Drug Development and Access: Top Issues in the Past Year

This past year has been one of tremendous activity at the Food and Drug Administration, and at other government agencies involved with healthcare, biomedical research, and national security. Scientists completed sequencing the human genome, generating optimism for a period of unprecedented advances in biomedical discovery. Congress completed a five-year effort to double funding for the National Institutes of Health (NIH) to more than $27 billion, prompting that agency to propose major changes in how it funds and encourages innovative biomedical research [see ACT View from Washington, November 2003]. The need to protect the nation from biological warfare also promises to stimulate development of new vaccines and medical treatments [see sidebar].

At the same time, public demand for more affordable medicines has shaped a wide range of policy initiatives. Congress tackled the daunting task of crafting a prescription drug benefit for the nation's 40 million+ Medicare beneficiaries. FDA has responded with regulatory and management initiatives to lower drug costs, while also challenging efforts to import less expensive drugs from foreign sources.

Jill Wechsler

Although out of the limelight, government officials continued efforts to improve oversight of clinical research. Work began on a process to register and obtain more information on institutional review boards. Academic and healthcare organizations began to sign up for voluntary accreditation of their human research protection programs. Congressional leaders worked on legislation to oversee conflicts of interest, international research, and other related issues, but failed to reach consensus. One milestone announced in October is that 1,000 privately sponsored clinical studies have been posted on the ClinicalTrials.gov web site, expanding the listings to more than 8,000 clinical trials.

Encouraging innovation

In his first year in office, FDA commissioner Mark McClellan unveiled a steady stream of initiatives designed to streamline FDA internal regulatory procedures and to clarify requirements for testing new therapies. A prime goal has been to reverse the recent slow-down in applications for important new drugs. McClellan emphasizes the importance of applying risk management strategies to FDA policies and programs, a concept that he explained further in a Strategic Action Plan, issued in August. Risk management involves targeting FDA's limited resources to oversight of higher risk products and processes. Initiatives that reduce the time, cost, and uncertainty of developing new therapies can improve public health, according to McClellan, by bringing new products to market more efficiently and thus facilitating consumer access to effective new treatments.

Key FDA initiatives aim to:

• Accelerate application reviews. Last January the commissioner unveiled a plan for "Improving Innovation in Medical Technology." It seeks to clarify regulatory standards and test data requirements, and to process more applications in only one review cycle.

• Focus on chronic diseases. The agency is developing more guidances on requirements for developing new treatments for diabetes, cancer, and obesity-top priority disease areas for government health agencies.

• Improve clinical trial design and methods. FDA is encouraging development of new methods for characterizing novel products and for assessing drug toxicity and immune reactions [speech Oct. 9, 2003 at the Phases conference in Washington, D.C.]. One idea is to reduce the need for some animal toxicity testing by refining methods for using tissue cultures and cellular assays that can better predict drug safety.

• Streamline manufacturing processes. FDA officials continue to implement a two-year campaign to overhaul FDA regulations governing good manufacturing practices (GMPs). An important component involves revising policies governing electronic records and signatures, which are important for clinical trial operations.

• Ensure medication safety. FDA held a three-day workshop in April to examine how risk management approaches can promote the safe use of medical products. Agency officials, manufacturers, and health professionals commented on FDA proposals for more extensive pre-approval testing of new products to better identify and study safety concerns. Participants also discussed how manufacturers could develop pharmacovigilance plans to detect and analyze safety issues that appear after a product reaches the market. FDA wants sponsors to do more to identify risk "signals" and to develop post-marketing risk management programs for drugs that pose increased safety concerns for patients. The agency is finalizing rules on these issues, and implementation will be a major challenge in coming months.

• Consolidate oversight of drugs and biologics. FDA transferred regulation of biotech therapies from the Center for Biologics Evaluation and Research (CBER) to the Center for Drug Evaluation and Research (CDER) to gain more uniformity in oversight programs. The consolidation became official Oct. 1, and has involved shifting to CDER some 200 staffers who evaluate applications for monoclonal antibodies, thrombolytics, cytokines, and growth factors. CBER staffers who review clinical data in applications formed a new office in CDER's Office of New Drugs, while CBER researchers and manufacturing experts created the Office of Biotechnology Products.

New challenges

A key concern of FDA staffers is whether significant budget cuts for 2004 will support these initiatives, many involving extensive use of personnel and resources. CDER plans to hire fewer additional staffers under its drug user fee program, and anticipates cuts in information technology personnel and research programs. This could create difficulties for plans to integrate fairly different CBER and CDER information and electronic submission systems.

Meanwhile, CDER leadership is shifting, at least temporarily. In October, CDER director Janet Woodcock started a six-month detail to McClellan's office to help implement "cross-cutting initiatives" outlined in FDA's strategic plan. Woodcock has headed CDER since 1994, but spent a few months in the commissioner's office to help develop FDA counter-terrorism plans following the 9/11 attack. She has played a lead role in overseeing the CDER/CBER consolidation, in developing risk management proposals, and in launching FDA's GMP overhaul.

CDER deputy director Steve Galson is heading the Center temporarily, assisted by Mark Goldberger, who moved up from the Office of New Drugs to be acting deputy director. The change gives Woodcock a break from the steady grind of managing a growing operation squeezed by serious budget constraints and provides her new opportunities to address broader policy issues, including biodefense initiatives and applying pharmacogenomics to drug development.

A fair share for R&D

While seeking to spur new product development, FDA also is fighting the campaign to allow reimporting of low-cost but unapproved drugs and biologics from Canada and other nations. McClellan insists that reimporting can bring unsafe counterfeit products into the United States, particularly through purchases via Internet pharmacies, many operating overseas. The debate has heated up during the past year, with the House approving a bill in July that permits drug reimporting-without any requirement that FDA first certify that such activity will not harm public health.

In September the Department of Justice filed suit against a leading pharmacy Web site, Rx Depot, for arranging drug imports from Canada. However, several states and local governments devised plans to buy Canadian medicines in order to reduce outlays on prescription drugs for Medicaid and local pharmacy benefit programs. The public generally believes that drugs and biologics from Canada are just as safe and effective as those available in the United States.

FDA and manufacturers fear that illegal reimporting opens the door for counterfeit and unsafe products to enter the U.S. market. FDA sponsored a well-attended meeting 15 Oct., 2003 to discuss proposals for preventing counterfeit products from slipping into the U.S. drug distribution system. The agency proposes to attack counterfeiting through a mix of stricter licensing standards for wholesalers and distributors; new technologies for identifying bogus products; and more public education to help health professionals and consumers identify counterfeits more readily.

Another approach to deterring illegal importing, McClellan explains, is to reduce the differences between United States and foreign pharmaceutical prices. At a September colloquium on generic medicine in Cancun, Mexico, the commissioner noted that higher drug prices in the United States create pressure for importing. Such pricing disparities also reflect an unwillingness of other wealthy nations to pay a "fair share" of the costs of bringing new treatments to the world, he noted, explaining that Americans account for about half of all pharmaceutical spending worldwide, while Germany pays less than 5 percent. With drug development now so complex and costly, such price regulation overseas threatens to "grind the global development of new drugs to a halt."

The commissioner proposed an international solution that relates the prices of new treatments to a nation's income, with rich nations paying more to support R&D so that developing nations can pay less. Realistically, there is little chance that political leaders in Europe, Japan, and Canada will accept higher pharmaceutical prices at a time of escalating healthcare costs. But relating the reimporting problem to wide disparities in pharmaceutical prices beyond U.S. borders raises important questions about who will finance future biomedical R&D.