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THE RACE FOR CHILDREN ACT WILL CHANGE THE LANDSCAPE FOR
PEDIATRIC CANCER RESEARCH: ARE YOU READY FOR AUGUST 2020?
DAVID HO...
M A K I N G T H E C O M P L E X S E A M L E S S
AGENDA
• Pediatric Drug Development Regulatory Framework
• RACE for Childr...
RACE FOR CHILDREN ACT
PEDIATRIC ONCOLOGY REGULATORY
FRAMEWORK
M A K I N G T H E C O M P L E X S E A M L E S S
• Historically, only a small proportion of drugs were specifically labeled...
M A K I N G T H E C O M P L E X S E A M L E S S
• Best Pharmaceuticals for Children Act (BPCA) - FD&C Act Section 505A
‒ 1...
M A K I N G T H E C O M P L E X S E A M L E S S
• Pediatric Research Equity Act (PREA) – FD&C Act Section 505B
‒ 1998 Pedi...
M A K I N G T H E C O M P L E X S E A M L E S S
PEDIATRIC LABELING CHANGES
7
Bourgeois FT, Kesselheim AS. NEJM. 2019.
• US...
M A K I N G T H E C O M P L E X S E A M L E S S8
Jingjing Ye (OB, OTS, CDER, FDA), 3rd Stat4Onc Symposium; April 2019
M A K I N G T H E C O M P L E X S E A M L E S S
PEDIATRIC ONCOLOGY THERAPIES
• Adult oncology therapies are used to treat ...
M A K I N G T H E C O M P L E X S E A M L E S S
• RACE (Research to Accelerate Cures and Equity) for Children Act
• Incorp...
M A K I N G T H E C O M P L E X S E A M L E S S
PEDIATRIC ASSESSMENTS
• Requirement for pediatric assessments that generat...
M A K I N G T H E C O M P L E X S E A M L E S S
PEDIATRIC STUDY DESIGN CONSIDERATIONS
RELEVANT ICH/FDA GUIDANCE
12
M A K I N G T H E C O M P L E X S E A M L E S S
PEDIATRIC MOLECULAR TARGET LIST
• Developed by the FDA with input from the...
M A K I N G T H E C O M P L E X S E A M L E S S
PEDIATRIC MOLECULAR TARGET LIST
• Molecular target definition
• Substantia...
M A K I N G T H E C O M P L E X S E A M L E S S
PEDIATRIC MOLECULAR TARGET LISTS
GENE ABNORMALITY
15
https://www.fda.gov/m...
M A K I N G T H E C O M P L E X S E A M L E S S
PEDIATRIC MOLECULAR TARGET LISTS
GENE ABNORMALITY
16
https://www.fda.gov/m...
M A K I N G T H E C O M P L E X S E A M L E S S
PEDIATRIC MOLECULAR TARGET LISTS
GENE ABNORMALITY
17
https://www.fda.gov/m...
M A K I N G T H E C O M P L E X S E A M L E S S
PEDIATRIC MOLECULAR TARGET LISTS
CELL LINEAGE
18
https://www.fda.gov/media...
M A K I N G T H E C O M P L E X S E A M L E S S
PEDIATRIC MOLECULAR TARGET LISTS
TUMOR MICROENVIRONMENT AND IMMUNOTHERAPY
...
M A K I N G T H E C O M P L E X S E A M L E S S
PEDIATRIC MOLECULAR TARGET LISTS
OTHERS
20
https://www.fda.gov/media/12033...
M A K I N G T H E C O M P L E X S E A M L E S S
PEDIATRIC MOLECULAR TARGET LISTS
NOT RELEVANT - AUTOMATIC WAIVERS
21
https...
M A K I N G T H E C O M P L E X S E A M L E S S
TARGET LIST CONSIDERATIONS
• Studies could be required even if target is n...
M A K I N G T H E C O M P L E X S E A M L E S S
• Considerable challenges prioritizing products to study that share
same r...
M A K I N G T H E C O M P L E X S E A M L E S S
• Paradigm shift – Proactive consideration and integration of pediatric
de...
M A K I N G T H E C O M P L E X S E A M L E S S
Promote the access to and advancement of much
needed cancer therapies for ...
PEDIATRIC CANCER
CLINICAL TRIALS
OPERATIONAL CHALLENGES AND
CONSIDERATIONS
M A K I N G T H E C O M P L E X S E A M L E S S
CHILDREN ARE DISTINCT FROM ADULTS
• Vulnerable population
• Medical and re...
M A K I N G T H E C O M P L E X S E A M L E S S
SPECIAL PROTECTIONS: REGULATORY
• Additional federal regulations govern re...
M A K I N G T H E C O M P L E X S E A M L E S S
PERMITTED CATEGORIES FOR RESEARCH IN
CHILDREN 21 CFR 50 SUBPART D
29
Resea...
M A K I N G T H E C O M P L E X S E A M L E S S
• Parents:
‒ Ensure both are in agreement to enroll child
‒ IRB may allow ...
M A K I N G T H E C O M P L E X S E A M L E S S
CONSENT, ASSENT & RE-CONSENT
ADDRESS CONSENT, ASSENT AND RE-CONSENT IN SIT...
M A K I N G T H E C O M P L E X S E A M L E S S
• A child should re-consent to the study when:
‒ They are still participat...
M A K I N G T H E C O M P L E X S E A M L E S S
DESIGN CONSIDERATION
• Rare disease, small populations
‒ Large number of s...
M A K I N G T H E C O M P L E X S E A M L E S S
AGE CLASSIFICATION OF PEDIATRIC PATIENTS
34
Preterm newborn
infants
Term N...
M A K I N G T H E C O M P L E X S E A M L E S S
SITE AND INVESTIGATOR SELECTION
• Physician champion
‒ Well published, wel...
RECRUITMENT & RETENTION
IT’S A FAMILY AFFAIR
M A K I N G T H E C O M P L E X S E A M L E S S
• Parents need to be recruited first
• Children must give assent
‒ Accordi...
M A K I N G T H E C O M P L E X S E A M L E S S
WHO ARE THE STAKE HOLDERS?
INFLUENCES ON DECISION-MAKING
• Family relation...
M A K I N G T H E C O M P L E X S E A M L E S S
RECOMMENDATIONS
• Cast a wider net for engagement
• Develop age-appropriat...
M A K I N G T H E C O M P L E X S E A M L E S S
• Concierge services
‒ Facilitate family travel
• Meal tickets
• Sibling a...
PROTOCOL
ASSESSMENTS UNIQUE
TO CHILDREN
M A K I N G T H E C O M P L E X S E A M L E S S
ASSESSMENTS UNIQUE TO CHILDREN
• Critically review every line item on
sche...
M A K I N G T H E C O M P L E X S E A M L E S S
ASSESSMENTS UNIQUE TO CHILDREN
BUDGETING FOR ITEMS SPECIFIC TO PEDIATRIC R...
M A K I N G T H E C O M P L E X S E A M L E S S
• Sexual maturation
‒ Endocrinology
• Hormones measuring sexual maturation...
M A K I N G T H E C O M P L E X S E A M L E S S
• Cognitive development
‒ Neuropsychological testing
‒ School performance
...
M A K I N G T H E C O M P L E X S E A M L E S S
• Sedation and general anesthesia
‒ Imaging
• Most pediatric sites will re...
OTHER CONSIDERATIONS
M A K I N G T H E C O M P L E X S E A M L E S S
• Age appropriate dosage forms should be developed
very early
‒ Suspension...
M A K I N G T H E C O M P L E X S E A M L E S S
• Adherence
‒ Chronological and developmental age
• Able to swallow tablet...
M A K I N G T H E C O M P L E X S E A M L E S S
• IRBs will need to review amount of blood taken
‒ Percentage of total blo...
M A K I N G T H E C O M P L E X S E A M L E S S
• Choose pharmacokinetic (PK) techniques that minimize the number
of sampl...
M A K I N G T H E C O M P L E X S E A M L E S S
• Not as simple as going in a cup:
‒ Bag collection, cotton balls in diape...
M A K I N G T H E C O M P L E X S E A M L E S S
CHALLENGING ISSUES
• Pregnancy testing
• Contraceptive requirements
• Disc...
M A K I N G T H E C O M P L E X S E A M L E S S
SUMMARY
• Children are a vulnerable population and have unique regulatory
...
QUESTIONS
THANK YOU
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The RACE for Children Act Will Change the Landscape for Pediatric Cancer Research: Are you ready for August 2020?

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In this webinar, we explore the regulatory implications of the RACE for Children Act and what this law means for your development program, particularly with navigating the change in requirements for pediatric oncology trials. Furthermore, we explore the challenges of executing oncology trials in pediatric populations and offer insight into design and operational aspects to seamlessly execute these studies as part of your clinical development plan

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The RACE for Children Act Will Change the Landscape for Pediatric Cancer Research: Are you ready for August 2020?

  1. 1. THE RACE FOR CHILDREN ACT WILL CHANGE THE LANDSCAPE FOR PEDIATRIC CANCER RESEARCH: ARE YOU READY FOR AUGUST 2020? DAVID HORTON, PHD DIRECTOR, REGULATORY AFFAIRS MARGARET (PEGGY) KAISER, MSN, APRN, PPCNP-BC ADVANCED CLINICAL PRACTITIONER
  2. 2. M A K I N G T H E C O M P L E X S E A M L E S S AGENDA • Pediatric Drug Development Regulatory Framework • RACE for Children Act ‒ Purpose ‒ Key Elements ‒ Target Lists ‒ Key Implications and Considerations • Pediatric Cancer Clinical Trials – Operational Considerations ‒ Research Protections ‒ Design Considerations ‒ Site Selection Strategy ‒ Recruiting and Retaining Patients ‒ Assessments Unique to Children 2
  3. 3. RACE FOR CHILDREN ACT PEDIATRIC ONCOLOGY REGULATORY FRAMEWORK
  4. 4. M A K I N G T H E C O M P L E X S E A M L E S S • Historically, only a small proportion of drugs were specifically labeled for pediatric use • Widespread off-label prescribing by necessity ‒ Treat off-label or withhold/delay treatment? • Off-label prescribing dependent upon the best efforts/judgement of the clinician ‒ Little to no clinically meaningful data to base treatment decisions ‒ Treatment could be ineffective due to wrong dose, regimen, or formulation • Pediatric populations should have access to therapies that have been properly evaluated for pediatric use PEDIATRIC LEGISLATION THE PROBLEM 4
  5. 5. M A K I N G T H E C O M P L E X S E A M L E S S • Best Pharmaceuticals for Children Act (BPCA) - FD&C Act Section 505A ‒ 1997 FDA Modernization Act (FDAMA) • Introduced 6-month extension of market exclusivity • Sunset date of January 1, 2002 ‒ 2002 BPCA • Amended and reauthorized the exclusivity provision in FDAMA • FDA issues a Written Request for Sponsor to conduct studies ‒ Studies are performed and exclusivity is awarded, irrespective of outcome • Applies to all potential indications for the active ingredient, not just the adult indication being pursued • Oftentimes studies completed late, resulting in the off-label use of drugs in pediatric populations for many years without data • Process for obtaining and satisfying a WR from the FDA can be challenging, so participation is voluntary PEDIATRIC REGULATION - BPCA AND PREA THE CARROT AND THE STICK 5
  6. 6. M A K I N G T H E C O M P L E X S E A M L E S S • Pediatric Research Equity Act (PREA) – FD&C Act Section 505B ‒ 1998 Pediatric Rule • Invalidated in 2002 by Federal Court ‒ 2003 PREA • Established FDA authority to mandate pediatric studies • Initial pediatric study plan (iPSP) is required for all 505 FD&C and 351 PHS applications within 60 calendar days from the End-of-Phase 2 (EOP2) meeting ‒ Applies to new active ingredients, indications, dosage forms, new dosing regimens, and new routes of administration, except where waived or deferred • Generic and orphan drug products have been exempt • PREA and BPCA were reauthorized in 2007 (FDAAA); made permanent in 2012 (FDASIA) PEDIATRIC REGULATION - BPCA AND PREA THE CARROT AND THE STICK 6
  7. 7. M A K I N G T H E C O M P L E X S E A M L E S S PEDIATRIC LABELING CHANGES 7 Bourgeois FT, Kesselheim AS. NEJM. 2019. • US pediatric legislative initiatives have resulted in more than 770 labeling changes pertaining to children over the last 2 decades
  8. 8. M A K I N G T H E C O M P L E X S E A M L E S S8 Jingjing Ye (OB, OTS, CDER, FDA), 3rd Stat4Onc Symposium; April 2019
  9. 9. M A K I N G T H E C O M P L E X S E A M L E S S PEDIATRIC ONCOLOGY THERAPIES • Adult oncology therapies are used to treat cancers that are typically rare, or never occur in children (ie, exempt from PREA) • Development programs for pediatric oncology treatments were viewed as risky or unprofitable ‒ Smaller market - small # of cancer cases for children compared to adults ‒ Challenging study considerations • Adverse events could be greater in pediatric populations or unique in children compared to adults • Drugs for adults haven’t been tested or approved in children despite many targeted agents that could have effects in pediatric cancers due to the targets ‒ Advancement of precision cancer medicine ‒ Increased understanding of cancer etiology 9
  10. 10. M A K I N G T H E C O M P L E X S E A M L E S S • RACE (Research to Accelerate Cures and Equity) for Children Act • Incorporated as Title V of the FDA Reauthorization Act (FDARA) enacted August 18, 2017 • Does not change BPCA, but amends PREA ‒ Requires assessment of drugs and biologics that are “intended for treatment of adult cancers and directed at a molecular target substantially relevant to the growth or progression of a pediatric cancer” ‒ Eliminates orphan exemption for pediatric studies for oncology treatments directed at relevant molecular targets • Comes into effect August 18, 2020 ‒ Sponsors are required to submit iPSPs for marketing applications planning to be submitted after August 18, 2020 unless the PREA requirement is waived RACE FOR CHILDREN ACT TITLE V OF FDARA 2017 10
  11. 11. M A K I N G T H E C O M P L E X S E A M L E S S PEDIATRIC ASSESSMENTS • Requirement for pediatric assessments that generate “clinically meaningful study data” to inform potential pediatric labeling ‒ Preclinical data ‒ Appropriate formulation development ‒ Starting doses and dose regimens • Extrapolation approaches • Consider variability in physiological characteristics ‒ Pharmacodynamic endpoints ‒ Leverage adult safety, efficacy, PK data • Encourage early meetings with Sponsors on preparation of pediatric assessments and iPSPs 11
  12. 12. M A K I N G T H E C O M P L E X S E A M L E S S PEDIATRIC STUDY DESIGN CONSIDERATIONS RELEVANT ICH/FDA GUIDANCE 12
  13. 13. M A K I N G T H E C O M P L E X S E A M L E S S PEDIATRIC MOLECULAR TARGET LIST • Developed by the FDA with input from the National Cancer Institute and the pediatric research community ‒ Based upon published peer-reviewed literature, abstracts, public databases • Per the Oncology Center of Excellence Pediatric Oncology Program, the molecular target lists include: 1. Molecular targets for which existing evidence and/or biologic rationale exists to determine their potential relevance to the growth or progression of one or more pediatric cancers; and 2. Molecular targets for which there is evidence that they are not associated with the growth or progression of pediatric tumors for which requirement for early pediatric evaluation of drugs and biologics which are directed at these targets would be waived. 13 https://www.fda.gov/about-fda/oncology-center-excellence/pediatric-oncology
  14. 14. M A K I N G T H E C O M P L E X S E A M L E S S PEDIATRIC MOLECULAR TARGET LIST • Molecular target definition • Substantially Relevant Targets ‒ Gene Abnormality ‒ Cancer Cell Lineage ‒ Tumor Microenvironment or Immunotherapy ‒ Other • Not Relevant Targets • Frameworks for target classification ‒ Presence of Target ‒ Function or Mechanism of Target ‒ Nonclinical/Clinical Evidence ‒ Biomarkers ‒ Location of Target 14
  15. 15. M A K I N G T H E C O M P L E X S E A M L E S S PEDIATRIC MOLECULAR TARGET LISTS GENE ABNORMALITY 15 https://www.fda.gov/media/120331/download Oncology Center of Excellence Pediatric Oncology Program
  16. 16. M A K I N G T H E C O M P L E X S E A M L E S S PEDIATRIC MOLECULAR TARGET LISTS GENE ABNORMALITY 16 https://www.fda.gov/media/120331/download Oncology Center of Excellence Pediatric Oncology Program
  17. 17. M A K I N G T H E C O M P L E X S E A M L E S S PEDIATRIC MOLECULAR TARGET LISTS GENE ABNORMALITY 17 https://www.fda.gov/media/120331/download Oncology Center of Excellence Pediatric Oncology Program
  18. 18. M A K I N G T H E C O M P L E X S E A M L E S S PEDIATRIC MOLECULAR TARGET LISTS CELL LINEAGE 18 https://www.fda.gov/media/120331/download Oncology Center of Excellence Pediatric Oncology Program
  19. 19. M A K I N G T H E C O M P L E X S E A M L E S S PEDIATRIC MOLECULAR TARGET LISTS TUMOR MICROENVIRONMENT AND IMMUNOTHERAPY 19 https://www.fda.gov/media/120331/download Oncology Center of Excellence Pediatric Oncology Program
  20. 20. M A K I N G T H E C O M P L E X S E A M L E S S PEDIATRIC MOLECULAR TARGET LISTS OTHERS 20 https://www.fda.gov/media/120331/download Oncology Center of Excellence Pediatric Oncology Program
  21. 21. M A K I N G T H E C O M P L E X S E A M L E S S PEDIATRIC MOLECULAR TARGET LISTS NOT RELEVANT - AUTOMATIC WAIVERS 21 https://www.fda.gov/media/120329/download Oncology Center of Excellence Pediatric Oncology Program
  22. 22. M A K I N G T H E C O M P L E X S E A M L E S S TARGET LIST CONSIDERATIONS • Studies could be required even if target is not on list • Similarly, waivers can be granted even if targets are considered relevant ‒ Developmental toxicity issues • Serious risk/harm based upon preclinical data/toxicity profile ‒ Feasibility to conduct studies or ability to incorporate into other designs ‒ Products not “1st in class” • Additional pediatric studies not needed due to lack of substantial differences in efficacy, safety, PK, etc • Targets based upon totality of evidence – “substantially relevant” • Lists updated on regular basis – public workshops 22
  23. 23. M A K I N G T H E C O M P L E X S E A M L E S S • Considerable challenges prioritizing products to study that share same relevant molecular targets • Decision-making based upon: ‒ Target involvement – multiple diseases vs single disease ‒ MOA/overall profile ‒ Unmet medical need/potential public health impact ‒ Availability of therapy ‒ Availability of biomarker • Collaboration across industry and stakeholders ‒ Strategy forums TARGET LIST CONSIDERATIONS PRIORITIZATION 23
  24. 24. M A K I N G T H E C O M P L E X S E A M L E S S • Paradigm shift – Proactive consideration and integration of pediatric development within the overall drug development plan ‒ Formulation ‒ Dose ‒ Dosing regimen/considerations ‒ Nonclinical data • Appropriate animal models • Relevant pharmacology/toxicology assessments ‒ Biomarker development ‒ Adaptive trial designs • Early partnership with key stakeholders is critical! KEY DEVELOPMENT CONSIDERATIONS RACE FOR CHILDREN ACT 24
  25. 25. M A K I N G T H E C O M P L E X S E A M L E S S Promote the access to and advancement of much needed cancer therapies for children • Focus is not to increase number of Phase 1 Pediatric studies, but rather “accelerate appropriate initial pediatric evaluation earlier” • Collaboration of Sponsors with Regulators will be critical for effective development for therapies with relevant molecular targets • Integration of pediatric assessments in clinical development plans is key to generate clinically meaningful data SUMMARY RACE FOR CHILDREN ACT 25
  26. 26. PEDIATRIC CANCER CLINICAL TRIALS OPERATIONAL CHALLENGES AND CONSIDERATIONS
  27. 27. M A K I N G T H E C O M P L E X S E A M L E S S CHILDREN ARE DISTINCT FROM ADULTS • Vulnerable population • Medical and regulatory issues are different than adults • Potential for impacting physical and cognitive growth and development • Pediatric oncology and pediatric IRBs are by their very nature more conservative 27
  28. 28. M A K I N G T H E C O M P L E X S E A M L E S S SPECIAL PROTECTIONS: REGULATORY • Additional federal regulations govern research in children ‒ 21 CFR 50 Subpart D ‒ If more than minimal risk or a minor increase over minimal risk: • The risk is justified by anticipated direct benefits to the child • The risk-benefit profile is at least as favorable as any available alternatives • Who qualifies as a child? ‒ Be aware of local/regional laws for age of consent • Children are persons who have not attained the legal age for consent to treatments or procedure involved in the research, ‒ Under the applicable law of the jurisdiction in which the clinical investigation will be conducted 28
  29. 29. M A K I N G T H E C O M P L E X S E A M L E S S PERMITTED CATEGORIES FOR RESEARCH IN CHILDREN 21 CFR 50 SUBPART D 29 Research not involving greater than minimal risk Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects Sec 50.52 Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject’s disorder or condition Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serous problem affecting the health of welfare of children
  30. 30. M A K I N G T H E C O M P L E X S E A M L E S S • Parents: ‒ Ensure both are in agreement to enroll child ‒ IRB may allow one parent to sign informed consent (preferred) • Legally appointed guardians: ‒ Ensure that guardianship remit covers enrollment in clinical trials in addition to standard health care • Wards of a court (specifically defined only by the FDA) ‒ 21 CFR 50.56 • Allows children who are wards of the state or any other institution to be included in clinical investigations ‒ Under the conditions described CONSENT, ASSENT & RE-CONSENT WHO CAN GIVE INFORMED CONSENT? 30
  31. 31. M A K I N G T H E C O M P L E X S E A M L E S S CONSENT, ASSENT & RE-CONSENT ADDRESS CONSENT, ASSENT AND RE-CONSENT IN SITE TRAINING • Children at certain ages are required to give assent ‒ Assent is defined as a child’s affirmative agreement to participate in research • Age of assent is determined by each IRB ‒ Generally starts at 7 years of age • Assent documents should be written in age appropriate language ‒ For each age group defined by the IRB 31
  32. 32. M A K I N G T H E C O M P L E X S E A M L E S S • A child should re-consent to the study when: ‒ They are still participating and attain legal age • Generally 18 years of age in the US ‒ They are not still participating but previously collected samples are being utilized, or medical records are continuing to be reviewed • Add re-consent provisions to the monitoring plan Consent, assent & reconsent should be part of site training CONSENT, ASSENT & RE-CONSENT RE-CONSENT 32
  33. 33. M A K I N G T H E C O M P L E X S E A M L E S S DESIGN CONSIDERATION • Rare disease, small populations ‒ Large number of sites ‒ Global • Phase 1 ‒ 3+3 ‒ Rolling six • Developing a practical protocol will optimize successful completion of the study • Include age sub-groups as appropriate ‒ Monitoring for age-related differences in safety profile 33
  34. 34. M A K I N G T H E C O M P L E X S E A M L E S S AGE CLASSIFICATION OF PEDIATRIC PATIENTS 34 Preterm newborn infants Term Newborn (0-27 days) Infants & Toddlers (28 days to 23 months) Children (2 to 11 years) Adolescents (12 to 16-18 years) • Sexual maturation • Hormonal changes • Height • Neurocognitive development • Psychomotor development • Physical growth • Onset of puberty • Neurocognitive development • High body surface- area-to weight ratio • Immature blood brain barrier • Less predicable oral absorption • Immature hepatic and renal clearance • CNS maturation • Immune system development • Total body growth • Renal clearance • Heterogeneous group • Adjusted age • Immature renal and hepatic clearance • Immature CNS • Unique neonatal disease states • Small total blood volume .E11 Clinical Investigation of Medicinal Products in the Pediatric Population. FDA Dec.2000
  35. 35. M A K I N G T H E C O M P L E X S E A M L E S S SITE AND INVESTIGATOR SELECTION • Physician champion ‒ Well published, well-respected, key opinion leader • Sites ‒ Division director that will prioritize study ‒ Regional referral site for indication ‒ Start-up times are reasonable ‒ Dedicated pediatric cancer units and staff • Principal Investigators ‒ Expertise in indication ‒ National and international recognition ‒ Enthusiasm for trial ‒ Trained in clinical research or involved mentor 35
  36. 36. RECRUITMENT & RETENTION IT’S A FAMILY AFFAIR
  37. 37. M A K I N G T H E C O M P L E X S E A M L E S S • Parents need to be recruited first • Children must give assent ‒ According to IRB age specifications • Study information often needs to be shared with extended family • Grandparents may expect to be involved in the discussions with the investigator RECRUITMENT DIFFERENCES ADULTS VERSUS CHILDREN 37
  38. 38. M A K I N G T H E C O M P L E X S E A M L E S S WHO ARE THE STAKE HOLDERS? INFLUENCES ON DECISION-MAKING • Family relationships ‒ Child ‒ Parents ‒ Step-parents ‒ Grandparents ‒ Extended family members ‒ Friends • Health care providers ‒ Oncology physician ‒ Primary nurse ‒ Social worker • Community – Family cultural groups – Disease advocacy groups – Faith communities – Social agencies – Support groups – Court system 38
  39. 39. M A K I N G T H E C O M P L E X S E A M L E S S RECOMMENDATIONS • Cast a wider net for engagement • Develop age-appropriate flyers • Provide materials parents can share • Keep parents and sites updated on progress 39
  40. 40. M A K I N G T H E C O M P L E X S E A M L E S S • Concierge services ‒ Facilitate family travel • Meal tickets • Sibling activities • Gaming or movie devices available for long days on site • Make visits as convenient as possible ‒ Parent schedule ‒ Patient schedule (school, activities) ‒ Sibling’s schedules RECOMMENDATIONS FAMILY SUPPORT 40
  41. 41. PROTOCOL ASSESSMENTS UNIQUE TO CHILDREN
  42. 42. M A K I N G T H E C O M P L E X S E A M L E S S ASSESSMENTS UNIQUE TO CHILDREN • Critically review every line item on schedule of assessments ‒ “Eliminate any research procedures (as unnecessary) that do not contribute to scientific objective” [21 CR 56.111(a)(1)] • Align procedures to standard of care as much as possible ‒ Example: tumor biopsies • Your protocol is key to operational success ‒ Design specifically for pediatrics ‒ Involve stakeholders 42 Research test more than minimal risk No clinical benefit Not approved by IRB
  43. 43. M A K I N G T H E C O M P L E X S E A M L E S S ASSESSMENTS UNIQUE TO CHILDREN BUDGETING FOR ITEMS SPECIFIC TO PEDIATRIC RESEARCH • Physical growth and development measures ‒ Weight AND height measured at every visit ‒ Head circumference ‒ Growth curve measured on growth charts ‒ Bone age ‒ Standing/sitting height • Baseline assessment of organ function 43
  44. 44. M A K I N G T H E C O M P L E X S E A M L E S S • Sexual maturation ‒ Endocrinology • Hormones measuring sexual maturation for pre and post puberty ‒ Tanner staging ASSESSMENTS UNIQUE TO CHILDREN BUDGETING ITEMS SPECIFIC TO PEDIATRIC RESEARCH 44
  45. 45. M A K I N G T H E C O M P L E X S E A M L E S S • Cognitive development ‒ Neuropsychological testing ‒ School performance • Psychosocial development ‒ School attendance • Long-term effects ‒ Post-marketing surveillance ‒ Long-term studies may be needed ASSESSMENTS UNIQUE TO CHILDREN BUDGETING ITEMS SPECIFIC TO PEDIATRIC RESEARCH 45
  46. 46. M A K I N G T H E C O M P L E X S E A M L E S S • Sedation and general anesthesia ‒ Imaging • Most pediatric sites will require a sedation or general anesthesia (GA) slot for ages 6 and under ‒ May attempt non-sedation/GA imaging at 5-6 years of age ‒ Bone marrow aspirates and biopsies ‒ Lumbar puncture UNIQUE TO CHILDREN BUDGETING FOR ITEMS SPECIFIC TO PEDIATRIC RESEARCH 46
  47. 47. OTHER CONSIDERATIONS
  48. 48. M A K I N G T H E C O M P L E X S E A M L E S S • Age appropriate dosage forms should be developed very early ‒ Suspension ‒ Chewable tablets ‒ Small volume vials ‒ Long-acting formulations if possible • Dosing mg/kg body weight ‒ Some with narrow therapeutic index based on mg/m2 • Bioavailablity • Taste • Palatability • Stability • Excipients ‒ Adverse reactions not observed in adults DRUG FORMULATION PEDIATRIC CONSIDERATIONS 48
  49. 49. M A K I N G T H E C O M P L E X S E A M L E S S • Adherence ‒ Chronological and developmental age • Able to swallow tablets? • If liquid or suspension, what is the volume? ‒ Vomiting, spitting, hiding ‒ Refusing • Mixing with fruit juice, milk, food • Crushing tablets • Gastric tube and nasogastric tube administration • Schedule of administration ‒ Need to give at school? ‒ Additional paperwork and process for school administration of investigational products DRUG ADMINISTRATION PEDIATRIC CONSIDERATIONS 49
  50. 50. M A K I N G T H E C O M P L E X S E A M L E S S • IRBs will need to review amount of blood taken ‒ Percentage of total blood volume (TBV) • At any single point in time • Cumulative volumes over a define time period (i.e. 30 days) • WHO 2011 guidelines1: ‒ Widely accepted, but may not represent restrictions across all IRBs/ECs • Other considerations ‒ Number of “sticks” acceptable ‒ Number of entries into a central venous catheter ‒ Minimization of discomfort/pain and emotional distress PEDIATRIC BLOOD VOLUMES BLOOD VOLUMES RESTRICTED IN PEDIATRICS 50 1 Howie S. Blood sample volumes in child health research: review of safe limits. Bulletin of the World Health Organization. 2011; 89:46-53
  51. 51. M A K I N G T H E C O M P L E X S E A M L E S S • Choose pharmacokinetic (PK) techniques that minimize the number of samples • Utilize assays that require less blood volume • Prioritize which samples should be drawn first- in the protocol • Specify minimum volumes needed PEDIATRIC BLOOD VOLUMES STRATEGIES 51
  52. 52. M A K I N G T H E C O M P L E X S E A M L E S S • Not as simple as going in a cup: ‒ Bag collection, cotton balls in diaper ‒ Clean midstream catches challenging for toilet-trained children ‒ 24 hour urine collection may not be feasible for younger children PEDIATRIC ASSESSMENTS URINE COLLECTION 52
  53. 53. M A K I N G T H E C O M P L E X S E A M L E S S CHALLENGING ISSUES • Pregnancy testing • Contraceptive requirements • Discovering sensitive information ‒ Consent/assent form should describe plans for disclosure/non-disclosure to parents, legal authorities and to the patients themselves • For example sexual activity, sexually transmitted diseases, use of illegal substances, HIV status, child abuse • Fertility 53
  54. 54. M A K I N G T H E C O M P L E X S E A M L E S S SUMMARY • Children are a vulnerable population and have unique regulatory protections • Write protocol specifically for children ‒ Involve pediatric cancer experts and other stakeholders, including parents ‒ Align protocol assessments with standard of care ‒ Address potential affects on growth and development • Consider appropriate drug formulations early in program development ‒ Impact on administration and adherence • Choose experienced pediatric cancer sites and investigators • Consider the family in recruitment and retention strategies 54
  55. 55. QUESTIONS THANK YOU

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