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Overcoming Barriers to Reporting Adverse Drug Events

Authors: Charles L. Bennett, MD, PhD, MPP; Cara C. Tigue, BAFaculty and Disclosures


Serious adverse drug events (ADEs) may emerge after a new drug is brought to market; in fact, a median of 7 years elapses before such incidents are described by pharmaceutical companies or the US Food and Drug Administration (FDA).[1] An important factor underlying this delay is low reporting of ADEs, with only 1% to 10% of all such incidents reported.

In an effort to improve detection of serious ADEs, the FDA is forming partnerships with large health insurers and is planning to monitor insurance claims, electronic medical records, and laboratory test results for persons who are covered by these health insurers. However, recent studies highlight the importance of clinicians reporting even small numbers of clinical events that may be involved in serious and potentially fatal ADEs.

For instance, clinician involvement was key in identifying problems with natalizumab- and rituximab-associated progressive multifocal leukoencephalopathy, epoetin-associated pure red blood cell aplasia,[2] ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura,[3,4] zolendronate-associated osteonecrosis of the jaw, and gadolinium-associated nephrogenic systemic fibrosis. These toxicities were elucidated based on comprehensive reporting of just 3 to a few hundred individual events to the FDA. These cases provide important lessons for clinicians and policy makers who are interested in improving the safety of pharmaceutical agents and devices.

In general, an important barrier to identifying and reporting ADEs is that the toxicity profiles of many agents are not well characterized at the time of FDA approval. In addition, increasing numbers of novel targeted agents are receiving approval for the treatment of serious diseases, especially cancer. The unique molecular pathways of these agents often increase efficacy while minimizing the side effects of older, more conventional therapies. However, several serious ADEs have been associated with these newer agents that were not associated with conventional therapies, and they have not yet been fully characterized.

Accelerated approval regulations were established in 1992 to enable patients with life-threatening diseases to have rapid access to therapeutics. The accelerated process allows for drug marketing based on surrogate outcomes that show meaningful therapeutic benefit. Drug sponsors are still required to conduct confirmatory phase III studies to verify clinical benefit. However, this requirement has not been met for many drugs that received accelerated approval, suggesting that the safety profiles of these agents may not be adequately described.

A recent study in The New England Journal of Medicine found that drug review deadlines imposed by the Prescription Drug User Fee Act lead to rushed approvals and unanticipated safety problems following FDA approval.[5] The study found that drugs approved in the 2 months before that deadline were more likely to be later withdrawn from the market for safety reasons, and more likely to receive a black box warning compared with drugs approved at other times.

In light of these findings, clinicians must be cognizant that some new drugs may not have undergone extensive safety reviews. If a novel agent receives accelerated FDA approval, the safety database may be as small as a few hundred carefully screened individuals. If an unexpected clinical event occurs with a novel agent, you can be fairly certain that neither the manufacturer nor the FDA has seen such an event before. This is especially true for novel agents that are used in off-label clinical settings or by individuals with complex medical histories.

For example, gemtuzumab ozogamicin, the first FDA-approved immunoconjugate, received its initial approval based on monotherapy findings from 3 phase II trials of older patients with acute myeloid leukemia. Immediately thereafter, clinicians at MD Anderson Cancer Center in Houston, Texas, evaluated the drug as an off-label treatment with combination chemotherapeutic regimens for younger persons with AML. Between 10% and 40% of these individuals unexpectedly developed ascites and hepatic dysfunction. In addition, a new syndrome termed sinusoidal obstructive syndrome was identified by a single astute leukemia clinician.[6]

Unfortunately, many clinicians are unaware of how to file ADE reports, or they feel that such efforts would be too costly or time-consuming, seeing little benefit in their voluntary actions. Fortunately, regulatory guidance offers some assistance. An astute clinician who identifies a potential serious ADE but does not have the time or resources to report comprehensive details of the case still has some options.

In the inpatient setting, hospital pharmacy personnel are usually willing to assist the clinician in filing a report with the FDA's ADE reporting system, MedWatch. These individuals generally are not paid specifically for this service, but hospital quality improvement regulations allow for them to review medical records and report the clinical details, laboratory findings, and outcomes of an ADE.

In the outpatient setting, such assistance may not be identified quite as easily. However, the clinician can summarize the relevant findings in a memo (without disclosing personal identification) and forward this information to the sales representative from the relevant pharmaceutical company. By law, this individual must forward the clinical information to MedWatch. In fact, the clinician should ask the sales representative to provide a copy of the MedWatch report after it is submitted.

Clinicians who identify an unexpected, serious ADE should also consider sharing de-identified information on the case with academic investigators who have expressed an interest in the subject area or in pharmacovigilance. These individuals are highly motivated to develop concise case summaries and to submit this information for review at scientific conferences and in peer-reviewed medical journals.

For example, the Research on Adverse Drug Events and Reports (RADAR) project of Northwestern University is very interested in reporting small case series of rare but serious ADEs. The RADAR team has identified and evaluated 38 reports of serious drug reactions over the last decade, with most of these toxicities identified in the oncology setting. The RADAR methodology has relied on initial recognition of sentinel cases that then prompt hypothesis-driven inquiries as to whether an unrecognized ADE signal is present in the population exposed to that drug. A clinician may contact collaborators with the RADAR project who, in turn, develop reports describing the case series. In our paper on clopidogrel-associated thrombocytopenic purpura, 4 clinicians who submitted case reports of individuals with this unexpected toxicity were co-authors on The New England Journal of Medicine report.[4] Their help in this investigation was indispensable.

Lawyers can also join the safety team. An observant attorney submitted to the RADAR group clinical information on a healthy volunteer in a phase I clinical trial of megakaryocyte growth and development factor who subsequently developed severe thrombocytopenia as well as a lymphoproliferative disorder. This report was followed by other clinicians submitting information on 12 healthy volunteers who also developed severe thrombocytopenia and 2 other volunteers who developed lymphoproliferative disorders.[7]

Patients are aware of the time and financial crunch that clinicians face. When a patient experiences a potential ADE, the immediate goal is getting through the complication and moving on. Subsequently, anger arises as they wonder why the FDA or the manufacturer did not warn them in advance about such a possibility.

If a clinician reports the event to the FDA (or to the pharmacist or sales representative), then a MedWatch report is generated. Patients generally are appreciative if they receive a copy of the MedWatch report and understand that the clinician took the extra step to report the clinical details to the proper authorities. If the FDA or drug manufacturer subsequently issues a report about this drug, the patient is likely to appreciate the previous notice even more.

With the increasing focus on pharmacovigilance, academic organizations have evolved with focused interests in specific toxicities. The Arizona Center for Education and Research on Therapeutics (CERT) has developed a novel Web site for reporting unexpected drug-associated Q-T prolongation events. The RADAR project focuses primarily on adverse drug reactions involving the disciplines of hematology and oncology.

The National Registry of Drug Induced Ocular Side-Effects focuses on drugs that unexpectedly result in blindness or severe vision changes. Several other toxicity-specific centers have developed around the country at academic centers (Table). These centers focus on liver failure, muscular-skeletal disorders, cardiovascular disorders, and many other toxicities. Contacting any 1 of these sites would help the pharmacovigilance investigators assist the busy clinician by summarizing relevant case information.

Table. Academic Organizations With Focused Interests in Specific Drug Toxicities

Organization Location Area of focus Website/ Contact information
Research on Adverse Drug events And Reports (RADAR) Chicago, Ill Hematology/Oncology
Surveillance Epidemiology and Risk Factors for Thrombotic Thrombocytopenic Purpura (SERF-TTP) Chicago, Ill Thrombotic thrombocytopenic purpura Charles Bennett, MD, PhD, Principal Investigation, [email protected]
Clinical Center for Liver Disease at University of Texas Southwestern Dallas, Tex Acute liver failure http://www8.utsouthwestern.
University of Alabama Center for Education & Research on Therapeutics (CERT) Birmingham, Ala Therapies for musculoskeletal disorders http://www.certs.cme.uab.
University of North Carolina CERT Chapel Hill, NC Therapeutics in the pediatric population
Duke University CERT Durham, NC Therapies in cardiovascular medicine Robert Califf, MD, Principal Investigator, Phone 919-668-8820
National Registry of Drug-Induced Ocular Side Effects Portland, Ore Blindness and severe vision changes
Arizona CERT Tucson, Ariz QT Cardiac Arrhythmia
Vanderbilt CERT Nashville, Tenn Prescription drug use in the Medicaid and veteran populations
Cleveland Clinic Cleveland, OH Cox-2 inhibitors Steven Nissen, MD
Phone 216-445-6852
University of Pennsylvania CERT Philadelphia, Penn Therapies for infection, antibiotic drug resistance

Source for CERT information: Centers for Education and Research on Therapeutics. Fact sheet. Agency for Healthcare Research and Quality. AHRQ Pub. No. 00-P048, Revised September 2000. Available at Accessed May 29, 2008

In addition, a number of Web sites offer social networking opportunities for clinicians, facilitating a discussion of suspected ADEs. Clinicians use sites such as Medscape and Sermo to share patient case details, observations, and comments. In fact, Sermo was originally conceptualized as an ADE reporting system. Other Web sites, such as, also can facilitate adverse event reporting. This site collects patient information and provides forums where members share advice and provide feedback on particular drugs or treatment issues.

In conclusion, most clinicians experience serious ADEs first-hand, yet fewer than 0.01% of them ever report this information to the FDA, the manufacturer, or a pharmacovigilance program. Reporting these incidents is crucial to improving drug safety. The objective is for fairly complete case descriptions to be added to the MedWatch database. Novel strategies exist by which a busy clinician can facilitate the timely and accurate reporting of ADEs to the appropriate authorities.

This activity is supported by an independent educational grant from PhRMA.

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