December 15, 2016 Navigating the Regulatory Requirements of Pediatric Research Nathan Lee, CIP Vice Chair, Schulman IRB
About Schulman IRB Established in 1983 Superior audit history with FDA five consecutive audits with no findings 21 CFR Part 11 compliant electronic systems Compliant with FDA, OHRP and Health Canada requirements Full Board meetings five days a week Dedicated daily expedited review of qualifying minimal risk protocols
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About Today s Presenter Nathan Lee, CIP Vice Chair, Schulman IRB With Schulman since 2007 Responsible for chairing IRB meetings and conducting expedited reviews Assists in leading Conflict of Interest and Board Education committees
Navigating the Regulatory Requirements of Pediatric Research
Objectives Identify and describe Subpart D regulations under FDA and HHS Analyze IRB s process for reviewing research in a pediatric population Discuss IRB s application of component analysis Describe regulatory basis for assent and parental consent requirements
Regulations Benefit No Benefit Minimal Risk 21 CFR 50.51 / 45 CFR 46.404 Greater than Minimal Risk 21 CFR 50.52 / 45 CFR 46.405 21 CFR 50.53 / 45 CFR 46.406 21 CFR 50.54 / 45 CFR 46.407
Regulations Benefit No Benefit Minimal Risk 21 CFR 50.51 / 45 CFR 46.404 Greater than Minimal Risk 21 CFR 50.52 / 45 CFR 46.405 21 CFR 50.53 / 45 CFR 46.406 21 CFR 50.54 / 45 CFR 46.407
Regulations Benefit No Benefit Minimal Risk 21 CFR 50.51 / 45 CFR 46.404 Greater than Minimal Risk 21 CFR 50.52 / 45 CFR 46.405 21 CFR 50.53 / 45 CFR 46.406 21 CFR 50.54 / 45 CFR 46.407
Regulations "Minimal risk" means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests Whose experience of minimal risk?
Regulations Category 1 50.51 46.404 Research not involving greater than minimal risk Category 2 50.52 46.405 Category 3 50.53 46.406 Category 4 50.54 46.407 Research involving greater than minimal risk But presenting prospect of direct benefit to individual subjects Research involving greater than minimal risk and no prospect of direct benefit to individual subjects But likely to yield generalizable knowledge about subjects disorder or condition Research not otherwise approvable Presents an opportunity to understand, prevent or alleviate a serious problem affecting health or welfare of children
Regulations Category 1 50.51 46.404 Research not involving greater than minimal risk Category 2 50.52 46.405 Category 3 50.53 46.406 Category 4 50.54 46.407 Research involving greater than minimal risk But presenting prospect of direct benefit to individual subjects Research involving greater than minimal risk and no prospect of direct benefit to individual subjects But likely to yield generalizable knowledge about subjects disorder or condition Research not otherwise approvable Presents an opportunity to understand, prevent or alleviate a serious problem affecting health or welfare of children
Regulations Category 1 Research not involving greater than minimal risk Eligible pediatric protocols may be reviewed via expedited review Examples Chart review Single finger stick Standard personality assessments Blood draws (under certain restrictions)
Regulations Category 2 Research involving greater than minimal risk but presenting prospect of direct benefit to individual subjects Additional considerations/requirements Risk is justified by the anticipated benefits to the subjects Relation of the anticipated benefit to the risk Examples Some organ biopsies Administration of investigational drug Certain imaging studies
Regulations Category 3 Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about subjects disorder or condition Additional considerations/requirements Minor increase over minimal risk Experiences to child subjects that are reasonably commensurate To yield generalizable knowledge Examples Skin punch biopsy with topical pain relief Urine via catheter
Regulations Category 4 Research not otherwise approvable which presents an opportunity to understand, prevent or alleviate a serious problem affecting health or welfare of children Additional considerations/requirements Refer to FDA or HHS for review May determine Category 1, 2, or 3 Receives review by panel of experts Offers opportunity for public review Examples Bone marrow obtained for genetic testing or future research Extending sedation time for nonclinical MRI
Regulations Category Category 1 2 Research not involving greater than minimal risk Research involving greater than minimal risk But presenting prospect of direct benefit to individual subjects Category 3 Research involving greater than minimal risk and no prospect of direct benefit to individual subjects But likely to yield generalizable knowledge about subjects disorder or condition
Putting It Together A researcher is attempting to validate a flu symptom questionnaire in a group of children between 12 and 16 years of age. Which regulatory category applies? Category 1 Research not involving greater than minimal risk Category 2 Research involving greater than minimal risk but presenting prospect of direct benefit to individual participants Category 3 Research involving greater than minimal risk and no prospect of direct benefit to individual subject, but likely to yield generalizable knowledge about subjects disorder or condition Category 4 Research not otherwise approvable that presents an opportunity to understand, prevent or alleviate a serious problem affecting the health or welfare of children
Putting It Together A researcher is attempting to validate a flu symptom questionnaire in a group of children between 12 and 16 years of age. Which regulatory category applies? Category 1 Research not involving greater than minimal risk Category 2 Research involving greater than minimal risk but presenting prospect of direct benefit to individual participants Category 3 Research involving greater than minimal risk and no prospect of direct benefit to individual subject, but likely to yield generalizable knowledge about subjects disorder or condition Category 4 Research not otherwise approvable that presents an opportunity to understand, prevent or alleviate a serious problem affecting the health or welfare of children
Putting It Together Single arm study of investigational oral flu preventative drug in healthy children between 12 and 16 years of age includes physical exam, administration of the IP and flu symptom questionnaire Which regulatory category applies? Category 1 Research not involving greater than minimal risk Category 2 Research involving greater than minimal risk but presenting the prospect of direct benefit to individual participants Category 3 Research involving greater than minimal risk and no prospect of direct benefit to individual subject, but likely to yield generalizable knowledge about the subjects disorder or condition Category 4 Research not otherwise approvable that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children
Putting It Together Single arm study of investigational oral flu preventative drug in healthy children between 12 and 16 years of age includes physical exam, administration of the IP and flu symptom questionnaire Which regulatory category applies? Category 1 Research not involving greater than minimal risk Category 2 Research involving greater than minimal risk but presenting the prospect of direct benefit to individual participants Category 3 Research involving greater than minimal risk and no prospect of direct benefit to individual subject, but likely to yield generalizable knowledge about the subjects disorder or condition Category 4 Research not otherwise approvable that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children
Parental Consent Defined as agreement...to participation of child...in clinical investigation 50.3(r), 46.402(c) See 50.55 and 46.408 One parent consent requirement Category 1 and Category 2 Two parent consent requirement Category 3 and Category 4 Defining reasonably available for two parent consent can be difficult
Did the IRB approve as risk category 3? Is 2 nd parent deceased? No Yes No Yes Complete consent process with 1 parent s signature Is 2 nd parent incompetent? No Does 1 st parent have sole legal custody of the child? (i.e. court has granted decision making power solely to 1 parent) Yes No Is 2 nd parent unknown? (e.g. father has not established paternity) No Is 2 nd parent not reasonably available? (Not reasonably available = not contactable by phone, mail, email, fax, etc.) No Yes Yes Complete consent process with both parents signatures
Parental Consent HHS regulations (not FDA) allow for waiver of parental permission Certain minimal risk studies Other very specific studies HHS and FDA allow for waiver of documentation of consent for certain minimal risk research
Child Assent Regulations require the assent of a child, when possible Children cannot consent to participate in research Documentation of assent is not a regulatory requirement Schulman s assent guidelines: Age Assent Documentation of Assent Infant to 6 years Waived Waived 7 to 11 years Yes Separate assent document 12 to age of majority Yes Sign an assent line of parent consent Consideration should be made for minors that become adults
Component Analysis To determine the overall acceptability of the research, the risk and anticipated benefit of activities described in a protocol must be evaluated individually as well as collectively. The National Commission, 1978 Evaluate a protocol by its interventions and procedures Differs from overall risk analysis
Component Analysis Interventions or procedures that Offer prospect of direct benefit Should be reviewed under Category 2 Do not offer prospect of direct benefit Should be reviewed under Category 1 or Category 3 Placebo arm of a study cannot be considered under Category 2 Component analysis will impact signature requirements
Putting It Together Randomized, placebo-controlled study of investigational oral flu preventative drug in healthy children between 12 and 16 years of age includes physical exam, administration of the IP (or placebo), 2 nasopharyngeal swabs, and flu symptom questionnaire Using a component analysis, which regulatory category applies for the IP arm? Category 1 Research not involving greater than minimal risk Category 2 Research involving greater than minimal risk but presenting the prospect of direct benefit to individual participants Category 3 Research involving greater than minimal risk and no prospect of direct benefit to individual subject, but likely to yield generalizable knowledge about the subjects disorder or condition Category 4 Research not otherwise approvable that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children
Putting It Together Randomized, placebo-controlled study of investigational oral flu preventative drug in healthy children between 12 and 16 years of age includes physical exam, administration of the IP (or placebo), 2 nasopharyngeal swabs, and flu symptom questionnaire Using a component analysis, which regulatory category applies for the IP arm? Category 1 Research not involving greater than minimal risk Category 2 Research involving greater than minimal risk but presenting the prospect of direct benefit to individual participants Category 3 Research involving greater than minimal risk and no prospect of direct benefit to individual subject, but likely to yield generalizable knowledge about the subjects disorder or condition Category 4 Research not otherwise approvable that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children
Putting It Together Randomized, placebo-controlled study of investigational oral flu preventative drug in healthy children between 12 and 16 years of age includes physical exam, administration of the IP (or placebo), 2 nasopharyngeal swabs, and flu symptom questionnaire Using a component analysis, which regulatory category applies for the placebo arm? Category 1 Research not involving greater than minimal risk Category 2 Research involving greater than minimal risk but presenting the prospect of direct benefit to individual participants Category 3 Research involving greater than minimal risk and no prospect of direct benefit to individual subject, but likely to yield generalizable knowledge about the subjects disorder or condition Category 4 Research not otherwise approvable that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children
Putting It Together Randomized, placebo-controlled study of investigational oral flu preventative drug in healthy children between 12 and 16 years of age includes physical exam, administration of the IP (or placebo), 2 nasopharyngeal swabs, and flu symptom questionnaire Using a component analysis, which regulatory category applies for the placebo arm? Category 1 Research not involving greater than minimal risk Category 2 Research involving greater than minimal risk but presenting the prospect of direct benefit to individual participants Category 3 Research involving greater than minimal risk and no prospect of direct benefit to individual subject, but likely to yield generalizable knowledge about the subjects disorder or condition Category 4 Research not otherwise approvable that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children
Putting It Together Randomized, placebo-controlled study of investigational oral flu preventative drug in healthy children between 12 and 16 years of age includes physical exam, administration of the IP (or placebo), 2 nasopharyngeal swabs, and flu symptom questionnaire Using a component analysis, which regulatory category applies for the placebo arm? Category 1 Research not involving greater than minimal risk Category 2 Research involving greater than minimal risk but presenting the prospect of direct benefit to individual participants Category 3 Research involving greater than minimal risk and no prospect of direct benefit to individual subject, but likely to yield generalizable knowledge about the subjects disorder or condition Category 4 Research not otherwise approvable that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children
The PICC Study Multinational, placebo-controlled study of an investigational product in children 2 to 7 years old IP (or placebo) administered (double blind) by IV infusion over 4 hours each day for 14 days Used a peripherally inserted central catheter to facilitate infusion
The PICC Study Multinational, placebo-controlled study of an investigational product in children 2 to 7 years old IP (or placebo) administered (double blind) by IV infusion over 4 hours each day for 14 days Used a peripherally inserted central catheter to facilitate infusion Would a component analysis be needed? Is there a prospect for direct benefit? What are the risk levels?
The PICC Study PlCCs used at 19 sites, approved by 12 IRBs 9 of 12 reported a risk determination for the study 7 of 9 IRBs approved both arms under Category 2 2 of 9 used component analysis 1 of 9 approved both arms as more than minimal risk (no category specified) 1 of 9 approved the active arm under Category 2 and the placebo arm under Category 3
The PICC Study FDA s Determination Use of PICC presented more than a minor increase over minimal risk PICC was justified in children receiving IP PICC use in children receiving placebo presented no direct benefit PICC use was not in compliance with 21 CFR 50 FDA s Direction Study has already been suspended by sponsor due to lack of efficacy Advised of conclusion of use of PICC
Conclusion Pediatric research must be scientifically and ethically sound Regulatory requirements are necessary to ensure adequate research protection to minors Subpart D analysis can be complex Determinations, including component analysis, should evaluate interventions and procedures When in doubt, ask the IRB!
Resources Draft Guidance (FDA) General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products Federal Register (FDA) Additional Safeguards for Children in Clinical Investigations of Food and Drug Administration- Regulated Products Institutional Review Board: Management and Function, Amdur and Bankert, 2002 Regulation (FDA) - 21 CFR 50 Subpart D Regulation (HHS) - 45 CFR 46 Subpart D Research Involving Children (Focusing on FDA Regulations), PowerPoint by Robert Skip Nelson, FDA Research with Children FAQs (HHS) Special Protections for Children as Research Subjects (HHS)
December 15, 2016 Navigating the Regulatory Requirements of Pediatric Research Nathan Lee, CIP IRB Vice Chair, Schulman IRB