CTSA Consortium Pediatric Drug and Medical Device Development Workshop February 26, 2009

1. CTSA Consortium Pediatric Drug and Medical Device Development Workshop February 26, 2009 Summary, Recommendations, & Next Steps Draft by: CC-CHOC Drugs & Devices Workgroup Leadership

2. Recommendations and Key Points Overview of CTSA Program as Framework for Expectations Key Points: • The CTSAS are a national consortium of academic health centers that enable and support transformative clinical research across the lifespan, including pediatric research • The clinical research infrastructure provided through the CTSAS can provide an anchor for development of effective partnerships to efficiently and effectively develop drugs and medical devices that meet the needs of children

3. Recommendations and Key Points Purpose, Vision and Expected Outcome To formulate a set of specifications for a national child health clinical research infrastructure to effectively and efficiently develop drugs and medical devices for children

4. Recommendations and Key Points Current Status of US Pediatric Clinical Research Infrastructure Key Points: • Based on inventory of US pediatric clinical research networks & interviews conducted Feb – July 2007, overarching concern of insufficient pediatric drug trial capacity. Reasons are many: • No systematic way to find, incentivize, & maintain pediatric clinical trial sites • Complexity/demands of conducting drug trials in clinical settings • Scarcity of qualified pediatric investigators capable of conducting GCP-quality studies • Clinical drug trial protocol designs that discourage pediatricians & parents from participating • Highly fragmented infrastructure with systematic lack of communication between disciplines • Absence of use of standards to support interoperability

5. Pediatric Clinical Research Infrastructure Recommendation(s): As a first step, • Urgent need to train clinical investigators in conducting GCP-quality trials, train or recruit study support personnel with sensitivity to pediatric/family issues, train protocol writers, and pediatric clinical pharmacologists • Bring together stakeholders, experts, & key decision makers to define priorities for a pediatric product development infrastructure

6. Recommendations and Key Points Panel 1: European Investigators Perspective on Pediatric Medical Product Development Lessons learned: • Be proactive • Legislation predicted the need for a platform to conduct pediatric studies. The contacts & networking among investigators were do-able in advance • Be responsive • Be prepared to respond rapidly & thoughtfully if presented with a drug development proposal • Be collaborative & inclusive • In-country networks often include significant percentages of all practicing pediatricians; most do not consider research their 1o occupation. Able to “deliver the patients” • Be international • Multinational networks: Limited numbers of pediatric patients • Avoid duplication: Be aware of ongoing & prior studies Additional Recommendation(s): • Ensure that all research for drug development is GCP • Harmonize human subject protection processes across networks • Develop a culture of research participation

7. Recommendations and Key Points Panel 2: US Regulatory Framework for Pediatric Drug & Devices • Trial design, implementation and data quality must meet FDA standards • Multiple Federal programs to facilitate and encourage pediatric studies with resultant increase in products with pediatric labeling • Extrapolation may be used to decrease resource burden for demonstrating efficacy but not safety • Different product types have different regulations and expectations • Orphan product development for rare diseases has additional FDA support including a funding option • FDA regulations that pertain to human subject protections for children differ from OHRP regulations • Monitoring of studies must be independent of the study team, risk based and responsive to problem identification • Pediatric studies have unique challenges that require international cooperation. FDA has specific collaboration with European Medicines Agency for information sharing and harmonization.

8. U.S. Regulatory Recommendation(s): • Importance of compliance with GCP in conduct of clinical trials • Need for education of clinical investigators about GCP, record-keeping, quality control, & FDA audits • Need to understand the difference between clinical trials acceptable to for publication and trials conducted to fulfill regulatory requirements • Pediatric product development requires a global perspective • Need to better understand a drug or device label • As a legal document • Substantial evidence

9. Recommendations and Key Points Panel 3: Perspective of Large Pharmaceutical Companies What pharmaceutical companies would like a CTSA network • Expert scientific input into protocols, product development plans, & translational technologies such as novel PK assessments • High quality data and adherence to applicable standards and regulations • Coordination among sites, particularly across borders • Ease and transparency addressing legal issues, cost accounting and data access • Access to patients and networks, recruitment & retention • Framing research in the most acceptable manner to patients and communities • Rapid and responsive IRB review • Access to core facilities • Better understanding of IP and business models

10. Large Pharmaceutical Recommendations Recommendation(s): • Educate clinical investigators in principles of regulatory compliant data quality and monitoring • A well-run study is in everyone’s best interest • Demonstrate value-added in business model • Justify “expensive” pediatric trials. Adhere to timelines. Be willing to pool resources if appropriate (research nurse, study coordinator) • Understand & negotiate IP, data sharing and publication issues up front • Public arguments after-the-fact are in no one’s interest

11. Recommendations and Key Points Panel 4: What do Biotech Companies expect & what can they offer? What Biotech needs from CTSA academic researchers • Generally concur with points made by PHRMA colleagues • Small biotech firms have more limited resources & therefore a greater need for assistance in: • Developing & validating endpoints appropriate to children • Developing & validating translational technologies & cores • Developing & maintaining pediatric networks and registries • Developing & maintaining specialized pediatric centers (e.g. PPRU) Small Biotech companies financially vulnerable and may need assistance in identifying other sources of funding to cover development costs What Biotech can offer: • Small biotech companies can be ideal partners • More nimble with business model, better able & willing to address the needs of pediatric populations through developing targeted therapies for limited patient populations

12. Recommendations and Key Points Panel 5: What do Device Manufacturers expect & what they can offer? General needs that are not CTSA-specific: • Development platform that will assist in: • Determining future market share of proposed medical device • Selecting the appropriate regulatory pathway (510K vs. PMA) • Identifying & applying for sources of funding Potentially CTSA-related needs: • Assistance with identifying & recruiting pediatric patient population • Infrastructure for device registries for initial post-market surveillance What can device manufacturers offer: • Business model in which it is feasible to develop a highly specialized product to meet the needs of a small group of pediatric patients • Technical expertise & willingness to partner in developing prototype devices under a “pilot grant” mechanism

13. Recommendations and Key Points Panel 6: What do advocacy and patient/parent groups expect and what they can offer? Key observations made by panel: • There is a widespread misperception that pediatric clinical trial subjects are rare or unavailable. From the patient advocacy standpoint, there are many parents who wish to enroll their children, but are unable to locate a clinical trial for which they qualify • The answer to the most daunting recruitment or retention challenge may be as simple as knowing the right question to ask • Consider who might be the responsible party for administering a TID drug under IND to a school age child • Sensitivity to pediatric/family issues such as transportation, time out of work, complexity of regimen and assessments, availability of nursing and social work support • Emotional stakes may be higher for pediatric clinical trials, beginning with whether or not child meets inclusion/exclusion criteria • Emotional impact of being told a child is “not qualified” for study • Considering the balance between quantity and quality of treatment and life experience • Feasibility of studies can be improved if parents are invited to participate in protocol development

14. Parents and Advocates Recommendation(s): • There is a need for a “matchmaker” to align willing pediatric clinical trial participants with representatives of pediatric clinical trials that are recruiting subjects • There is a compelling need for greater pediatric/family issue sensitivity throughout the clinical trials process. A dedicated “patient/family advocate” is worth considering

15. Recommendations and Key Points Panel 7: What do non-profit organizations and academic investigators expect and what can they offer? What can they offer? • A model of pediatric medical device development as a regional hub anchored by an academic children’s hospital, a regional medical leadership, a regional technology community, entrepreneurs, & investors What do they need from the CTSA consortium? • Partnership for developmental collaborations & clinical trials • Pilot grants to establish early “proof of concept” • Existing clinical trials networks offer an infrastructure to conduct mid & late phase clinical trials • Infrastructure to conduct post-marketing surveillance to improve safety Recommendations: • Inventor/entrepreneur education program including handling & protecting IP, device development, business relationships/investments, clinical testing

16. Overall Conclusions & Next Steps Infrastructure for pediatric clinical trials for drug & device development is insufficient & fragmented • First step today has been to assemble the key stakeholders, experts, & decision makers to define priorities Complex and redundant regulatory & legal requirements • Next steps: Webinar on alternative IRB models for multi-site pediatric clinical trials to be held April 23, 2009 Need for training in understanding of regulatory compliance for data monitoring and submission. • Next steps: Training in regulatory compliance for data monitoring and submission for clinical investigators to be held on NIH campus as trans-NIH event September 2009 with follow up development of on-line training modules Need for systematic identification of needs and opportunities • Next steps: Prioritization process meeting for pediatric pharmaceuticals & medical devices to be held on NIH campus October 2009