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Columnist H. James Harrington

Photo: Scott Paton, publisher


The Medical Industry’s Move Toward Quality, Part Six

The FDA issues new initiatives for improving pharmaceutical reviews.

he first article in this series discussed recent FDA initiatives designed to speed up the introduction of drug and biologic products into the marketplace while improving their quality and safety (Quality Digest, Feb. 2004). These initiatives introduced risk management and process analytical technology into the pharmaceutical review process, paralleling some medical device initiatives already underway both in the United States and the rest of the world.

Succeeding articles discussed related efforts in the medical devices sector, including the introduction of ISO 13485:2003 and ISO 14971:2000, as well as international harmonization of both medical device and pharmaceutical review processes. This article looks at the FDA’s latest initiatives in risk management for pharmaceuticals.

Early in 2003, the FDA issued risk-management concept papers outlining its intended approach. Now, the agency’s Center for Drug Evaluation and Research, as well as its Center for Biologics Evaluation and Research, have released three draft guidance documents to help manufacturers achieve greater benefits from drugs and biologics while minimizing their risks. Collectively, the documents describe safety issues that can arise throughout a product’s life cycle, including development, review, approval and market availability.

The documents are designed to bring more attention to what the agency is already doing, states Steven Galson, acting director of the CDER. According to Galson, voluntary recommendations wouldn’t lengthen the drug development process. So far, pharmaceutical R&D laboratories and manufacturing companies are welcoming the FDA’s guidances on risk management strategies, saying the documents will help them better understand the agency’s expectations in an increasingly important area for the pharmaceutical industry.

On June 12, 2002, Congress authorized the Prescription Drug User Fee Act for the third time. Under PDUFA III, drug manufacturers pay a fee for FDA inspections, while the FDA is charged with improving both the speed and efficacy of the new drug review process. One of the FDA’s goals in response to PDUFA III is to produce industry guidance on risk management for drug and biological products. As an initial step, the FDA sought public comment on risk management by issuing three concept papers last year. Each one focused on a separate aspect of risk management--premarketing risk assessment, risk minimization tools and postmarketing pharmacovigilance and pharmacoepidemiologic assessments.

The FDA solicited written comments on the three papers and held a public workshop in April 2003 to discuss them. The agency then considered the comments received while it produced three draft guidance documents on risk management activities. The following documents have now been issued and are available online (www.fda.gov/cder/meeting/riskManageI.htm):

Premarketing Risk Assessment (Premarketing Guidance)

Development and Use of Risk Minimization Action Plans (RiskMAP Guidance)

Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (Pharmacovigilance Guidance)

Each draft guidance document focuses on one aspect of risk management. The premarketing and pharmacovigilance documents focus on premarketing and postmarketing risk assessment, respectively, while the Risk MAP document focuses on risk minimization. Under the FDA’s terminology, risk assessment and risk minimization are the components of risk management. Note that this definition is similar to the one found in ISO 14971:2000, which refers to risk assessment and risk control as the two components of risk management.

The FDA views risk management as a four-part iterative process:

1. Assessing a product’s benefit-risk balance

2. Developing and implementing tools to minimize risks while preserving benefits

3. Evaluating each tool’s effectiveness and reassessing the benefit-risk balance

4. Adjusting the tools to further improve the benefit-risk balance

This process continues throughout a product’s life cycle, and the results of ongoing risk assessment continually influence the manufacturer’s decisions regarding risk minimization. It is an integral part of the intensive and continual improvement process that must be applied to every product that involves human health and safety.

Note, too, that these FDA guidance documents don’t establish legally enforceable responsibilities. They’re primarily designed to provide industry guidance on good risk assessment practices during the development of prescription drug products, including biologics. They describe the agency’s current thinking on the topic and are only recommendations--unless specific regulatory or statutory requirements are cited.

The topics covered in the documents are also being discussed in a variety of international forums, such as the International Conference for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. The FDA actively participates in these discussions to ensure that the recommendations in the guidance documents reflect current international thinking on related issues.

In the past, the FDA’s oversight of new drug quality involved reviewing technical information submitted by the manufacturer as well as inspecting facilities for conformance to the Code of Federal Regulations’ requirements regarding current good manufacturing practices for pharmaceuticals. These two approaches combine to help ensure the quality of medical products available in the United States.

The FDA is evaluating these programs’ currency as we approach the 25th anniversary of the last major revision to the pharmaceutical cGMP. New drug products, the increased use of drugs in treating illness and the medical industry’s globalization are straining the FDA’s resources. To meet these challenges, the agency has announced an initiative known as Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach. It’s hoped that these three guidance documents will help contribute to a new era in oversight of the pharmaceutical industry.

About the author
Stanley A. Marash, Ph.D., is chairman and CEO of The SAM Group, which includes STAT-A-MATRIX Inc. and Oriel Inc. He is the author of the recently published Fusion Management (QSU Publishing Co., 2003). Fusion Management is a trademark of STAT-A-MATRIX Inc. ©2004 STAT-A-MATRIX Inc. All rights reserved.