According to an article published in the October 22/29 issue of JAMA, about 25% of biological medicinal products that United States and European authorities have approved since 1995 have had at least one regulatory action issued due to safety within 10 years after approval. Around 11% of these antibody, enzyme, and insulin products have even received “black box” warnings that indicate the possibility of serious side effects.
A product is considered a biological medicine if its active substance is produced by or extracted from antibodies, enzymes, hormones, or some other biological source. Representing an important and growing part of medical therapies, over 250 biologicals have been approved since 1982. Thijs J. Giezen, Pharm.D. (Utrecht University, Utrecht, the Netherlands) and colleagues write that, “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. They add that, “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.”
Giezen and colleagues sifted through biologicals approved in the United States and/or the European Union between January 1995 and June 2007 to study the nature and probability of safety-related regulatory actions. The researchers excluded vaccines, allergenic products (anything capable of leading to allergic reaction), and products for further manufacture and transfusion purposes.
During the 12.5 year period, 136 biologicals were approved in the U.S. and 105 in the European Union – 67 of these were approved in both regions (for a total of 174). For 41 of the 174 biologicals – 23.6% – 82 safety-related regulatory actions were issued between January 1995 and June 2008. These warnings consisted of 46 written communications to health care professionals in the U.S. warning of health hazards, 17 in the European Union, and 19 black box warnings. None of the biologicals were withdrawn because of safety reasons.
On average it took about 3.7 years before a safety-related regulatory action was issued, and almost 71% of these actions were issued within five years after the medicine’s approval. A biological had probabilities of 14% and 29% that it would require its first safety-related regulatory action three years and ten years after approval, respectively. If a biological was the first to be approved in its chemical, pharmacological, and therapeutic subgroup, it had a much greater probability of requiring its first safety-related regulatory action compared with products in the same subgroup that were approved later.
Of the 82 safety-related regulatory actions issued, 26.8% involved the system organ classes of general disorders and administration site conditions, 22% involved infections and infestations, 15.9% involved immune system disorders, and 12.2% involved benign, malignant, and unspecified neoplasms. “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,” note the authors.
Giezen and colleagues conclude that, “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.”
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 in an accompanying editorial improvements are needed in the areas of drug approval and postmarketing surveillance system.
“As shown in the study by Giezen et al, many safety problems are identified only after drug approval,” write DeAngelis and Fontanarosa. “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.”
They conclude: “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.”
Safety-Related Regulatory Actions for Biologicals Approved in the United States and the European Union
Thijs J. Giezen; Aukje K. Mantel-Teeuwisse; Sabine M. J. M. Straus; Huub Schellekens; Hubert G. M. Leufkens; Antoine C. G. Egberts
JAMA (2008); 300[16]: pp. 1887-1896.
Written by: Peter M Crosta