To reverse this trend, McClellan seeks to speed the process and clarify the regulatory requirements for research. FDA has launched a major risk management program to relate the level of oversight to a product’s risk of generating safety concerns. However, the risk management program threatens to increase demands on clinical trials to produce more data before a sponsor can get regulatory approval for a new product launch.

Seeking solutions
To boost the payoff of clinical research, FDA unveiled a broad initiative in January 2003 to accelerate the development of new medical technologies by improving FDA research and review processes. The aim is to increase the predictability of product development and regulatory oversight by:

• Identifying the root causes of multiple review cycles through early communication with sponsors.
• Making the FDA review process more efficient by adopting a “quality systems approach” to application reviews.
• Improving the quality of submissions to FDA by providing clearer guidance for particular indications and emerging technologies. New guidances on the development of treatments for cancer, diabetes, and obesity top the priority list.

Another FDA proposal contains a number of items that pharmaceutical companies fear will add to the size and cost of clinical trials. FDA is developing a series of guidances on risk management of prescription drugs, as required in the Prescription Drug User Fee Act (PDUFA), which was reauthorized by Congress last year. The aim is to relate preapproval and postapproval regulation of medical products to a range of risk factors: product novelty, intended population, severity of condition treated, duration of use. Sponsors of products with high risk may have to provide more preapproval safety analysis, and the regulations may require more extensive monitoring of and restrictions on marketing and prescribing once a product is on the market.

The agency published three concept papers on these issues in March and held a multiday public workshop to discuss the proposals in April (www.fda.gov/cder/meeting/riskmanagement.htm ). The draft concept paper on risk management programs for marketed drugs proposes four levels of actions to ensure that consumers use the product safely. For example, safety issues for relatively low-risk products might be addressed by changing package inserts and labeling. Safety issues for the highest-risk products might require setting up restricted access systems and limiting prescribing and dispensing to registered physicians and pharmacists. A second FDA paper on postmarketing risk assessment proposes a range of pharmacovigilance plans that manufacturers would use to assess adverse event reports and other safety “signals” for approved therapies.

Although pharmacists and manufacturers expressed concern that a proliferation of differing risk management programs may confuse subjects and health professionals, the FDA concept paper on premarketing risk assessment generated the most concern from sponsors and researchers. They fear that this effort to better assess product safety during product development could lead to a significant expansion in the size and scope of clinical trials. In addition to designing studies to detect unanticipated interactions with other medications and to assess that the product’s name, labeling, and packaging will not inadvertently contribute to medication errors in the market, FDA suggests that effective risk management might call for trials with larger subject safety databases, a broader range of dosing studies, more diverse populations, comparative safety trials, and large safety studies.

Establish larger subject safety databases. FDA agrees that a standard 1500 subjects should be exposed to an investigational product to treat a long-term chronic or recurrent condition, but suggests that larger databases may be needed when a product’s benefit is small, if adverse events are hard to detect, if the treatment is preventative for a healthy population, or if there is concern that a drug might generate later adverse events.

Include a broader range of dosing studies during Phase 3. This could better characterize the relationship between exposure and resulting clinical benefit and risk, and it could lead to improved dosing advice, particularly for special populations.

Study more diverse populations in Phase 3 studies. The aim is to examine safety data in important demographic groups such as elderly persons, subjects with concomitant diseases, and subjects taking certain other medications.

Include comparative safety trials to show that a novel therapy has a benign safety profile compared with that of a well-established product.

Include large, simple safety studies (LSSS) as part of premarket development, particularly when troubling safety signals emerge from clinical trials or when the sponsor is developing a preventative in healthy individuals.

Representatives of PhRMA (Pharmaceutical Research and Manufacturers of America) protested at the April workshop that, because such proposals would require more research prior to getting market approval for a product, they seem to run counter to McClellan’s emphasis on cost-effective drug development. Instead of focusing on documenting that a product is basically safe and demonstrates some efficacy, FDA pressure to develop large, diverse safety databases could raise additional questions about product efficacy, and delay market approval. A broader fear of manufacturers is that FDA’s proposals to expand safety studies could become routine and alter current standards for product testing and approval.

Robert Temple, director of the Office of Medical Policy in the Center for Drug Evaluation and Research (CDER), responded that broader evaluation of safety signals in clinical development could reduce the chance of drugs being pulled off the market because of safety concerns. Manufacturers also may benefit from learning early if safety issues are significant enough to discontinue a development program. He advises that sponsors consider earlier in drug development what information and what subject population is needed to generate appropriate safety signals in Phase 3 studies.

CDER deputy director Steven Galson said that FDA staffers will digest all comments with an eye to publishing draft guidances on the three risk management proposals this fall. FDA officials say that the concept papers aimed to stimulate discussion about what constitutes appropriate safety information. The agency does not seek to change FDA safety standards for approval, but to balance premarket and postmarket safety assessment to capture all signals and ensure product safety.

Evaluating cost-effectiveness
Another factor enlarging the scope of clinical studies is the now-standard need of manufacturers to document the value and cost-effectiveness of new therapies, in addition to their safety and efficacy. At the annual meeting of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) in May, commissioner McClellan reiterated that FDA does not evaluate the value of medications and has no plans to add product cost to the criteria for approving a new therapy for market. But he agreed with many other speakers at the meeting that it is increasingly important for manufacturers to demonstrate product value to the entities that provide and pay for health care.

Robert Califf (director, Duke University Medical Center’s Clinical Research Institute) noted that, to have valid data available at product launch, sponsors need to begin examining cost-effectiveness issues early in clinical development. Pharmaceutical companies can’t afford to run two sets of clinical trials, he observes; thus they need to integrate outcomes research into the basic clinical trial structure. Califf urged examining the real costs of clinical trials, pointing to expensive monitoring and data auditing practices as ripe for reassessment. Ralph Swindle of Eli Lilly similarly noted that it’s never too early for sponsors to start analyzing what data should be generated by clinical trials to provide payers with the information needed to get a product on a formulary. This involves talking to potential customers to find out what they want to know about certain therapies and examining model dossiers for formulary committees.

Outcomes researchers no longer feel tangential to the drug development process, because pharma company executives today recognize the need to demonstrate product value. Executives are devoting more resources to health economics and health outcomes research, says Joseph DiCesare (executive director, health economics and outcomes research, Novartis). The larger concern is that each plan and payer wants data that fit its own needs, and manufacturers have neither the money nor the time to produce multiple custom studies.

The good news, DiCesare commented, is that today there is more focus on product value than on drug price. This fosters more collaboration between economic analysts and clinical development groups in pharma companies, which now pay more attention to collecting data to meet customer needs. Moreover, the situation is encouraging more dialogue between manufacturers and managed care decision makers and more awareness on all sides of the importance of health economic information.