Regulatory Beat: FDA Seeks Safer Drugs and Biologics

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BioPharm International, BioPharm International-08-01-2005, Volume 18, Issue 8

A more recent challenge for CBER is to ensure the safety of an expanding number of tissue and cellular products used in transplants.

The Food and Drug Administration (FDA) is under intense pressure to shore up public confidence in the safety and quality of prescription drugs, biologics, and medical products. Following the outcry over risks associated with long-term use of COX-2 inhibitors, the agency has initiated labeling changes for several new therapies, including Biogen Idec's Avonex (interferon beta-1a) and Novartis' cancer treatment Zometa (zoledronic acid).

Jill Wechsler

FDA also is taking steps to make drug safety information more accessible to the public, to better identify product safety signals, and to determine the need for major changes in current policies and programs. Initial actions have involved establishing a drug safety oversight board and a Drug Watch website that will post information about emerging safety concerns.



The larger issue is whether and how to shift from FDA's current post-approval safety monitoring system for drugs and biologics, which relies on a spontaneous adverse event reporting system (AERS) that receives reports from manufacturers, health professionals, and patients through the MedWatch program. This system is good at catching signals of serious problems for all approved drugs, is relatively simple to operate, and can detect adverse events (AEs) that do not appear in premarket clinical trials. But because it relies on third parties to submit AE reports, the system can be slow and often yields incomplete and sometimes irrelevant information.

FDA has established additional systems to monitor the safety and manufacturing quality of inherently complex vaccines, blood products, and emerging cellular products. Because vaccines and biologics often are critical to public health and lack substitutes if quality concerns necessitate pulling a product off the market, FDA's Center for Biologics Evaluation and Research (CBER) emphasizes manufacturing process controls and product risk management to prevent and limit safety problems, explained CBER Director Jesse Goodman at the April meeting of the FDA Science Board.

This involves extensive screening of blood donors and additional testing of donated blood to detect viral infections and ensure the safety of the nation's blood supply and blood products. Blood facilities have added procedures to prevent blood contamination by "mad cow disease" prions and to detect the presence of West Nile virus. Vaccine safety issues are collected and analyzed by a vaccine AERS, which is jointly operated by FDA and the Centers for Disease Control and Prevention. The two agencies also collaborate on studying vaccine safety issues using data obtained from healthcare systems.

A more recent challenge for CBER is to ensure the safety of an expanding number of tissue and cellular products used in transplants. Earlier this year, CBER adopted procedures for assessing adverse reactions associated with human cells, tissues and related products, and a CBER Tissue Safety Team is developing policies for responding to tissue-related AEs.

AEs involving biologics are analyzed by CBER's Office of Biostatistics and Epidemiology to determine the need for further enforcement action. Biotech companies are required to report manufacturing problems (biological product deviations or BPDs) that may affect the safety, purity, or potency of biologics within 45 days of discovery. In 2004, CBER received more than 20,000 BPDs, the majority involving blood collection and blood products. CBER's Office of Compliance and Biologics Quality is responsible for following up with manufacturers on adverse event or product deviation reports, and may request a field investigation or initiate a product recall or market withdrawal if warranted.


In addition to new safety monitoring policies already adopted by FDA, the agency has commissioned the Institute of Medicine (IOM) to assess its current system and make recommendations for further action by July 2006. The committee is examining how FDA fits into the nation's broader system for ensuring drug safety; current efforts by FDA and industry to evaluate and manage safety problems; and whether FDA needs additional legal authority or organizational changes to deal more effectively with post-marketing safety issues. Specific policy options on the table include:

  • Reorganize FDA's structure and operations for safety surveillance.

  • Give FDA authority to require manufacturers to revise approved product labels and to complete prearranged post-approval studies.

  • Increase FDA resources devoted to drug safety oversight, particularly to make greater use of drug utilization databases at outside organizations. (Please see Signals from Medicare).

Signals From Medicare

  • Allow FDA to grant "provisional" approval for more risky therapies, with well-defined requirements for additional safety and efficacy studies so the drugs may remain on the market.

  • Restrict direct-to-consumer advertising for newly approved drugs and biologics.


Manufacturers acknowledge that FDA requires more resources to ensure that the US has the world's safest drug supply. But industry is wary that excessive preapproval testing to detect rare safety problems, plus multiple postmarketing monitoring requirements, may block new products from coming to market. It is important to integrate drug safety information more effectively and to improve the assessment of true signals of potential safety problems, said Amit Sachdev, executive vice president of the Biotechnology Industry Organization to the IOM panel.

But Sachdev cautioned that creating post-approval regulatory processes that create uncertainty in the product approval process could delay patient access to innovative products. And he raised concerns that mandating any one "toolbox" for post-approval safety surveillance could waste valuable resources. One particular fear of manufacturers is that FDA may make raw AE data available to individuals who cannot assess it properly, potentially raising unnecessary alarms.

Instead, industry and FDA leaders believe a broader use of pharmacogenomics, biomarkers, and diagnostics may be more effective in enhancing the safe use of therapies. FDA acting Deputy Director Janet Woodcock advocates using genomic, proteomic, and metabolomic markers to identify those patients at high risk for certain side effects as part of a shift from today's empirical clinical research towards a more "personalized" approach for developing new therapies. Sachdev agrees that more active integration of health system data and pharmacogenomic information would be more effective than FDA's passive MedWatch system.

Jill Wechsler is BioPharm International's Washington editor, 7715 Rocton Avenue, Chevy Chase, MD 20815, 301.656.4634,