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5 Challenges and Opportunities for the Future D espite progress made in the development and study of drugs for use in pediatric populations, many such drugs have not been tested substantially in children. Accordingly, workshop participants dis- cussed ways to achieve further progress. The discussion addressed both systemic solutions and potential means of eliminating the economic bar- riers reviewed in Chapter 3. Systemic Solutions Speaking as a pediatrician, Dr. Murphy offered several suggestions for improving the system for pediatric drug research: • More transparency in research • Continued development of pediatric endpoints and assessment tools • Real-time inspections of pediatric trials • Continued development of juvenile animal models • Better approaches to assessing the long-term safety of drugs • Active surveillance systems focused on pediatric populations • More studies in neonates and premature infants Dr. Murphy asserted that pediatric drug development must become more global because pediatric populations are smaller than the adult 36

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CHALLENGES AND OPPORTUNITIES FOR THE FUTURE 37 population, children are protected from participation in studies, and there is little commercial motivation to test drugs in children. Surveillance Dr. Murphy stressed that, because pediatric drugs are studied in a very limited population in a very defined way, a great deal of the safety information on these products emerges only after they have been mar- keted. Her call for the collection of data on long-term outcomes, with better postmarket safety surveillance, was echoed throughout the meet- ing. Dr. Snodgrass asserted that postmarket surveillance must be more extensive and thorough than is the case today. It needs to encompass adverse events as well as other outcomes and to quantify long-term ben- efit. Dr. Fleischman suggested that the only way to make postmarket surveillance feasible is to support the development of uniform electronic medical records with appropriate privacy protections. Regulation Dr. Murphy also suggested combining incentives and requirements for conducting research in pediatric populations into one process, as the Europeans have done. In the United States, the two are handled separately in the legislative process and within the U.S. Food and Drug Administration (FDA). Summaries of research should be available to the public for studies that fall under both the Best Pharmaceuticals for Chil- dren Act (BPCA) and the Pediatric Research Equity Act (PREA). How much information would be provided and in what format would have to be determined. Dr. Nelson suggested that Written Requests should be made public, as knowing what the FDA is asking a sponsor to do is help- ful in evaluating what the sponsor has actually done. Ms. Ireland seconded the call for greater transparency, adding that there is also a need for better coordination of studies done under PREA and BPCA. She suggested that there is no reason why the Pediatric Advi- sory Committee reviews adverse events for BPCA and not for PREA studies. In addition, Ms. Ireland favors looking beyond pediatric-specific laws to the broader movement in Congress to address drug safety issues. The Senate Health, Education, Labor, and Pensions (HELP) Committee is exploring the idea of broadening the authority of the FDA to require postmarket studies and is considering the development of a clinical trials database. According to Dr. Ward, the PREA requirement that pediatric studies be requested only for those indications applied for in adults is too limit- ing. Multiple examples can be cited in which new therapeutic uses have

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38 ADDRESSING THE BARRIERS TO PEDIATRIC DRUG DEVELOPMENT emerged during a product’s lifespan. An example is sildenafil (Viagra), which is now used for pulmonary hypertension in premature infants but was developed for erectile dysfunction. Ms. Ireland cautioned that reauthorization of BPCA will require Con- gress to address new cost issues because of the recent changes result- ing from the Medicare prescription drug benefit. The benefit is likely to increase costs to the government, so cost–benefit considerations will be central to the reauthorization debate. Dr. Snodgrass responded that the cost of not conducting pediatric studies should also be examined. Training and Research Several participants expressed the need for more physician training. Dr. Spielberg called for better training in therapeutics in medical school because many of today’s physicians do not fully understand how to use drugs wisely. Physicians must not only be able to understand drug labels, but also be thoughtful in challenging the labels on the basis of good pharmacological principles. Dr. Ward added that the majority of medi- cal schools fail to recognize therapeutics as a discipline to be taught to students. As a result, the importance of clinical drug studies is not fully recognized. Dr. Patricia Horsham, a member of the audience from the College of Physicians and Surgeons in Canada, noted that drug companies are approaching pediatricians in private practice to recruit patients for clinical trials so they will not have to deal with the stringent rules for academic research. Pointing to the Pediatric Research in Office Settings (PROS) Net- work of the American Academy of Pediatrics, Dr. Spielberg suggested that office-based pediatricians are an opportunity. This approach finds favor among pediatric practitioners because they believe they are participat- ing in the development of new knowledge. Dr. Spielberg encouraged the development of more networks of primary care pediatricians to partici- pate in such efforts under the proper auspices and ethics. Finally, Ms. Ireland agreed with others who stated that off-patent stud- ies are not optimally conducted through the Foundation for the National Institutes of Health (FNIH), which relies on charitable contributions for the necessary support. Dr. Mathis acknowledged that the National Insti- tutes of Health (NIH) also has had difficulty in securing funding for off- patent studies. Additional federal funding for these studies is needed. Elimination of Economic Barriers Dr. Giacoia outlined several possible solutions to the economic bar- riers to pediatric drug studies. The following solutions were devised by

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CHALLENGES AND OPPORTUNITIES FOR THE FUTURE 39 the Economics and Partnerships Working Group of the Pediatric Formula- tions Initiative: • Development of global standards for oral liquid preparations, and expansion of the market for these preparations by combining incentives for pediatric and geriatric populations • A reduction in cost, risk, and time-to-market • Use of “existing” formulations (some pharmaceutical companies produce formulations that do not enter commercial use, so perhaps they could donate these formulations to not-for-profit organizations) • Importation of approved pediatric drugs (several products are approved in Europe and other countries but are not available in the United States; legal, regulatory, and legislative issues would need to be addressed) • Additional incentives (limited exclusivity), funding, and tax breaks • Incentives for priority extemporaneously formulated drugs • Incentives for pediatric formulations of generic drugs (similar to the 12 years of data exclusivity granted by the European union) • Public–private partnerships for orphan drugs Concluding Thoughts Several themes emerged from the workshop as participants discussed how to move pediatric drug development forward to spur more research and improved safety. The current regulations, both of which sunset in 2007, have had an important positive effect on pediatric drug development. Both industry and FDA participants agreed that PREA has led drug developers to think about pediatric applications when they begin developing a drug for an adult condition that exists in children as well. Furthermore, the incentive of expanded market exclusivity under BPCA has improved the labeling on more than 100 medications for children. Many participants agreed that incentives work, but perhaps more are needed. Additional incentives worth exploring are limited liability, incentives to work on formulation and taste issues to improve pediatric patient adherence, and debt forgiveness for students entering academic careers in pediatrics and clinical investigation. Dr. Califf, remarking on the need for transparency and the difficulties of finding information on the FDA website, also suggested an incentive to display publicly how a study was conducted and what its results were, as well as how its results should be interpreted. Dr. Spielberg said that the FDA will be dealing with greater uncer-

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40 ADDRESSING THE BARRIERS TO PEDIATRIC DRUG DEVELOPMENT tainty and more risk with the new compounds now in the pipeline, in terms of both the costs of studies and market size. Because none of these factors bode well for encouraging drug makers to test their products in children, Dr. Murphy stressed that incentives may become more impor- tant than ever. An additional challenge is funding for off-patent studies. Dr. Mathis and others suggested that relying solely on FNIH for funding for these studies is unrealistic. Dr. Nelson also argued that the process used by NIH to get contracts for studies of these drugs, as well as for on-patent drugs that a sponsor chooses not to study, is cumbersome and unnecessarily lacking in transparency. A number of participants, including Dr. Gorman and Ms. Jarrett, agreed that the infrastructure needed to conduct multisite pediatric stud- ies is lacking. Enhancing this infrastructure would require not only the additional training in therapeutics discussed above, but also increased funding for practice-based research networks. In addition to better train- ing, increasing the numbers of trained pediatric clinical investigators is also important; the debt forgiveness for students incentive mentioned earlier could be helpful in this regard. Pediatric-specific adverse events must also be defined so that pedia- tricians and parents will know what to look for and how to manage events that occur. Dr. Murphy and Dr. Snodgrass advocated for a more active surveillance system to identify adverse events, especially after a pediatric indication has been approved for marketing. They also stressed the importance of better communication to prescribers and consumers so they will know not only how to deal with adverse events, but also how to use the medications properly. Finally, lessons can be learned from the European Union’s recent regulations, which represent a coordinated effort to improve the study of on-patent, off-patent, and orphan drugs. The compensation fund and information sheets that are integral to vaccine drug development can also serve as models for pediatric drug development.