EXTENDED EXCLUSIVITY SUGGESTED AS REWARD FOR COMPARATIVE, SPECIAL-POPULATION STUDIES: REP. WYDEN PROPOSES INCENTIVES TO ENCOURAGE DRUG, DEVICE DATA FLOW

Executive Summary

Companies that conduct one or more clinical studies comparing their new drug or device to a product already used for the same indication would receive three years of extended exclusivity for the first study performed under a proposal being developed by Rep. Wyden (D-Ore.). In addition, FDA could be authorized to grant incremental one- year extensions for additional or particularly large-scale comparative studies, Wyden said at an Oct. 21 hearing before his Small Business/Regulation Subcommittee. Clinical studies analyzing the effectiveness of a now product in a geriatric, pediatric or at-risk minority population could also be rewarded with additional exclusivity grants. A product would receive two years additional exclusivity if the study were completed in time for results to be incorporated into initial product labeling, and one year if the study were completed and supplemental labeling were approved prior to the expiration of any other exclusivity enjoyed by the product, Wyden explained. FDA approval of a special-population study design would be required before the study could qualify a product for extended exclusivity. FDA would be required to give its judgment on the study design within 60 days of submission to the agency under the Wyden sketch. The Oregon Democrat's proposal to establish incentives for companies to conduct comparative and special-population studies is intended to address "our inability to purchase and use medical technology wisely," the congressman explained at the Oct. 21 hearing. The subcommittee was convened to discuss voluntary incentives that would encourage the development of comparative information on new drugs and devices, in the hope that such information will help make the twin health care goals of access to medical technology and cost containment compatible. In his opening remarks, Wyden charged that "opponents of health reform" have engaged in "fear-mongering" by suggesting to the public that they "must choose between medical cost containment and access to lifesaving technologies." In truth, Wyden argued, "if national health reform makes it possible for health buyers and users to conveniently compare competing medical technologies, cost savings can be achieved while simultaneously improving the health of our citizens." Institute for Health Care Delivery Research Executive Director Brent James, NM, estimated that only 10% to 20% of common medical practices have a basis in scientific research. "The remainder are based on tradition and anecdotal experience," James said. While "that does not mean that 80% to 90% of medical practices are wrong, it does mean that practitioners can hold legitimate differences of opinion about which medical practices achieve the best results." Eliminating inappropriate variations in medical practice may improve outcomes, lower costs and create an environment where it is possible to generate valid scientific knowledge for future practice improvements," James suggested. Furthermore, the legitimate differences of opinion among practitioners "extend into expert consensus panels and consensus guidelines," which are, as a result, highly "subjective." This subjectivity is one problem with the work done by HHS' Agency for Health Care Policy Research, Eric Topol, MD, Cleveland Clinic Foundation, told the subcommittee. Working with AHCPR to prepare guidelines for clinical medicine has made it "remarkably clear how frequently we do not have sufficient data from rigorous trials in order to make appropriate recommendations," Topol explained. "Instead, the process largely relies on the opinions of an expert panel, which can be particularly subjective and are often proven wrong at a later date." Jerry Avorn, MD, Harvard Medical School, suggested that reliable information about different drugs or devices that physicians need is not available because "it is presently no one's responsibility to do the research needed to generate such information, or to make sure that it is available to the practicing physician when he or she makes recommendations to the patient." For example, Avorn noted, "it is not the legislated mission of FDA to compare drugs with one another to see which is better, or more cost effective." The primary requirement imposed by FDA "is for a drug manufacturer to show that its drug is better than nothing, a placebo - and FDA officials will be the first to point out to you that it is not their job to evaluate drugs beyond this point, and they seem to have no enthusiasm for taking on this new role." The National Institutes of Health, which does engage in supporting the kind of university-based investigators who could conduct this research, "sees its role as supporting basic biological research, and often has a rather condescending attitude toward mundane studies comparing different ways of treating patients' common clinical problems," Avorn charged. "NIH does not see this as part of its core mission, and has not been eager to fund such research." Despite the pharmaceutical industry's large R&D budget, it is not "prudent public policy" to expect drug manufacturers to conduct comparative studies voluntarily and to "subject their products to tougher testing than is required of them," Avorn maintained. "It is naive to think that a company that has invested a nine- figure amount in developing a drug will be enthusiastic to subject it to a costly study comparing it head-to-head with an older product that may cost a tenth or a fiftieth of its price and might work just as well," Avorn reasoned. While some companies will engage in comparative evaluation if they feel their products will come out ahead, "that can leave a lot of important comparisons untested," Avorn noted. Another incentive Wyden has included in his proposal would grant expedited approval to products that have been shown to be superior to other products used for the same indication, relying on comparative trials conducted prior to product approval. Under the proposal, FDA would have 30 days after receiving the final results of an approved comparative trial to determine whether the study establishes the product as a superior product, either by offering clinical superiority for a defined patient population or by offering equivalent effectiveness while significantly reducing the cost of caring for a defined patient population. If a product is deemed superior, FDA would be obligated to give the product's application priority over all other products except those of similarly demonstrated superiority. If approval occurs more than 60 days after FDA has deemed the product superior, the manufacturer would receive an additional month of exclusivity for each month beyond 60 days. Wyden may reconsider this provision in light of testimony received from witnesses, who pointed out several difficulties with conducting premarketing comparative trials. Alan Hillman, NM, University of Pennsylvania, pointed out to Wyden that postmarketing studies of comparative efficacy are generally more "reliable" than those conducted prior to FDA approval. Postmarketing studies, unlike premarket studies, "mirror actual, clinical practice," Hillman noted. One drawback of premarketing clinical studies, Hillman suggested, is that they "are done under very special circumstances ...in which patients are carefully selected, followed and cajoled to use the new intervention in an ideal way." In addition, he noted, in real-world use "physicians are free to use drugs and devices in any way they choose," and as a result "the true costs and benefits of new medical interventions as they are actually used in actual clinical practice are not known for long periods of time, if they are ever known at all." John Burke, NM, LDS Hospital, noted that "drugs must be tested under real clinical conditions, when they are often used in tandem with others," and previously unseen adverse events may arise. Avorn suggested the use of provisional FDA approval contingent on prompt completion of a randomized clinical trial to bridge the gap between the information that is necessary for approval and the information that needs to be and can only be collected postmarketing. "There needs to be something between a yes and no approval," Avorn said. Burke suggested exploring "preliminary FDA approval that would restrict use to certain sites where intensive surveillance would be conducted," Hillman pointed out that there is room for premarketing studies, despite their faults. "Combining effectiveness research with preclinical studies also can be very fruitful, if done carefully and adjusted to account for the protocol- driven nature of the studies," Hillman observed. The most important thing is for studies "to be conducted according to the highest standards for scientific research," Hillman emphasized. Hillman directs a joint public-private-academic task force, sponsored by grants from 13 pharmaceutical and biotechnology firms to the Leonard Davis Institute of Health Economics. The group expects to have voluntary principles for the conduct and publication of effectiveness research on drug and biotech products ready by next autumn. Wyden urged the task force to move its timetable forward, if possible, so that he might have its principles in hand during the health care reform debate. A final incentive included in Wyden's proposal is a government seal of approval proposal. Wyden would have the government actively disseminate to health plans and health practitioners trial results showing a product's superiority with the statement that the government found the company's clinical study design met a rigorous quality standard. The results could be disseminated on an electronic bulletin board and through other means, Wyden explained. Some payor companies, like Blue Cross/Blue Shield, already conduct comparative trials. BCBSA Executive Director of Medical and Quality Management Susan Gleeson discussed BCBSA's Technology Evaluation program ("The Pink Sheet" Sept. 13, T&G-14) as an example of the association's efforts to disseminate "good data on the relative efficacy and cost benefit of technologies." The four breast cancer trials which BCBSA is funding to evaluate the efficacy of high dose chemotherapy with autologous bone marrow transplant compared to traditional chemotherapy are "accruing very well," Gleeson reported. In prepared testimony, Gleeson presented three BCBSA recommendations to encourage clinical research. The first is "the establishment of a national research advisory board to evaluate and prioritize all the clinical research on new and existing technologies." This board would be comprised of clinical research experts, practitioners, ethicists and consumers, and "should also attempt to estimate the cost of each study." The development of federal incentives such as tax credits "to encourage health plans to support high priority clinical trials" is the second BCBSA recommendation. These incentives would include tax credits. BCBSA also suggests that the government consider providing legal protection to health plans to shield it from suits by members seeking access to non-priority trials. Gleeson added that BCBSA "do[es] not believe the government should mandate coverage of patient care costs for an investigational technology under evaluation in clinical trials." Thirdly, BCBSA recommends that manufacturers and researchers collaborate on cost- sharing joint research.