Addressing the Barriers to Pediatric Drug Development: Workshop Summary (2008)

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4 Models for Enhancing Pediatric Drug Development T he need to identify other models for enhancing drug discovery and development for pediatric populations was addressed by sev- eral speakers. Potential models that were presented and discussed included vaccine development in the United States, an incentive-based model based on the European Union’s (EU’s) new regulatory approach, and an academic health center initiative exemplified by the model devel- oped by St. Jude Children’s Research Hospital. Vaccine Development IN THE UNITED STATES Vaccine development in the United States can offer lessons for p ­ ediatric drug development. Both vaccines and drugs are covered by the Pediatric Research Equity Act (PREA), and requirements for safety and efficacy are similar. In addition, both vaccines and drugs are often tested initially in adults. While the similarities stop there, according to Dr. Orenstein, two of the systems in place for vaccines—public informa- tion fact sheets and the no-fault compensation system—may be helpful models for pediatric drugs. In 1986, vaccines were available to prevent 8 diseases in children; vaccines today prevent 16 diseases. However, vaccine development is difficult and costly; only a handful of large pharmaceutical companies This section is based on the presentation of Dr. Walter Orenstein, Professor of Medicine and Pediatrics, Emory University. 29 

30 ADDRESSING THE BARRIERS TO PEDIATRIC DRUG DEVELOPMENT dominate the vaccine market. Exclusivity is not an incentive because there are no competitors waiting to produce generic versions of vaccines. Several incentives do exist for vaccine development, some by virtue of what vaccines do and how they are distributed, and some that were put in place specifically to spur development. Vaccine makers are often guaranteed a large market because of universal vaccination policies that reflect standards of care set by recommending bodies. Vaccines are fun- damental to pediatric practice and are a regular component of well-clinic visits. Moreover, vaccination often offers protection to the community as well as to individuals; therefore, many vaccines are eventually mandated through school and/or day care laws. Because vaccines are mandated to provide a community benefit, Con- gress established the National Vaccine Injury Compensation Program as Title XXI of the Public Health Service Act of 1987. The program offers a no-fault compensation system for patients (or their families) who suffer serious adverse reactions from required childhood vaccines. The aim is to help stabilize the supply and price of vaccines by removing most of the liability burden from manufacturers for immunization-related injuries. The program is funded by an excise tax of $0.75 on every dose of covered vaccine that is purchased. Also in place is the Vaccine Adverse Event Reporting System (VAERS), a national vaccine safety surveillance program that collects information about adverse events occurring after the administration of U.S.-licensed vaccines. Reports are made by vaccine manufacturers, health care provid- ers, state immunization programs, vaccine recipients, and other sources. VAERS is a passive system (meaning that reporting is generally volun- tary), though certain adverse events are required to be reported by law. Two-page public information fact sheets on each vaccine describing ben- efits and risks, issued by the government and written for the lay public, also stimulate reporting by consumers. In addition, the Vaccine Safety Data Link (VSDL) was established to monitor immunization safety and address gaps in knowledge about rare and serious side effects associated with immunizations. It monitors rates of adverse events from eight man- aged care organizations that cover roughly 2 percent of the population. VAERS works by identifying signals that indicate there may be a problem, while VSDL is better for assessing causality. Dr. Orenstein suggested that two components of vaccine devel- opment might transfer well to pediatric drug development: the fact sheets used for vaccines would likely be helpful for pediatric drugs as well, and a no-fault compensation system could remove a barrier to the industry’s testing and distribution of products among pediatric populations. Dr. Orenstein also suggested development of a docu- ment similar to the Red Book, a pediatric infectious disease reference 

MODELS FOR ENHANCING PEDIATRIC DRUG DEVELOPMENT 31 produced by the American Academy of Pediatrics’ (AAP’s) Committee on Infectious Diseases. In the discussion following Dr. Orenstein’s presentation, Dr. Ward described an AAP collaboration with the Royal College of Pediatrics in the United Kingdom to develop a drug handbook for pediatrics that would include off-label prescribing information based on expert opinion. The key challenge, he noted, is correlating adverse events with exposure to medications. Dr. Murphy emphasized the importance of making the public aware of the depth of the problem; without significant changes, she suggested, we are essentially experimenting on children in an uncontrolled manner. The Adverse Event Reporting System, the Food and Drug Administra- ton’s postmarket safety surveillance program for all approved drugs and therapeutic biologic products, is similar to VAERS, but Dr. Murphy noted that there is tremendous underreporting. She indicated that she would prefer to see an active surveillance system. The European Union’s New Regulatory Approach Dr. Weyersberg described a new EU regulation on pediatric drug development. The regulation, which entered into force on January 26, 2007, is applicable and obligatory for all 25 EU member states. Its goals include imp����������������������������������������������������������������� roving the health of children by fostering high-quality, ethical research on pediatric medicines; increasing the availability of medicines authorized for children; and expanding the information base on the use of medicines in pediatric populations. The objective is to achieve these goals without conducting unnecessary studies in children and without delaying authorization for adults. The regulation has five major components: • The formation of a new Pediatric Committee working at the ��������� European Agency for the Evaluation of Medicinal Products����������������� (EMEA) in London • Incentives for patent-protected medicinal products • Incentives for off-patent medicinal projects • The Pediatric Investigation Plan (PIP)—a��������������������� document describing �������������������� proposed studies of the drug in pediatric populations, which must be approved by the Pediatric Committee and must be complied with if the associated incentives are to be received This section is based on the presentation of Dr. Annic Weyersberg, National Expert Paediat- rics, European Agency for the Evaluation of Medicinal Products. The information provided in this section is based on information available in 2006, and may have been subject to changes in the course of the implementation process. For more detailed and up-to-date information on the EU Pediatric Regulation, refer to the EMEA website: www.emea.europa.edu. 

32 ADDRESSING THE BARRIERS TO PEDIATRIC DRUG DEVELOPMENT • Several additional measures that also support pediatric drug development The Pediatric Committee The Pediatric Committee will consist of one representative and one alternate from each EU member state, five of whom will also be members of the Committee on Human Medicinal Products (the EU committee that recommends the granting of marketing authorization for new medicinal products submitted through the centralized procedure), as well as six members and alternates to represent health professionals and patient associations. The committee will include experts in pediatric research, pharmacology, pharmacy ethics, clinical science, and other areas. It will meet three days a month to assess and make opinions on PIP applications, including deferrals and requests for waivers. Incentives Incentives will vary according to whether a product is patent- p ­ rotected, off-patent, or an orphan drug. For patent-protected ­products, submission of an application for marketing authorization or any applica- tion for a variation will incur a new obligation to provide study results in accordance with an agreed-upon PIP. The reward will be a 6-month extension of the patent protection (supplementary protection certificate). Older, off-patent products will be able to receive a new form of mar- keting authorization called a Pediatric Use Marketing Authorization (PUMA). A PUMA will be granted on the basis of studies conducted in children that lead to an authorization for use in children, including a specific pediatric formulation, also according to an agreed-upon PIP. The reward for submitting pediatric study results will be a 10-year period of data protection. The applicant will be able to use the existing brand name for the product for adults and place a symbol on the label to show that there is a pediatric indication as well. In contrast with patent-protected products, however, applying for the new authorization and subsequent reward will be optional for off-patent products. An incentive for orphan drugs will also exist. Dr. Weyersberg said this is important because 15 to 20 percent of rare diseases affect only children, while 55 percent affect both adults and children. Upon submission of study results according to an agreed-upon PIP, the reward will be 2 years of extra market exclusivity in addition to the existing 10 years. Thus, a sponsor of an orphan product will have 12 years of market exclusivity if it has conducted studies in children. 

MODELS FOR ENHANCING PEDIATRIC DRUG DEVELOPMENT 33 In each case, the rewards will be granted even if the results of the studies conducted fail to lead to authorization of a pediatric indication. The intent is to reward the effort made to collect pediatric data. Pediatric Investigation Plans The PIP will be a detailed document describing proposed studies for the preclinical and clinical development of a drug for use in pediatric populations. It will include the schedule for the studies and the means to be used to demonstrate quality, safety, and efficacy. It will also describe how the drug’s formulation will be adapted for children, with consider- ation of different pediatric populations. Each PIP will be assessed and must be approved by the Pediatric Committee, and will be binding if the sponsor is to receive the incentives described above. The committee will have a maximum of 120 days to review the PIP. There will be an option to amend an agreed PIP, but the Pediatric Committee must approve each amendment. The PIP will also include justification for any waivers or deferrals—for example, if there is no significant therapeutic benefit over existing treatments for children or for a particular pediatric population, or if it is more appropriate to initiate studies in children after sufficient data for adults are available. Additional Measures All applicants will be eligible to receive free scientific advice from the EMEA on the design and conduct of pediatric studies and on pharmaco- vigilance measures for the postauthorization period. Each EU member state will have to collect all available data on existing uses of all medici- nal products in children. They will have 2 years to collect these data, which will be assessed by the Pediatric Committee so that an inventory of therapeutic needs can be developed. A European Research Network will be established at the EMEA to link existing networks, investigators, and centers with expertise on studies in pediatric populations. The regulation is expected to increase transparency because, unlike results of studies in adults, results of all pediatric studies, completed and ongoing, will be publicly available. Community funding will be available for studies of off-patent medicines. Funding will be determined on the basis of the needs identified in the inventory mentioned above. If a pharmaceutical company benefits from the rewards described above but then wishes to withdraw the product from the market, it will have to transfer the marketing authorization to an interested third party or provide access to the data on the product. 

34 ADDRESSING THE BARRIERS TO PEDIATRIC DRUG DEVELOPMENT Obligations and Postauthorization Requirements Rewards will come with two major obligations. First, study results must be included in the summary of product characteristics and, if appro- priate, in the product’s package leaflet. Second, the product must be authorized in every EU member state so that all children in the EU may benefit. There are also postauthorization requirements, including the stipulation that applicants must place the product on the market within 2 years after receiving a reward. In addition, the Pediatric Committee can ask the applicant to propose measures for ensuring long-term follow-up on safety, a risk management system or risk minimization plans, and specific postauthorization studies. The St. Jude’s Model for Pediatric Oncology Drugs St. Jude Children’s Research Hospital in Memphis has assumed the challenge of bringing new molecularly targeted therapies to bear on chil- dren’s cancer research. Until now, none of the research focused on per- sonalizing cancer treatments by directly targeting the molecular changes that occur within an individual has focused on childhood cancers. Ima- tinib (Gleevec, for chronic myeloid leukemia), trastuzumab (Herceptin, for breast cancer), and other drugs in the development pipeline are all intended for the treatment of adult cancers. However, molecular abnor- malities in pediatric cancers are distinct from those in adult cancers. As with pediatric medications generally, market forces work against the development of pediatric cancer drugs. Each year 9,000 pediatric cancers are diagnosed in the United States, compared with a much larger number of adult cancers (e.g., 200,000 new breast cancer cases, 190,000 prostate cancer cases, and 160,000 lung cancer cases). These 9,000 pediatric cases comprise 50 to 100 different types of cancer. Despite impressive progress made in the cure rates for childhood cancers by using adult anticancer agents, cancer remains the leading cause of death by disease in U.S. children over 1 year of age. Furthermore, less toxic therapy is needed to ensure a better quality of life for pediatric cancer survivors. The St. Jude’s model is an effort to follow through on the 2005 Insti- tute of Medicine report Making Better Drugs for Children with Cancer (IOM, 2005). That report called for public–private partnerships to lead the dis- covery and development of pediatric cancer drugs so that children can benefit from the new wave of science and molecularly targeted medicine for cancer. This section is based on the presentation of Dr. Evans. 

MODELS FOR ENHANCING PEDIATRIC DRUG DEVELOPMENT 35 Dr. Evans and others convened a group of doctors and scientists to create a scientific plan that would clearly outline what needed to be done to develop new drugs for pediatric cancers. The effort involved partner- ships with academia, large and small pharmaceutical companies, govern- ment health agencies, and philanthropic foundations. St. Jude Children’s Research Hospital has focused on filling the gap in the discovery of pediatric cancer drugs by building a Good Manufactur- ing Practices (GMP) facility, and launching a Chemical Biology and Thera- peutics initiative. There is interest in leveraging these efforts through the National Cancer Institute’s (NCI’s) Pediatric Cancer Drug Discovery Con- sortium under an expanded public–private–government initiative. The GMP facility is producing gene therapy vectors, vaccines, and monoclonal antibodies. The Chemical Biology and Therapeutics initiative will involve putting viable targets in pediatric tumors from the research laboratories of St. Jude’s and others through high-throughput screens of very large librar- ies of small molecules—currently more than 1 million compounds. This is similar to the type of drug screening a pharmaceutical company might conduct, although St. Jude’s has objectives other than simply developing new drugs. The goals are to identify small molecules that are inhibitors of specific targets in pediatric cancers and could be used to explore the path- ways involved in pediatric cancers, identify candidate small molecules for preclinical testing, and network with others to improve capacity and ultimately advance these agents to the level of the pediatric clinic. Finally, NCI is funding the Pediatric Cancer Drug Discovery Consortium to screen adult cancer drug candidates in animal models with pediatric tumors. In response to Dr. Evans’ presentation, Dr. Nelson raised concerns about relying on independent, well-funded pediatric institutions to com- pensate for the deficits in funding for traditional academic research. Dr. Evans replied that all involved need to do what they can, and that he is concerned about the flat funding for the National Institutes of Health. To address the funding issue, he plans to rely more on team science, looking to academic partners and others for what they do well. Dr. Susan Weiner, a member of the audience from the Children’s Cause for Cancer Advocacy, asked whether St. Jude’s expects to file a New Drug Application if an entity is found that is effective in only a small group of children. Dr. Evans replied in the affirmative and noted that St. Jude’s has acquired various libraries of compounds through different arrangements. Some have been purchased outright; others involve the right to first refusal if a lead compound or potential therapeutic is found. Dr. Evans warned that, with molecular characterization of tumors, more and more drugs will be found to be useful in smaller subsets of patients. A new business model needs to be devised for the development of these drugs with small potential markets, a need that is growing for adult diseases as well.