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

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3 Current Challenges in Developing and Prescribing Drugs for Children W orkshop participants described several barriers to the devel- opment of drugs for pediatric populations, including ethical concerns, economic barriers, and logistical and technical issues. The industry perspective on these barriers was discussed as well. Partici- pants also described several challenges in using drugs to treat children— problems with formulations and issues of dosing, bioavailability, and drug response. Barriers to pediatric drug Development Barriers to pediatric drug development identified by workshop par- ticipants include ethical concerns, economic barriers, and logistical and technical issues. Delays in pediatric drug testing that result from these barriers have led to unnecessary exposure to ineffective drugs or inef- fective dosing of effective drugs, both of which prevent patients from receiving appropriate therapies. Dr. Murphy noted that, absent the results of pediatric drug testing, it is impossible to know whether a drug found effective for adults will work well in children, or might work in children if the dose were adjusted. Without pediatric testing and long-term sur- veillance, it is also impossible to know what safety signals to watch for and how to manage them, and adverse events that might be unique to pediatric populations remain unknown. 20 

CHALLENGES IN DEVELOPING AND PRESCRIBING DRUGS FOR CHILDREN 21 Ethical Concerns According to Dr. Nelson, ethical concerns should not be a barrier to pediatric research. Although children cannot consent to participate in research studies, there is broad international agreement on three core ethical principles that should guide pediatric research: • Children should not be enrolled in research unless necessary to answer an important scientific question about the health and welfare of children. • Research involving children must be characterized by a balance of risks and potential benefits comparable to that of available alternatives. • Research offering no direct benefit to children must be restricted to that posing minimal risk. Although definitions of “minimal risk” and “low risk” vary, Dr. Nel- son argued that the differences are insignificant. For research with the prospect of direct benefit to the study population, every health authority uses similar language. The pertinent U.S. Food and Drug Administration (FDA) language appears in Subpart D of the Code of Federal Regulations, “Additional Safeguards for Children Involved in Clinical Investigations” (21 CFR §50.52). This language suggests that risks must be justified by anticipated benefits, and anticipated benefits and risks must be balanced in both arms of a study. The variability seen in Institutional Review Board (IRB) determinations is not driven by differences in definitions, but by the inevitable differences in individual judgments within any group of people (Sugarman, 2004). Better definitions are not likely to eliminate that variability. According to Dr. Nelson, ethical barriers to the study of pediatric drugs fall into four categories: • Clinicians are willing to prescribe drugs off label without sufficient pediatric data (adults, of course, are prescribed drugs off label as well). This willingness to use drugs without sufficient data results in delays in needed research. • Sponsors, as expected, act in their financial self-interest. They often pursue pediatric clinical trials late in a drug’s life cycle, after its true mar- ket value has been determined. Once they have decided to conduct a trial, cost considerations may trump considerations of study design quality. • Academic institutions do not reward investigators for participat- This section is based on the presentation of Dr. Robert Nelson, Associate Professor of Anesthesiology and Critical Care, Children’s Hospital of Philadelphia. 

22 ADDRESSING THE BARRIERS TO PEDIATRIC DRUG DEVELOPMENT ing in clinical trials. Their goal is to have independent investigators with National Institutes of Health (NIH) R01 grants, not co-investigators in multi-institutional trials. A discordance exists between academic and industry goals in terms of data use, publication, and intellectual property. There is also a lack of academic interest in investigating old drugs. • All levels of the clinical research enterprise lack transparency, which undermines the public trust. Factors contributing to this lack of transparency include the following: – Absence of justification for requested studies in FDA Written Requests – Potential wasted effort in the NIH Request for Proposals process for off-patent drugs (Dr. Nelson suggested that, in seeking a study to col- lect data on a drug, NIH should simply hire a third party to conduct the study, rather than soliciting proposals that require a great deal of grant writing.) – A closed IRB system. A transparent system would allow the pub- lic to be informed about the substance of the decisions made, not just the decision process. The public would also know of failures and delays by the industry in investigating or publishing information on adverse events In closing, Dr. Nelson suggested that the ethical principles men- tioned above pose barriers not to the responsible conduct of appropriately designed pediatric studies, but to studies that should not be conducted. The barriers that exist to appropriate studies may instead arise from a reluctance to alter existing practices and focus on the goal of finding efficient and effective ways to develop adequately studied drugs for the treatment of children. In responding to Dr. Nelson’s presentation, Dr. Alan Fleischman, a member of the audience from the New York Academy of Medicine, noted that several major reviews of Subpart D definitions have been performed in the past 5 years by the National Human Research Protections Advisory Committee, two Institute of Medicine (IOM) committees, and the Secre- tary’s Advisory Committee on Human Research Protection. He raised the question of whether those reviews are adequate in light of clarifications soon to be published by the Office of Human Research Protections. Dr. Fleischman and Dr. Stephen Spielberg, a member of the audience from Dartmouth University, also raised the question of a child’s ability to give informed consent, but the question was not answered by the panelists. When asked whether a centralized IRB would address the issues he had raised, Dr. Nelson responded that this would be a potential solution if transparency were the result. He pointed to the facilitated IRB used by the National Cancer Institute (NCI): NCI sends the local IRB a package that describes the NCI IRB decision-making process and how the specific 

CHALLENGES IN DEVELOPING AND PRESCRIBING DRUGS FOR CHILDREN 23 issues within that protocol were analyzed. In his view, this approach provides the local IRB with sufficient information to decide whether the process and the determination make sense. Ethical considerations will continue to be an important aspect of pedi- atric drug studies. Better definitions of risk categories, direct benefit, and other concepts would be helpful. Dr. Murphy suggested that oversight of trials needs to be an ongoing, active process, and that more transparency for all pediatric studies and resulting data is needed. Economic Barriers According to Dr. Giacoia, economic factors are the major barriers to the development of better formulations for children. These barriers include relatively small market size and perceived high risk, as well as, for small companies, the cost of maintaining a pediatric sales force. The relatively small market for pediatric drugs is economically unat- tractive for many large companies. U.S. pharmaceutical sales were $250 billion in 2005, and the annual sales growth rate is 5.4 percent. In con- trast, U.S. pediatric pharmaceutical sales in 2005 were $37 billion, with an annual growth rate of 4 percent. The majority of the pediatric market is concentrated in a few therapeutic areas, such as anti-infective, central nervous system, allergy, and asthma drugs. The pediatric drug market is further segmented by the need for differing formulations and dosing for different age groups. In addition, testing of drugs in pediatric populations is considered to be high risk, with little expected return on investment. When adverse events occur in a trial, sponsors face product liability risks, as well as the risk of having to add a warning to the product label. An example is the elevated risk of suicide in adolescents taking selective serotonin reuptake inhibitors (SSRIs), which was made public because the pediatric trials were conducted under the Best Pharmaceuticals for Children Act (BPCA). Logistical and Technical Issues The infrastructure needed to effectively conduct pediatric drug stud- ies is lacking, according to several of the workshop speakers. As noted This section is based on the presentation of Dr. George Giacoia, Project Director of the Pediatric Pharmacology Research Units Network, National Institute of Child Health and Human Development. This section is based on the presentation of Dr. Richard Gorman, Chair of the Section on Clinical Pharmacology and Therapeutics, American Academy of Pediatrics. 

24 ADDRESSING THE BARRIERS TO PEDIATRIC DRUG DEVELOPMENT by Dr. Gorman, the number of pediatric pharmacologists is declining. Therapeutics is no longer, or rarely, taught in medical schools. In addition, too few physician scientists are able to conduct research that bridges the gap between basic science and clinical practice. Pediatric clinical research units are rare, and pediatric expertise on IRBs is limited, with the excep- tion of children’s hospitals. Significant technical barriers to pediatric drug testing also exist. Dr. Gorman cited limited baseline information on frequency of disease and treatments of choice. According to Dr. Murphy, accepted endpoints and validated pediatric assessment tools are also lacking. In addition, she emphasized that defining the pediatric-specific adverse events associated with a drug is critical so that the pediatrician and the family know what events to look for and how to manage them. Without such knowledge, the common response when an event occurs is to stop use of the drug; however, it could be more appropriate to adjust the dosage or manage the effects. During the discussion of Dr. Gorman’s presentation, Dr. Robert Califf of the Duke University Medical Center and a member of the IOM Forum on Drug Discovery, Development, and Translation identified an issue that he believes is critical and needs to be discussed more openly: the pharmaceutical industry routinely seeks scientists outside of the United States to conduct studies because the nation’s pediatric clinical research capability is not adequate for the purpose. In addition, as noted earlier, major academic institutions in the United States fail to reward pediatri- cians for conducting clinical research. Dr. Califf suggested that the IOM needs to help address these issues. Dr. Spielberg agreed, adding that the United States has the technologies in molecular biology, proteomics, and metabolomics to be able to conduct the needed studies. However, most institutions, including those with well-known pediatric hospitals, are not set up to perform the studies effectively and efficiently. Dr. William Evans, Director and CEO, St. Jude Children’s Research Hospital, noted that one clear exception is childhood cancer, for which more than 70 percent of patients are treated in clinical trials, and Phase I and II drug studies are common. Industry Perspective on Barriers to Pediatric Drug Development  Ms. Jarrett and Mr. Hassall provided presentations on the barriers to pediatric drug development from the perspective of the industry, echo- This section is based on the presentations of Ms. Natasha Jarrett, Director of Regulatory Affairs, Hoffmann-LaRoche, and Mr. Thomas Hassall, Senior Director of Global Scientific, Medical, and Regulatory Affairs, Abbott Laboratories. 

CHALLENGES IN DEVELOPING AND PRESCRIBING DRUGS FOR CHILDREN 25 ing many of the points made by previous speakers. Ms. Jarrett noted a shift away from protecting pediatric patients against experimentation and toward protecting them through the generation of data from drug trials. She discussed the industry’s ethical incentives to conduct research in pediatric populations, including the responsibility to share pharma- ceutical knowledge with the community and to protect pediatric patients and further their treatment through provision of the data generated by industry trials. Current regulations, in particular those associated with the Pediatric Research Equity Act (PREA), have led the industry to think about conducting pediatric research much earlier in a drug’s develop- ment, often at the very beginning. Ms. Jarrett noted further that for every incentive, there are challenges in pediatric drug development. �������������������������������������������� Trial designs for pediatric patients differ greatly from those for adult patients in the same disease area (see Box 3-1). Recruitment of subjects is also a difficulty for pediatric trials������� . Pedi- atric patients are recruited from different sites than adult patients, sites for which the networks and infrastructure necessary for recruitment are often not in place. The pediatric population is also smaller than the adult population, and sufficient numbers of subjects are frequently not avail- able in one country. Sponsors must therefore go outside the United States or the European Union to recruit enough patients, particularly in the younger age groups. Doing so necessitates the involvement of more than one health authority (comparable to the FDA) and several ethics commit- BOX 3-1 Differences Between Adult and Pediatric Trial Designs • The nature of the disease can be different, requiring different endpoints. • There are more restrictions on pediatric trials; for example, the volume of samples that can be taken requires more innovative statistical design. • There are additional safety considerations, such as growth and develop- ment, in pediatric trials. • “Pediatric” patients include neonates through adolescents, with very differ- ent considerations for each age group. • The formulation of a drug needs to be different for younger and older patients. • The expertise needed for pediatric trials often is not available in house, so external experts need to be consulted. SOURCE: Jarrett, 2006. 

26 ADDRESSING THE BARRIERS TO PEDIATRIC DRUG DEVELOPMENT tees. ������������������������������������������������������������������� Regulatory agreements on protocols or Written Requests can require many rounds of feedback and sometimes years to achieve, particularly if more than one health authority is involved. Ms. Jarrett suggested that technical and preclinical difficulties also exist. For example, as discussed earlier, adult formulations are not always suitable for pediatric patients. Reformulation work can take years and involve special considerations, such as palatability. Sometimes reformu- lation is not possible or feasible, but years can be required to obtain an agreement that due diligence has been exercised. Mr. Hassall observed that the incentives for pediatric trials have not changed since the inception of pediatric exclusivity through the FDA Modernization Act (FDAMA) in 1997, but expectations have grown: to obtain the 6-month exclusivity, more effort is expected of a drug’s spon- sor. With BPCA, the emphasis has shifted from developing information on how to use currently available drugs to developing an entirely new product line for pediatric populations, but with no additional incentives. In addition, the Prescription Drug User Fee Act (PDUFA) used to exempt pediatric applications from user fees; however, this is no longer the case�� . Therefore, companies seeking to develop a pediatric formulation, submit an application to the FDA, and get a drug on the market now face a cost of three-quarters of a million dollars for the drug to be reviewed. Mr. Hassall concluded that “the challenge is to try to strike a balance between expectations and incentives for the next decade.” Ms. Jeanne Ireland, a member of the audience from the Elizabeth Glaser Pediatric AIDS Foundation, asked Mr. Hassall about his view of proposals to tier the size of the incentive according to the cost of the study or the profit or sales of the product. Mr. Hassall responded that he does not believe this to be the best solution. FDAMA presented an elegant solu- tion because it limited the scope of the behavior expected of the industry, focusing on the goal of generating data and information for labeling. Formulations According to Dr. Giacoia, a significant number of drug formulations are not suitable for children. Each type of formulation poses difficulties, depending on the age of the child. Younger children, for example, may be unable to swallow pills, may spit out chewable tablets, and may dislike effervescent tablets. As a result, physicians frequently manipulate existing formulations for use in children. These extemporaneous formulations may be unsafe, as quality control is often lacking; moreover, the process may include the compounding of drugs, which carries additional risks. For most This section is based on the presentation of Dr. Giacoia. 

CHALLENGES IN DEVELOPING AND PRESCRIBING DRUGS FOR CHILDREN 27 drugs, however, suitable formulations and administration pathways are possible. Dosing instruments may be as important as the formulation itself. Many medications for children are in the form of oral liquid preparations, which are often dispensed from droppers and teaspoons. Because table- ware teaspoons can vary in capacity from 4 to 7 mL, medication errors can occur unless a measuring instrument is provided with the medication. In addition, appropriate testing of drug taste and palatability—important to adherence among pediatric populations—is lacking. The science of blocking bitter taste, for example, is in its infancy. Alternatives to oral liquid formulations are needed. One alternative dosing instrument is a patch, but it is difficult to keep a patch on a child unless it is placed on the back, and an occlusive dressing may be needed to keep it in place. In addition, there are major gaps in knowledge regarding different drug delivery systems. The recently launched Pediatric Formulations Initiative has several aims: • To identify on- and off-patent drugs for which no suitable formula- tions are available • To determine scientific and technical barriers to the development of pediatric formulations • To summarize current knowledge on drug palatability, taste mask- ing, bitterness reduction, and pediatric taste studies, and to identify gaps in knowledge in these areas • To determine current knowledge of the toxicity of flavorings, dyes, sweeteners, and preservatives • To identify current practices for dispensing drugs without appro- priate pediatric formulations and to determine the suitability of different methods for oral administration • To identify regulatory issues that affect the development and approval of pediatric formulations • To create a forum for information exchange To carry out this initiative, four working groups composed of repre- sentatives from industry, academia, the FDA, and NIH were formed. The first planning session was held in December 2005. For a pilot study on extemporaneous formulations, the initiative is seeking the participation of about 30 children’s hospitals in the United States and Canada. A detailed survey will include both inpatient and outpatient children, and will solicit financial information, determine the extent of use of and deviation from published formulations, and identify those drugs for which formulation stability data are needed. 

28 ADDRESSING THE BARRIERS TO PEDIATRIC DRUG DEVELOPMENT Dosing, bioavailability, and drug response When pediatric labeling information is lacking, pediatricians often refer to the available scientific literature to estimate dosing for children. If such studies exist, they are frequently based on very small, selected populations. Dr. Ward gave a neonatologist’s perspective on treating new- borns, whom he views as the most susceptible pediatric patients. He provided several examples of how pharmacokinetics and organ function (such as that of the heart and the kidneys) vary in important ways among a 23-week premature infant, a 30-week premature infant, and a 40-week full-term infant. He also cited studies that have revealed ethnic variations in the distribution of certain enzymes that cause faster or slower metabo- lism of drugs. Moving from dose guessing to informed prescribing will require additional studies of the pharmacokinetics, safety, and efficacy of new drugs and older, off-patent drugs. Those studies will need to be coupled with the study of developmental variations relevant to dosing, such as changes in drug clearance, during the first few months after birth and beyond. In responding to Dr. Ward’s presentation, Dr. Snodgrass described some shortcomings in the existing framework for pediatric drug use. Although the current system offers a good mechanism for testing on- patent drugs (see the discussion of this issue in Chapter 2), it falls short for older, off-patent drugs. With a common drug such as morphine, little information is available on optimal use and basic pharmacokinetics in different age groups. Dr. Snodgrass also expressed concern that pedia- tricians lack a good evidence-based reference for making prescription decisions. For example, there is disagreement on whether dosing should be based on weight or surface area. Dr. Snodgrass further suggested that dissemination of information to physicians could be improved so they can make the best choices in prescribing medications for individual patients. Finally, Dr. Snodgrass and others seconded Dr. Giacoia’s emphasis on the importance of the taste and formulation of a drug to adherence in pediatric patients—more so than is the case with adults. This section is based on the presentation of Dr. Robert Ward, Director, Pediatric Pharma- cology Program, University of Utah.