making it difficult for providers to assess the relative importance of different reactions. The FDA has recently changed the format of drug labels in an attempt to present the information more effectively. New drug labels have a highlights section in which manufacturers are required to place information obtained during the preceding year in order to keep physicians updated on new indications and interactions. Another concern is that drug labels do not currently communicate the likelihood that a particular adverse event will occur when taking the drug. Participants suggested that labeling should inform consumers and physicians about the level of causal certainty of suspected adverse reactions. To make risk communication effective, the medical and scientific community, users, media, industry, and regulators must have a common understanding of the decision-making principles behind risk labeling, must agree on the meaning of terms such as adverse reaction, adverse event, and risk, and must use such terminology consistently. Drug labels also do not communicate effectively a drug’s potential side effects or interactions with other substances. Participants discussed the need for a third party (neither the FDA nor the pharmaceutical industry) to decide what information about DDIs is relevant to consumers and useful to prescribers and should therefore be included on labeling. Several related FDA initiatives to improve drug safety were discussed. The electronic labeling rule requires industry to submit e-labels to the FDA beginning in June 2006. This rule requires bar-coding on all over-the-counter medications. Paperless labeling will eliminate the requirement for paper package inserts, which cost companies about $1 million per year per product. In order to address the rising demand for better drug safety surveillance, the American Board of Medical Specialties (ABMS) is developing a “Patient Safety” Module that will address drug safety in physician certification and recertification. INCREASING CONSUMER INVOLVEMENT IN ADVERSE EVENT REPORTING Because they are directly affected by ADEs, consumers have an incentive to report them to their clinicians or pharmacists. However, there are few efforts to more actively engage consumers in the process, and there is no comprehensive system in place for consumer reporting of adverse events. The fact that reporting systems such as MedWatch capture only a fraction of ADEs may be due, in part, to a lack of meaningful consumer engagement in this process. Mechanisms that were discussed by workshop participants to increase

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Adverse Drug Event Reporting: The Roles of Consumers and Health-Care Professionals - Workshop Summary the involvement of consumers in ADE reporting included the development of outreach programs to provide the public with information about drugs and potential adverse effects. For example, the Consumers Union initiated the Best Buy Drugs website (www.crbestbuydrugs.org) to educate consumers about medications, specifically the drugs that give the best value. Increased ADE reporting can be encouraged through public service announcements, by direct-to-consumer advertising, and by providing consumers with multiple avenues for reporting events. Other suggestions discussed by participants included the formation of a drug safety oversight board with its own regulatory power, composed of consumer representatives and scientists with no industry ties or involvement in the approval process. Increased involvement in reporting ADEs may also be achieved by looking to successful reporting programs, such as the United Kingdom’s yellow card system. This system was presented as a potential model for a more integrated approach to voluntary reporting in the United States. The yellow card system is used to collect information from health professionals and consumers on suspected ADEs. It allows consumers to report online, by prepaid mail, and by phone. The system actively seeks reports and can be accessed in some form in almost any relevant care delivery setting, such as pharmacies and physician offices.

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