Improved Postmarketing Surveillance Needed for Biologic Agents

Roxanne Nelson

October 21, 2008

October 21, 2008 — Biologic agents are a relatively new class of drugs, and a number of them are helping to revolutionize cancer therapy. However, according to a report in the October 22/29 issue of the Journal of the American Medical Association, associated safety problems are often not identified until the agents have been approved by regulatory agencies and have entered the market, indicating a need for improving the postmarketing surveillance system.

The investigators point out that since 1995, approximately 1 in 4 biologic agents approved in the United States and Europe have had at least 1 safety-related regulatory action issued for them. Of this group, 11% received a black-box warning.

"It is generally accepted that knowledge of a new drug is incomplete at the time of approval, especially with reference to its safety profile, because of a variety of reasons, including constraints in the sample size and the design of randomized clinical trials," said lead author Aukje Mantel-Teeuwisse, PhD, from the Utrecht Institute for Pharmaceutical Sciences, Utrecht University, in the Netherlands. "Therefore, unexpected adverse drug reactions will always occur in the postmarketing setting. Proactive monitoring of identified and potential risks has been acknowledged as the way to move forward by both the [Food and Drug Administration] and the [European Medicines Agency]."

In 1982, recombinant insulin became the first biologic agent approved in the United States. Since then, more than 250 agents have received approval by regulatory authorities. These include recombinant products, monoclonal-antibody-based products, and recombinant vaccines. The increased growth of these products has been expediential; biologic agents accounted for nearly a quarter of all new chemical entities approved by American and European Union regulatory agencies between 2003 and 2006.

Identifying Safety Problems

Safety problems identified after approval are often related to the immunomodulatory effect, but limited information is available on the nature and timing of safety problems that were identified after approval.

"Our study shows that approximately half of safety-related regulatory actions for biologicals involved the system organ classes, including infections, immune-system disorders, and both benign and malignant neoplasms," Dr. Mantel-Teeuwisse told Medscape Oncology. "These safety issues were often related to the immunomodulatory effects of these biologicals."

"Therefore, we call for more indepth evaluation of the mode of action of biologicals during the preregistration phase, which may help to better predict potential risks that should subsequently be monitored during the postmarketing phase," she added

Dr. Mantel-Teeuwisse and colleagues evaluated the nature and probability of safety-related regulatory actions issued for biologic agents approved in the United States and/or the European Union between January 1995 and June 2007. A total of 174 biologic products obtained approval during the study period, of which 136 were approved in the United States, 105 in the European Union, and 67 in both regions.

They found that between January 1995 and June 2008, 82 safety-related regulatory actions were issued for 41 of the approved biologic agents (23.6%): 46 "dear healthcare professional" letters, 17 direct healthcare professional communications, and 19 black-box warnings. None of the agents were withdrawn from the market for safety reasons.

Biologic Agents Used in Cancer Therapy That Received Black-Box Warnings

Name Date approved Warning Time to black-box warning
Cetuximab ( Erbitux) February 12, 2004 Cardiopulmonary arrest 2.0 years
Gemtuzumab ozogamicin (Mylotarg) May 17, 2000 Hypersensitivity reactions, including anaphylaxis, infusion reactions, pulmonary events, and hepatotoxicity 0.8 years
Ibritumomab tiuxetan (Zevalin) February 19, 2002 Severe cutaneous and mucocutaneous reactions 3.6 years
Rituximab (Rituxan) November 26, 1997 Fatal infusion reactions, tumor lysis syndrome, and severe mucocutaneous reactions 8.2 years
    Progressive multifocal leukoencephalopathy 9.2 years
Trastuzumab (Herceptin) September 25, 1998 Infusion reactions, pulmonary toxicity 3.2 years

The researchers also observed that biologic agents that were first in class to obtain approval had a higher risk for a first safety-related regulatory action, compared with later-approved products in the same class (12.0/1000 vs 2.9/1000 months; hazard ratio, 3.7). "This finding suggests that pharmacovigilance should be especially stringent for these biologicals," said Dr. Mantel-Teeuwisse. .

Their data also demonstrated that within the group of biologic agents, monoclonal antibodies, cytokines, growth factors, interferons, and receptors might be more susceptible to adverse drug reactions than hormones. "We therefore recommend close monitoring of these biologicals in the postmarketing phase," she added.

Proactive risk management aims to identify safety issues as soon as possible, explained Dr. Mantel-Teeuwisse, and therefore, it is extremely important that possible adverse events are recognized as such by physicians.

"Many biologicals have a safety-related regulatory action issued for them, and our results confirm that the nature of these actions is in the range of what could be expected for these drugs," she said. "Although new safety issues will arise during the postmarketing phase, one should try to increase knowledge about the mode of action during the developmental phase, which may help to better predict potential risks that should subsequently be monitored during the postmarketing phase. We should also try to identify new safety issues as soon as possible, and both close monitoring and enhancement of spontaneous reporting may play important roles."

Improvements Needed in Postmarketing Surveillance

In an accompanying editorial, Catherine D. DeAngelis, MD, MPH, editor-in-chief of JAMA, and Phil B. Fontanarosa, MD, MBA, executive deputy editor of JAMA, write that the results of this study help demonstrate the necessity for improving the drug-approval process and the postmarketing surveillance system.

They note that many safety problems, as observed in this study, 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," the editorialists write. "Furthermore, some serious adverse drug effects are quite uncommon and require use of the drug in large numbers of patients to become evident."

The current postmarketing surveillance system has several fundamental shortcomings and flaws, they point out. These include the voluntary passive collection of adverse drug reactions, unreliable denominators for calculating rates of adverse effects, and difficulty determining whether the adverse effect is due to the drug or the condition for which the drug is used. "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 the use of other approved medications," they write.

The department employing many of the authors of the study, including Dr. Mantel-Teeuwisse, has received unrestricted research grants from GlaxoSmithKline, Organon, Merck, and Novo Nordisk to conduct of pharmaco epidemiological research. Neither Dr. DeAngelis nor Dr. Fontanarosa have disclosed any relevant financial relationships.

JAMA. 2008;300:1887-1896, 1939-1941.


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