Regulatory Beat: FDA Ambitiously Encourages Innovation While Ensuring Safe Therapies

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BioPharm International, BioPharm International-05-01-2005, Volume 18, Issue 5

FDA will allow nonprescription NSAIDs to share the market with products carrying black-box warnings.

The need to regain public trust in the safety and quality of drugs and biotech therapies has been a prominent theme of FDA officials in recent weeks. They stress the importance of identifying critical factors early in the biomedical research process that may affect product quality and have issued new policies to achieve those goals. At the same time, the regulators have taken steps to show they can be tough enforcers of manufacturing rules and willing to pull questionable therapies off the market.

Jill Wechsler


One FDA initiative encourages manufacturers to provide genomic data to the agency, either as part of a market application or through a new voluntary process, to encourage pharmacogenomic research leading to more "personalized" medicine. FDA notes that voluntary data submissions can help both regulatory and industry scientists keep abreast of new developments in this area.

Last month, FDA released a concept paper on the co-development of new drugs and diagnostics that identify patients who could benefit or suffer from a new therapy. This followed a March guidance explaining how manufacturers may submit pharmacogenomic data to FDA. The agency maintains the information will not affect the review of formal applications for new drugs and biologics, but it will be examined separately by a new interdisciplinary pharmacogenomics review group. Despite these reassurances, pharma and biotech companies are concerned that FDA will expand requirements for including pharmacogenomic information in applications as reviewers and researchers learn more about the value of this information.


This guidance specifically addresses only pharmacogenomics data related to ensuring appropriate clinical testing and use of certain drugs — and not genetic or genomic techniques used for biological product characterization or quality control, a topic FDA plans to address in future guidance documents. The current guidance also does not cover data resulting from proteomic or metabolomic analysis techniques, although it notes that manufacturers may submit such data to FDA for consideration and discussion under the voluntary submission process. The pharmacogenomics guidance, along with additional information on submitting data to FDA is available at

Scientists from industry, academia, NIH, and FDA discussed the documents and their implications at a three-day conference designed to translate three years of deliberations into practical proposals for using pharmacogneomics in drug development. FDA Acting Deputy Director Janet Woodcock opened the meeting, co-sponsored by FDA, industry, and the DIA, by outlining the "real imperative" for improving the current wasteful, uninformative system for testing drug candidates. She urged a shift to research methods that use biomarkers to predict drug side effects and benefits, more specifically. Success in this area can address the current "affordability and access" healthcare crisis, she said, as well as the need for a more agile process to produce medical countermeasures in response to public health emergencies.

Although FDA's policies emphasize that broader assessment of pharmacogenomics data offers potential benefits in clinical trial design and drug development, the advent of more individualized medicines may bring significant changes to the biotech industry. A recent report by Price- WaterhouseCoopers on "Personalized Medicine: The Emerging Pharmacogenomics Revolution" predicts an eventual erosion of the current blockbuster drug business model, a development that offers significant opportunities for smaller life sciences companies. Initial pharmacogenomic breakthroughs are most likely to occur in oncology, and developing and launching new drugs in this area will require further changes in regulatory and clinical practices to incorporate genetic testing as part of patient diagnosis and treatment.


FDA also published final guidances that describe ways to minimize drug risk through full collection of safety data prior to approval and more sophisticated management of risky medical products on the market. Although focused on clinical trial design and post-market risk management, the guidances present a number of issues important to biotech manufacturers.

The guidance on premarket risk assessment, which outlines additional testing and study approaches likely to enhance a sponsor's understanding of product safety concerns, could affect demand for clinical supplies and encourage expanded clinical assessment of proposed packaging and product design. Another guidance describes the development and use of risk minimization action plans or RiskMAPS to assure that patients safely use certain high-risk products. While emphasizing that only a limited number of products will warrant such efforts, FDA notes it has authority to require product recalls, safety alerts, seizures, or injunctions to prevent the possibility of "serious risks to the public health" if risk minimization efforts fail.

A third document presents approaches for manufacturers to establish good pharmacovigilance programs for marketed therapies. In outlining strategies for identifying and analyzing safety signals, FDA recommends that manufacturers also investigate signs of confusion about a product's name, labeling, packaging, or use. The guidances are available at


FDA officials point to these documents as an indication that the agency can take action to ensure drug safety. One aim is to fend off moves on Capitol Hill to establish a new drug safety office that would be more independent of FDA's drug approval "bureaucracy." Perhaps to demonstrate that FDA can be a tough enforcer, in March the agency took the unusually severe action of seizing two major drugs produced at the GlaxoSmithKline (GSK) manufacturing facility in Cidra, Puerto Rico. FDA and the Justice Department cited ongoing manufacturing quality problems and the company's failure to take requested action on "significant violations" of GMPs described in a 2002 warning letter and subsequent inspection reports. The regulators specifically noted lack of product uniformity in lots of the diabetes treatment Avadamet (rosiglitazone /metformin) and evidence that some Paxil (paroxetine) controlled-release tablets could split apart. GSK explained it had taken steps to recall supplies of the troubled products — as FDA requested — and was working to identify and correct its manufacturing problems.

FDA compliance officials acknowledged that this high-profile seizure was designed to prompt all manufacturers to take GMP violations and warning letters more seriously. FDA Associate Commissioner for Regulatory Affairs John Taylor said that once FDA discovers a company is not following safety and quality standards, "we expect them to correct the deficiencies in an expedited manner." As FDA had more benign ways to deal with the GSK manufacturing problems, the decision to seize these widely used products was guaranteed to generate press coverage of FDA as a tough enforcer of drug safety rules.

A few weeks later, FDA took even stronger action by telling Pfizer to halt sales of Bextra (valdexocib) and use black-box warnings for Celebrex (celecoxib), the only remaining COX-2, and for all prescription non-steroidal anti-inflammatory drugs (NSAIDs). In what is probably a regulatory first, FDA will allow nonprescription NSAIDs to share the market with products carrying black-box warnings. OTC NSAIDs must add more warnings to their labels, but FDA officials decided they should remain available because they provide lower doses, and patients generally use them on a short-term basis.

Pfizer promised a long-term study comparing Celebrex safety to other drugs and suggested it might resume direct-to-consumer advertising, an activity FDA may permit if the marketer addresses all risk clearly and completely. Pfizer hopes to renew limited sales of Bextra, despite speedy moves by trial lawyers to file new suits against the drug.

FDA's actions, heralded as its most sweeping challenge ever to marketed drugs, went beyond the recommendations of its advisory committees. Congressional members praised FDA's aggressive approach, but manufacturers fear these actions signal a more risk-averse regulatory stance. Ten years ago, FDA was accused of dragging its feet over new drug applications. Now, the charge is it's moving so fast that unsafe, insufficiently tested products are permitted on the market. The question is whether FDA is tipping the delicate risk-benefit balance for prescription drugs and biologics too much to the risk side and how that will affect the development of new therapies.

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