Regulatory Beat: FDA Seeks Safer Drugs and Biologics

Published on: 
BioPharm International, BioPharm International-03-01-2007, Volume 20, Issue 3
Pages: 40–45

An underlying theme of FDA's drug safety program is that new discoveries in biomedical science can detect risk issues earlier in clinical development.

The Institute of Medicine (IOM) issued a strong report last September urging major changes in Food and Drug Administration operations to better balance the agency's assessment of risks with benefits. FDA commissioner Andrew von Eschenbach responded a few weeks ago with a detailed plan for improving how the agency detects and assesses safety problems for drugs and biologics.

Jill Wechsler

The report on "The Future of Drug Safety" describes initiatives for developing safety "report cards" on important new products, publishing an online drug safety newsletter, and accessing more health system databanks to detect safety signals more quickly. FDA also is clarifying conflict-of-interest policies for advisory committees and establishing a new advisory committee on communication to provide more outside expertise on conveying risk information. The agency plans a formal assessment of Risk Management Plans (RiskMAPS) to see if they really address serious safety problems and is expanding scientific efforts for testing and developing safer medical products.

Steven Galson, director of the Center for Drug Evaluation and Research (CDER), promised to address the tension between pre-and post-approval staffs by engineering a "true culture change" at CDER that gives more authority to safety analysts. The Center for Biologics Evaluation and Research (CBER) has established an integrated risk–benefit analysis program, with cross-cutting product safety teams to deal with safety issues involving vaccines, blood, and cellular products. CBER also is collaborating with the Centers for Disease Control and Prevention (CDC) to expand the use of databases for monitoring and analyzing flu vaccine safety.

The unstated goal of these actions is to head off legislation requiring more significant FDA organizational changes and added mandates for manufacturers and regulators. FDA intentionally does not address IOM proposals that require Congressional action, such as providing authority to levy fines on pharma marketers that fail to complete promised post-approval studies. The FDA announcement covered those activities that the agency can implement on its own, provided Congress provides added resources from user fees and appropriated funds. But, if FDA and industry want Congress to reauthorize the Prescription Drug User Fee Act (PDUFA) by fall, they probably will have to agree to some new requirements for ensuring drug safety.



An underlying theme of FDA's drug safety program is that new discoveries in biomedical science can detect risk issues earlier in clinical development. Janet Woodcock, FDA deputy commissioner and chief medical officer, is leading a broad spectrum of activities to accelerate risk assessment by manufacturers and government scientists, many launched under the Critical Path Initiative.

For example, FDA is collaborating with industry and academia to validate new tests for organ toxicity and for cardiovascular risk of drugs. A consortium of manufacturers, FDA, and the National Institutes of Health (NIH) is assessing biomarkers that can spur development of new treatments, beginning with lung cancer and lymphoma. And a new Serious Adverse Event Consortia plans to identify and validate genetic variants that may help predict the risk of drug-induced reactions.

These efforts to reduce development time and cost were described in FDA's Critical Path Opportunities List, which was issued in March 2006 and updated in a January 2007 report on collaborations and research activities undertaken in 2006. The aim is to "build safety into products" by better understanding the genetic basis of adverse events, explained Woodcock. These approaches can detect toxic compounds early and identify patients most likely to have adverse events—or to respond well—to a test medicine. FDA, she said, wants to "make products safer from the get-go."


One part of this campaign to improve R&D success rates is to "move manufacturing into the 21st century" by developing standards for laboratory and production analytical methods. To encourage adoption of Process Analytical Technology (PAT), for example, FDA is partnering with pharmaceutical manufacturers and instrument producers to test validation reference systems for imaging methods, such as near-infrared, mid-infrared, Raman chemical imaging (RCI), and terahertz technologies.

Related efforts seek to ensure safe biotech manufacturing processes. An FDA collaboration with the National Institutes of Allergy and Infectious Diseases (NIAID) is examining methods for detecting infectious contaminants in cell cultures and whether such contaminants increase the risk of causing tumors. To improve characterization of complex biological products, FDA is exploring how to adapt high-tech imaging methods, such as nuclear magnetic resonance spectroscopy, to better characterize glycoprotein vaccines, and allergen extracts. A collaboration of FDA, NIH, and other partners is evaluating how well new microarray technologies and other tools can predict the quality of cell substrates used to manufacture vaccines, protein drugs, and gene vectors.

Additional projects focus on modernizing vaccine production. The agency is supporting research to shift influenza vaccine production from egg-based systems to cell culture substrates and to establish libraries of pandemic influenza virus strains to facilitate testing of new vaccines for potency and efficacy. These initiatives support efforts to produce safe and low-cost vaccines for developing countries, such as new vaccines for meningitis and tuberculosis. Also, FDA scientists are collaborating on research to evaluate the efficacy of mumps vaccines and to develop biomarkers to evaluate the stability and safety of future vaccines for malaria and leishmaniasis.


FDA is encouraging new standards for novel drug dosage forms to expand options for drug delivery. One project aims to refine scientific standards for chemical identity, particle size, and distribution characteristics of active pharmaceutical ingredients in aqueous nasal spray suspensions. If successful, this approach could be applied to dry powder and metered dose inhalers. Another FDA–industry collaboration is developing methods to assess the adhesive properties and permeation of different transdermal products. The objective is to compare drug diffusion and skin permeation through different in vitro methods.

The agency is working to characterize liposomal drug products for their encapsulation efficiency, leakage, and particle size. The project involves testing performance under physiologic stress factors to develop in vitro cell line bioassay methods to assess changes in liposomes under different conditions.

Another high-profile initiative is to establish standards for multicolor flow cytometry measurements in laboratories and across instrument platforms. Because flow cytometry data is important in developing many products, a collaboration involving FDA, NIH, CDC, the National Institute of Standards and Technology (NIST), and industry aims to develop, test, and validate standards that will ensure comparability of such measurements.

Moreover, FDA is working with other agencies to understand how nanotechnology may contribute to the development of new treatments. A collaboration with NIST and the National Cancer Institute Nanotechnology Characterization Laboratory has been formed to develop characterization assays and methods for preclinical and early clinical testing of such products. The agency has also established a Nanotechnology Task Force and Nanotechnology Interest Group of scientists to provide input on product development.

As part of their efforts to prevent the spread of transmissible spongiform encephalopathy, or Mad Cow disease, FDA scientists are collaborating with colleagues in other government agencies, academia, and industry to develop technologies to identify prior contamination of biological products. Such tests could be valuable in ensuring the purity of biotech manufacturing processes as well as screening blood and tissue.

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