Investigators release data on unexpected ADRs
Ten percent of patients died from adverse reactions
In 1998, a multidisciplinary team of investigators initiated RADAR (Research on Adverse Drug events And Reports), a clinically based postmarketing surveillance program that is funded independently of the pharmaceutical industry. RADAR systematically investigates and disseminates information describing serious and previously unrecognized adverse drug and device reactions (ADRs).
The investigator team evaluates initial reports of the ADRs, identifies additional reports of each ADR, develops hypotheses for mechanistic pathways, evaluates related laboratory and pathologic findings, and derives reporting and incidence rate estimates. They then synthesize summary safety information into reports disseminated in medical journals, revised package inserts, and Dear Doctor letters. The information also is presented at medical conferences and at meetings with officials of the FDA, the relevant pharmaceutical manufacturers, and to officials in the public sector who are evaluating pharmaceutical safety issues.
In the May 4 issue of the Journal of the American Medical Association, the 25 core investigators described the RADAR project and gave statistics about their findings: Between 1998 and 2004, they identified serious ADRs associated with 16 different drugs that affected 1,699 patients, 169 (10%) of whom died. The toxicities affected multiple organ systems and included TTP (thienopyridines), hypersensitivity (drug-eluting cardiac stents), interstitial pneumonitis (nonsteroidal anti-androgens and gemcitabine), sinusoidal obstructive syndrome (gemtuzumab), immune-mediated anemia (epoetin), thrombocytopenia (megakaryocyte growth and development factor [rHu-MGDF]), thromboembolism (thalidomide), hepatotoxicity (nevirapine), optic neuritis (amiodarone), pseudoaneurysms (enoxaparin), jaw osteonecrosis (zolendronate), and lymphoproliferative disorders (rHu-MGDF).
ADRs associated with 16 drugs
Initial cases were identified by seven RADAR investigators, four collaborating physicians, two attorneys, and by reviewing three published reports, the investigators said. Additional sources included queries of occupational health programs and medical directors of interventional cardiology laboratories (three types of ADRs), published manuscripts and clinical trials (11 types of ADRs), review of medical records at a RADAR site (two types of ADRs), unpublished clinical trial reports (three types of ADRs), and reports from attorneys, family members, or patients (four types of ADRs).
Incidence estimates, ranging from 0.4% to 33%, were derived from five clinical trial reports, two physician queries, and two observational databases. Laboratory support for hypotheses included identification of three neutralizing antibodies and three histopathological findings. ADR reports were disseminated as eight revised package inserts, seven Dear Doctor letters, and nine peer-reviewed articles.
"In conclusion," the investigators said, "our investigations exemplify the potential benefits of establishing clinically based, postmarketing surveillance collaboratives that focus on serious ADRs. The RADAR group has identified and evaluated 16 serious ADRs and in response, package insert revisions, Dear Doctor letters, and peer-reviewed medical articles describing our findings have been disseminated. It is hoped that the efforts of the RADAR project will ultimately improve safety through early detection and treatment of serious ADRs."