Inside Washington: Biotechnology is Central to Medical Progress

There was a celebratory mood in the air this June at the annual convention of the Biotechnology Industry Organization (BIO). President George W. Bush called on industry to fight bioterrorism and world hunger. He placed biotech companies in the forefront of improving healthcare for all Americans and urged them to help make their important new treatments available to seniors served by Medicare.

Some representatives from the convention's large European contingent objected to Bush’s critique of their governments' opposition to biotech crops (such opposition, he said, was based on "unfounded, unscientific fears"). Still, they filled the exhibit hall and worked hard to convince U.S. biotech firms to partner with domestic companies and to consider their locales for future expansion.

The timing of the meeting happily coincided with an industry upswing. While biotech stocks were rising in the wake of optimistic announcements about promising cancer therapies, FDA was in the midst of an approval spree. MedImmune gained a final okay to market FluMist (the first inhalable flu vaccine), and right on its heels, FDA approved Genentech's Xolair (omalizumab), a monoclonal antibody for treating severe allergy-related asthma. The agency also approved two new orphan drugs, and many companies used the convention to predict pending good news for exploratory treatments.

Spurring Innovation

Continuing the product approval trend, FDA commissioner Mark McClellan announced FDA actions to encourage development of safer, more effective, and more high-value medical products as part of his strategic plan to improve innovation in medical technology. McClellan's main strategy for reversing a recent decline in applications for truly new biologicals is to establish a more efficient and predictable system for regulating biomedical products. He expects this will translate into lower-cost products accessible to more patients.

McClellan's main news at BIO 2003 was FDA's plans to reduce the total amount of time it takes to review new market applications. The current Prescription Drug User Fee Act (PDUFA 3) requires FDA to review standard new drug applications (NDAs) and biologics license applications (BLAs) in 10 months, which means issuing an action letter in that time frame. However, that "action" often falls short of final market approval while FDA seeks additional clinical or manufacturing data, completes pre-approval inspections, or negotiates final labeling.

In the coming year, McClellan said the agency will implement strategies to reduce total median times for new product applications by 10%, carving one or two months off the current 15- to 16-month median approval time for new therapies. FDA estimates that a two-month reduction in total review time will reduce the cost of product development by more than $12 million. Success, however, involves carrying out a number of new initiatives already launched as part of the agency's strategic plan:

• More hand-holding. To speed up FDA application reviews, manufacturers will have to file more complete submissions to avoid multiple review cycles. PDUFA 3 supports an increase in FDA meetings with sponsors during the investigational stage, particularly for biotech therapies. The agency recently issued draft guidances for implementing pilot programs to provide more feedback and interaction with manufacturers developing fast-track products and submitting continuous marketing applications. FDA officials anticipate that more frequent communication between manufacturers and FDA reviewers will prevent sponsors from filing incomplete submissions that require amendments later on — or that the agency will refuse to file.
• More guidance. To help manufacturers get the research right the first time, FDA seeks to clarify agency expectations for pre-approval testing, starting with products for oncology, diabetes, and obesity. New guidances for cancer treatments, for example, will examine a broad spectrum of issues affecting the design of oncology trials, such as control group selection and whether manufacturing or formulation issues may raise questions about product consistency throughout a clinical study. Some guidances will be developed in collaboration with other research organizations. FDA and the National Cancer Institute (NCI) have formed an oncology task force to develop biomarkers for evaluating new cancer medicines and to create a cancer bioinformatics infrastructure to improve data collection, integration, and analysis for research.
• Nurturing new technologies. FDA also plans to issue guidances to spur advances in pharmacogenomics, novel drug delivery systems, and cellular and gene therapies. One project is to develop safety assays for xenotransplantation products to address concerns about quality. The Center for Biologics Evaluation and Research (CBER), which will continue to oversee these products, also is collaborating with other organizations to evaluate endpoints and research policies for such life-saving treatments and novel drug delivery systems. FDA and NCI plan to expand joint programs on proteomics and genomics to develop standards for safety, purity, and potency of tumor vaccines. FDA also is working with the American Society for Gene Therapy to bring together gene therapy researchers to discuss and define the design of toxicology studies to support licensure of such cutting-edge treatments.
• More accelerated approvals. A related initiative involves expanding FDA-accelerated approval policy so more new life-saving treatments can benefit from the program. The policy allows FDA to reduce premarket study requirements for important therapies that meet “unmet medical needs” for treating cancer, AIDS, and other critical diseases. In return, sponsors commit to conducting additional postapproval research to confirm initial results. Up until now, FDA has designated accelerated approval for only one product in a treatment area. Consequently, sponsors of other products that address similar patient populations must perform the usual range of premarket testing, delaying patient access to possibly useful therapies. Under the new proposal, FDA will grant accelerated approval status to multiple qualifying agents, even if they treat the same indication. However, once one sponsor confirms clinical benefit in phase 4 trials, no additional products will be granted accelerated status. The aim is to make it easier for new therapies to enter the market and encourage sponsors to complete phase 4 studies as promised (see “Keeping Commitments,” below).
• Modernizing manufacturing methods. At BIO, McClellan reiterated FDA's aim to implement "best practices" in manufacturing technologies and methods. He referred to efforts by the semiconductor industry to eliminate impurities and inaccuracies in production through adoption of "six sigma" production methods and urged biotech companies to implement similar continuous quality improvement methods. FDA is updating its good manufacturing practices (GMPs), McClellan noted, so that outdated regulatory policies do not block manufacturers from implementing innovative technologies.

Consolidation Begins

Probably the most notable FDA initiative affecting biologics is the shift of oversight for biotech therapies from CBER to the Center for Drug Evaluation and Research (CDER). The consolidation plan went into effect 30 June 2003 by "detailing" more than 200 CBER staffers to CDER; the change becomes official on 1 October 2003, the beginning of the federal government's new fiscal year. The first phase of consolidation will run about two years. CBER staffers will remain together in their previous units but now as part of CDER offices. Two groups that handle review of BLA clinical data have formed a sixth new drug evaluation office in CDER's Office of New Drugs, while CBER's laboratory-based units, which review and evaluate biotech manufacturing data, have become the Division of Monoclonal Antibodies and Division of Therapeutic Proteins in CDER’s Office of Pharmaceutical Science. FDA officials say that these lab divisions will continue to conduct research on immunology and cell biology and ways to control adventitious agents in manufacturing, but prospects for long-term support of such lab-based activities remains uncertain.

In addition to spelling out the shift in personnel, FDA informed manufacturers of the product categories and applications under review that have transferred from CBER to CDER. The aim is to maintain a seamless review process, with the same staff continuing to review and oversee the same products and applications as before.

To establish a more consistent and coordinated review program for drugs and biologics, though, FDA officials will have to address a number of issues over the next two years. The two centers have different electronic filing systems for applications and distinct internal systems for tracking and monitoring applications and reviews. Clearly, CBER staffers will have to adjust to working in a more hierarchical “super office.” But it’s an office with considerable resources and opportunities.

Keeping Commitments

Although FDA is approving more new products that require the completion of postapproval studies to confirm the validity of surrogate endpoints and preliminary safety data reports, the agency finds that many sponsors fail to meet these commitments. FDA’s first annual report on postmarketing study obligations, which was posted on its website in May (see

www.fda.gov/cber/pstmrket/

), shows that sponsors have completed about 400 (20%) of promised studies on NDAs and BLAs, but that most are "pending," "ongoing," or "delayed."

FDA finds "considerable room for improvement" by industry. Therefore, the agency is taking steps to more clearly specify for sponsors the nature of postmarketing studies and timelines for initiating and completing these studies to ensure that new data can be added to labeling promptly.

FDA also has posted on its website a system for tracking phase 4 research commitments, as required by the FDA Modernization Act of 1997. The listing provides a glimpse of the range of postmarketing studies FDA has negotiated with manufacturers since 1991, their status, and which companies have the most to do. However, the site carries information on only about one-half of all the promised studies because it leaves out those with confidential manufacturing data. BPI