Approximately one in four biological medicinal products (such as antibodies, enzymes and insulin) approved since 1995 in the U.S. and Europe have had at least one safety-related regulatory action issued for them 10 years after their approval, including about 11 percent receiving a "black box" warning, according to a study in the October 22/29 issue of JAMA, a theme issue on the Health of the Nation.
Biologicals are preparations in which the active substance is produced by or extracted from a biological source, such as antibodies, enzymes and hormones. They represent an important and growing part of medical therapies, with more than 250 biologicals having been approved since 1982, according to background information in the article. "Between 2003 and 2006, biologicals represented 24 percent and 22 percent of all new chemical entities approved by the U.S. and EU [European Union] regulatory authorities, respectively," the authors write. "Biologicals are a relatively new class of medicines that carry specific risks (e.g., immunogenicity [the ability to stimulate an immune response]). However, limited information is available on the nature and timing of safety problems with their use that were identified after approval."
Thijs J. Giezen, Pharm.D., of Utrecht University, Utrecht, the Netherlands, and colleagues examined the nature and probability of safety-related regulatory actions issued for biologicals approved in the United States and/or the European Union between January 1995 and June 2007. Vaccines, allergenic products (a substance capable of causing an allergic reaction), and products for further manufacture and transfusion purposes were excluded.
A total of 174 biological medicinal products obtained approval during the study period, including 136 biologicals approved in the U.S. and 105 in the European Union, of which 67 biologicals obtained approval in both regions during this time. The researchers found that between January 1995 and June 2008, 82 safety-related regulatory actions were issued for 41 of the 174 biologicals (23.6 percent). These included 46 written communications (warnings of health hazards) to health care professionals in the U.S., 17 in the European Union, and 19 black box warnings (warning of serious health hazards). No biologicals were withdrawn due to safety reasons.
The average time to a safety-related regulatory action was 3.7 years and 70.7 percent of the safety-related regulatory actions were issued within five years after approval. The probability of a biological requiring its first safety-related regulatory action was 14 percent three years after approval and 29 percent ten years after approval. Biologicals that were the first to be approved in their chemical, pharmacological, and therapeutic subgroup had a significantly higher risk for the occurrence of its first safety-related regulatory action compared with later approved products.
The safety-related regulatory actions issued for biologicals mostly involved the system organ classes of general disorders and administration site conditions (26.8 percent of 82), infections and infestations (22 percent), immune system disorders (15.9 percent), and neoplasms benign, malignant, and unspecified (12.2 percent). "The safety-related regulatory actions issued in the system organ class of general disorders and administration site conditions can be partly explained by the infusion reactions occurring after the parenteral [intravenously or by injection] route of administration, which is the mode of administration for most biologicals. A more in-depth evaluation of the mode of action of biologicals might have predicted some safety problems during the developmental phase."
"Although the limitations of preclinical trials for biologicals are acknowledged, results from pharmacology studies, preclinical studies, and clinical studies might result in the prediction of potential risks related to the drug for which close monitoring is needed in the postapproval setting. Health care professionals should be aware of the specific risks related to the relatively new class of biologicals to be able to provide a link between the use of the biological and the patient presenting with a clinical problem," the authors write.
Editorial: Prescription Drugs, Products Liability, and Preemption of Tort Litigation
In an accompanying editorial, Catherine D. DeAngelis, M.D., M.P.H., Editor-in-Chief, JAMA, and Phil B. Fontanarosa, M.D., M.B.A., Executive Deputy Editor, JAMA, Chicago, write that these findings show the need for improvement in the drug approval process and the postmarketing surveillance system.
"As shown in the study by Giezen et al, many safety problems are identified only after drug approval. The human body is in a constant state of change and the effects of some drugs will manifest only after exposure over time. Furthermore, some serious adverse drug effects are quite uncommon and require use of the drug in large numbers of patients to become evident. The safety of drugs in a clinical trial, the study type used for Food and Drug Administration approval, is based on specific participant types, numbers, and design that cannot ensure the true safety of a drug. In addition, manipulation of study results by the drug manufacturers (who almost always sponsor studies used for decisions about drug approval) can obscure the true safety profile of a drug."
"Given the current imperfect process for approval and the flawed postmarketing surveillance system, the drug and device regulation process is at best an inexact and incomplete science. Until these deficiencies in the system are remedied, some patients inevitably will continue to experience harm from the use of newly marketed products as well as from use of other approved medications. Just as with other consumer products that cause harms, consumers (i.e., patients) who are injured by defective medical devices or by pharmaceutical products with inadequate warnings of potential harms may have to resort to legal action as recourse for their injuries."
- Giezen et al. Safety-Related Regulatory Actions for Biologicals Approved in the United States and the European Union. JAMA The Journal of the American Medical Association, 2008; 300 (16): 1887
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