Successful Pediatric Studies: Key Study Design and Site Selection Considerations

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The industry recognizes the importance of ensuring the safety and well‐being of children involved in research studies. Medical and regulatory bodies have worked to provide a framework to support appropriately designed studies through regulations and guidance documents in this vulnerable population. However, it is crucial to understand the nuances associated with pediatric trials, for the site, patient and family, in order to manage them to successful completion.

During the 2012 ACRP Annual Meeting, Dr. Charlene Sanders and Angi Robinson from Premier Research reviewed topics including the evaluation of study design considerations such as duration of treatment, required assessments, use of placebo, and inclusion of specific age groups; selection of appropriate sites for pediatric trials and the unique needs of these sites; identification of pediatric recruitment/retention hurdles and site specific strategies to overcome these as well as a reflection on ethical concerns related to pediatric research.

For more information, go to http://www.premier-research.com/pediatrics.

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Successful Pediatric Studies: Key Study Design and Site Selection Considerations

  1. 1. Successful Pediatric Studies: Key Study Design and Site Selection Considerations1 April 14, 2012 4:15 PM – 5:15 PM
  2. 2. Successful Pediatric Studies: Key Study Design and Site Selection Considerations Presented by Charlene Sanders, M.D. and Angi Robinson Premier Research April 14, 20122
  3. 3. Disclosure We have no relevant financial relationship in relation to this educational activity3
  4. 4. Research is Making a Difference Pediatric research has resulted in: More than products labeled with new pediatric information More than products with pediatric focused post labeling safety reviews Source: FDA website accessed on February 29, 20124
  5. 5. What Makes Pediatrics Different?5
  6. 6. Pediatrics does not deal with miniature men and women, with reduced doses and the same class of diseases in smaller bodies, but ... it has its own independent range and horizon and gives as much to general medicine as it receives from it - Abraham Jacobi, 18896
  7. 7. Pediatric Subpopulations Each age group is considered an indication Pre-term Newborns Infants & toddlers Children Adolescents newborns 27 days 28 days to 23 months 2 to 11 years 12 to 16-18 years7
  8. 8. Age Appropriate Formulations Consider age, physical development, illness, dosage, dosing frequency, treatment duration, and route of administration Need pediatric formulations that are: • Easy to both administer and swallow • Acceptable in taste and volume • Appropriate in dosage and strength • Tolerable with minimal and safe excipients • Adequate bioavailability • Less frequent administration8
  9. 9. Age Appropriate Formulations Children will refuse an unpleasant formulation Foster compliance by delivering formulations with an acceptable taste Poor compliance increases the risk of therapeutic failure and emergence of resistances Need to ensure safe and precise administration Foster compliance with an easy administration Provide appropriate dosing/administration devices Important to have child-proof container for product9
  10. 10. Plant the SEED to Succeed! Scientifically meaningful Need scientifically rigorous protocols Ethical Need special protections with this vulnerable populations Enrollable Need protocols that are patient and family friendly Directed Need appropriate sites and targeted patient recruitment strategies10
  11. 11. Scientifically Meaningful Study Design11
  12. 12. Study Design Why up to 50% of pediatric studies fail: Not well defined PK–PD Small sample or pediatric correlations that size, low relevant are not enrollment endpoints established Incorrectly Ethical identified Feasibility constraints in dosages for issues protocol efficacy studies development12
  13. 13. Pediatric Study Design Protocols need to be designed specifically for the population and not simply re-worked from adult protocols → Design must be customized for the specific populations → Primary endpoint in children may be different or even inappropriate in adults → Developmental variability should be considered in inclusion criteria, sample size calculations, and analysis → Study design must be realistic for families to commit Unsuitable designs will lead to slow enrollment and low retention resulting in higher costs and approval delays13
  14. 14. Traditional vs. Population PK Sampling Traditional PK Population PK Approach is to conduct a study Approach requires a larger of single or multiple doses of number of subjects and the drug in a small number of utilizes infrequent or sparse subjects with relatively sampling frequent blood sampling While current FDA and ICH recommendations do not indicate which method should be used, they do describe the population PK methodology as a useful technique to minimize the number of samples obtained from each patient14 Guidance for Industry: E11 Clinical Investigation of Medicinal Products in the Pediatric Population, Dec 2000.
  15. 15. FDA Guidance for Pediatric Studies Pediatric Study Decision Tree - Integration of PK-PD Reasonable to assume (pediatrics vs. adults) • Similar disease progression? • Similar response to intervention? NO YES TO BOTH • Conduct PK studies Reasonable to assume similar • Conduct safety/efficacy trials concentration-response (C-R) in pediatrics and adults? NO NO YES Is there a PD measurement that can be used to predict efficacy? • Conduct PK studies to achieve levels similar to adults YES • Conduct safety trials • Conduct PK studies to get C-R for PD measurement • Conduct PK studies to achieve target concentrations based on C-R • Conduct safety trials Guidance for Industry: Exposure-Response Relationships — Study15 Design, Data Analysis, and Regulatory Applications, April 2003.
  16. 16. Use of Placebo Use of placebo typically more restricted in pediatric trials simply because children cannot consent While not ideal, the use of a placebo may be acceptable if there is no approved or adequately studied therapies Placebo use has to be justified scientifically and ethically16
  17. 17. Use of Placebo It is important to minimize placebo exposure: Number of Study subjects duration Need Randomization pre-defined ratio discontinuation criteria17
  18. 18. Pediatric Specific Endpoints/Follow-up Physiological Measures and Benchmarks • Weight • Height • Thyroid hormone, Insulin-like growth factor-1 (IGF-1) • Skeletal growth • Sexual maturation Development and Cognitive function (short and long-term effects) • Attention, memory and learning • Language skill18
  19. 19. Pediatric Specific Endpoints/Follow-up Behavioral and Psychological Maturation/Milestones • Child Behavioral Checklist (CBCL) • Quality of Life, school performance, etc. • Infants and young children – mental, motor and behavioral development • Neonates – known complications and effects of prematurity19
  20. 20. Duration of Treatment, Follow-up, and Retention → Long-term treatment or recurrent treatment may necessitate: – Tracking of growth and development changes – Potential need for patient to sign multiple assent forms/consent form over time → Outline process for study drug delivery during school days, with alternate caregivers, etc… → Working parents and school attendance issues will present additional practical problems20
  21. 21. Ethical Considerations and Special Protections21
  22. 22. Special Protections in Pediatric Research Need for special protections in vulnerable populations is mandated by regulations, enacted by: Assent/ IRB assessment Data Safety Parental of research risk Monitoring Permission category Boards (DSMBs) process Treatment Limiting use of continuity after placebos clinical study22
  23. 23. Ethical Considerations Ethics of conducting pediatric research has not been studied as extensively as ethics of adult research Pediatric research means decision- making for another and involves more than just the patient Potential risks and inconvenience are accepted by parent, but may affect child, siblings, and parents23
  24. 24. Ethical Questions to Consider Is it ethical to enroll children in: Poorly designed studies? – According to FDA, 50% of all pediatric studies are not interpretable24
  25. 25. Ethical Questions to Consider Is it ethical to enroll children in: Studies without the possibility of direct benefit? – Normally only allowed if risk is low – Should have access to necessary health care after being enrolled in a clinical trial – Rules and definitions differ by country • Non-therapeutic studies in children are not allowed in some countries • Definition of low risk varies by country25
  26. 26. Potential Ethical Conflicts in Pediatric Research Weighing of ethical principles is integral part of process Beneficence Autonomy, Self-Determination Potential or real benefit to child vs. Child’s dissent Justice Beneficence Potential or real benefit to child vs. Potential costs or harms to other family members Beneficence, Justice Non-maleficence Possibility of obtaining information vs. Potential risk to child that could benefit many Privacy, Confidentiality Non-maleficence Drug testing, vs. Potential harm from researcher pregnancy testing results not reporting risky behavior26
  27. 27. Enrollable Protocols27
  28. 28. Child Friendly Study Procedures Minimize intensity and frequency of the study assessments • Limit number and volume of blood draws – coincide the collection of protocol-specified blood samples with routine clinical samples • Limit invasive procedure as much as possible Minimize pain and distress • Use topical anesthesia, butterfly needles, pediatric sampling tubes • Indwelling catheters rather than repeated venipunctures for blood sampling28
  29. 29. Child Friendly Study Procedures In addition: • Handle pregnancy testing in minors with care • Consider not only the child but also the parents and siblings when planning the frequency and length of visits/assessments29
  30. 30. Drug Administration Considerations Dosing is more difficult to manage than in adults: • Often based on experience in adults and weight/BSA • Titration rates and AE monitoring need to be carefully evaluated • Administration of investigational product can pose problems Timing of dosing can also be a challenge: • Issues with dosing in school-age children • Strict dosing times may be difficult to adhere to30
  31. 31. Directed and Executable31
  32. 32. Operational Considerations for Pediatric Investigative Site Selection In general, use same principles as selecting sites for adult trials: Access to Degree of Expertise and adequate interest number of experience expressed appropriate by the site patients Facilities need appropriate Consider using equipment/ a Pediatric activities to Research accommodate Network32 children/families
  33. 33. Medical Considerations for Pediatric Investigative Site Selection • Absolutely MUST have person experienced in pediatric lab draws • Depending on protocol, may also need personnel with expertise in catheterizing small children, pediatric IV starts, placing pediatric NG tubes, etc. • Sites that are not pediatric based must have access to resources needed for the pediatric population33
  34. 34. Enrollment Strategies Conduct studies in familiar environments such as hospital or clinic where participants normally receive their care Support on site and off site activities Be mindful of age specific issues34
  35. 35. Enrollment Strategies Each age group has it own issues with enrollment Babies and toddlers Consider naptimes Young children The use of cartoons to explain the study may be useful for younger patients (some countries are requiring pictorial information sheets for young children) School age Time missed from school may be important factor Teenagers Teenage girls may decline to participate once they learn that a pregnancy test is required35
  36. 36. Enrollment Strategies Avoid coercion or even its appearance Advertisements • Consider different media – TV, radio, internet, parenting publications, etc. • Ads need to target the parent, not the child • Not always appropriate Payments • Reimbursements for travel expenses may be better approach • AAP recommends to not disclose payment/reimbursement information to children until they have completed the study36
  37. 37. Enrollment Strategies Siblings are frequently brought along to study appointments distracting both the parents and patients This can cause: • Missed reporting of AEs and con meds • Potentially incorrect responses on questionnaires • Early termination if siblings are not made to feel welcome37
  38. 38. Enrollment Strategies Plan to address this with: 1 Secure area for siblings to wait Personnel or family/friends available to “babysit” 2 younger children during study visits 3 DVD player with children’s movies/shows 4 Snacks for longer visits Making siblings feel welcome and parents 5 comfortable with their decision to bring them38
  39. 39. Pediatric Assent/Parental Permission Plan in advance whether and how pediatric assent will be solicited and have trained personnel obtain this Considerations for forms: • In most cases it is appropriate to have one or more assent forms separate from parental permission form • Assent forms need to be aimed at the appropriate reading grade level for the youngest person who will sign39
  40. 40. Retention Strategies Make sure stipend is Provide resource appropriate and families materials for patients are compensated for and families expenses associated with child’s participation Appointment reminder Close, ongoing review of and missed appointment discontinuation reasons postcards, emails or (one-page retention questionnaire to help determine text messages reason for withdraws)40
  41. 41. Retention Strategies Consider appropriate strategies for the different age groups and indications Example: For adolescents, Example: Depending on consider a study subject indication, conduct a blog; this group loves webcast with famous technology and it is person with condition appealing to communicate including education with other kids around segment and ability to the country who also have submit questions the same condition41
  42. 42. Retention Strategies Incentive/Rewards • For milestone achievements, depending on age consider reward certificate with 10 free music downloads or movie theatre passes • Organizer folder/portfolio with place to carry medication to and from visits that includes calendar with stickers for appointments as well as books and materials to educate on condition and making living with it not only possible, but FUN!! • Family incentives such as a refrigerator magnet with notepad or calendar42
  43. 43. Retention Strategies Parent/guardian support is vital to retention and compliance with visits and drug administration Must remove barriers to trial participation including: • Clear instructions for drug administration and compliance • Difficult visit schedules – include appropriate windows • Scheduling – parent’s job, school attendance, nap times • Transportation costs43
  44. 44. Take Home Message With experience, pediatric studies can be easy as PIE Protocol Need scientifically rigorous protocols that are also child/parent friendly Investigators Choose sites that can handle issues unique to pediatric studies Enrollment and retention Develop parent-targeted recruiting/enrollment strategies Maximize compliance/retention using child-specific strategies44
  45. 45. Charlene Sanders, M.D. Vice President, Global Regulatory Affairs & Pediatric Strategic Consulting Email: charlene.sanders@premier-research.com Phone: 215.282.5500 Angi Robinson Executive Director, Clinical Trials Management Email: angi.robinson@premier-research.com Phone: 215.282.5500 www.premier-research.com45

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