UTRECHT, the Netherlands, and CHICAGO, Illinois—Safety-related regulatory data for biologicals approved in the US and the EU since 1995 show that nearly one-quarter required stronger warnings after they reached widespread clinical use. First-in-class drugs were nearly four times as likely as later products to have late-breaking safety problems, Thijs J. Giezen, PharmD, et al reported in Journal of the American Medical Association.¹

More than 250 biologicals have been approved since 1982. They represented 24% of all new chemical entities approved by the FDA between 2003 and 2006 and 22% of all new chemical entities approved by the EU. Within 10 years after approval, 11% received “black box” warning labels, according to Dr. Giezen.

”In summary, this study has shown that almost 50% of the safety-related regulatory actions for biologicals were issued in the system organ classes of general disorders and administration site conditions, and infections and infestations. Warnings issued in the system organ class of infections and infestations were often related to the immunomodulatory effect of many biologicals. 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,” Dr. Giezen said.

The researchers identified 82 safety-related regulatory actions issued for 41 (23.6%) of the 174 different biologicals approved during the study period. Of these, 136 were approved in the US, 105 in the EU, and 67 in both regions. There were no safety-related withdrawals, but there were 19 black-box warnings and 17 “Dear Doctor” letters. The average time to safety-related regulatory action was 3.7 years after approval.

The probability of a safety-related action was 14% in the 3 years after approval and 29% 10 years after approval. First-in-class biologicals were 3.7-times more likely to have a first safety-related regulatory action than latter approved products. “Because the biologicals first to be approved in a class were more likely to be subjected to regulatory action, close monitoring is recommended,” Dr. Giezen said.

Do product liability lawsuits “close the gap”?

The volume of these problems popping up 3 or more years after regulatory approval throws a harsh spotlight on the holes in the current drug and device approval process, JAMA Editor in Chief Catherine D. DeAngelis, MD, MPH, and Executive Deputy Editor Phil B. Fontanarosa, MD, MBA, charge in an accompanying editorial.²

The JAMA editors see lawsuits by patients as “in effect...a way to close regulatory gaps in the FA premarketing approval process and to provide a mechanism for postmarketing surveillance,” as well as an important source of clinical information.

“Without the information revealed by the public release of documents in the tort liability actions, many of these behaviors [such as off-label promotion, guest and ghost authorship, and reporting of safety findings] would remain unknown, some drug manufacturers' judgments about safety issues would be hidden from view, review, or oversight, and the FDA would not be able to uncover them either,” Drs. DeAngelis and Fontanarosa write.

The JAMA editors warn that this stop-gap might disappear if the US Supreme Court decides in Wyeth v Levine that FDA approval of prescription drug labeling “preempts” state law products liability claims against companies whose drugs are later found to have safety risks and to cause harm. If so, patients would not be permitted to bring claims against companies for harms resulting from “failure to warn” of potential risks.

Slower, safer—and fewer—new drug approvals

The result is likely to be a regulatory nightmare.

“If the court rules for preemption in Wyeth v Levine, congressional action will be necessary to remove preemption of state tort litigation involving claims of products liability for prescription drugs. Otherwise, the current system of FDA approval of drugs would have to be changed to preserve the health of the public. Under this alternative approach, no drug could be fully approved until long-term studies with large numbers of participants had been completed, and marketing would have to be greatly limited until full FDA approval is achieved,” warn Drs. DeAngelis and Fontanarosa.

The irony of a decision in favor of preemption is that it might worsen safety problems by creating a new moral hazard: an incentive for drug and device developers to minimize or bury safety concerns until after approval, when they would be shielded from product liability lawsuits.

Current flaws include approval decisions based on efficacy trials in small, carefully selected groups of patients that obscure the full risks likely to be encountered in clinical use; only voluntary, passive reporting of adverse effects; unreliable denominators in calculating adverse effects rates; and a limited ability to differentiate problems related to the drug or device from those related to an underlying condition.

This becomes especially problematic when adverse events are rare, such as the problems with progressive multifocal leukoencephalopathy (PML) in a rheumatoid arthritis patients treated with rituximab (Rituxan^®, Genentech-Biogen Idec) that sparked a September FDA warning.

Genentech spokeswoman Tara Cooper told MSKreport.com how that company deals with late-emerging safety problems. She said that, in addition to conducting extensive postmarketing surveillance, the company works “with the FDA to inform doctors and their patients about new safety information reported in the postmarketing setting. As appropriate, this information is added to the product prescribing information and as necessary (eg, a new warning) communicated to potential prescribers in a ‘Dear Healthcare Provider’ letter.” The September warning letter went out over the signatures of both Genentech Chief Medical Officer Hal Barron, MD, and Biogen  Idec Vice President David Hagerty.

References

1. Giezen TJ, Mantel-Teeuwisse AK, Straus SMJMm et al. Safety-related regulatory actions for biologicals approved in the United States and the European Union. JAMA. 2008;300:1887-1896.
2. DeAngelis CD, Fontanarosa PB. Prescription drugs, products liability, and preemption of tort litigation.  JAMA.  2008;300:1939-1941.