The Scientific and Ethical Path Forward in Pediatric Product Development Applying 21 CFR 50, Subpart D

1. The Scientific and Ethical Path Forward in Pediatric Product DevelopmentApplying 21 CFR 50, Subpart D Robert M. Nelson, M.D., Ph.D. Pediatric Ethicist Office of Pediatric Therapeutics Office of the Commissioner, US Food and Drug Administration <Robert.Nelson@fda.hhs.gov> Workshop on Cell and Gene Therapy Clinical Trials in Pediatric Populations, Nov. 2, 2010

2. Introduction • Over the past 15 years, we have evolved from a view that we must protect children from research to a view that we must protect children through research. • Clinicians have a professional obligation to ensure that there are adequate data to support the safe and effective use of drugs and biological products in infants, children and adolescents. • The critical need for pediatric research on drugs and biological products reinforces our responsibility to assure that children are only enrolled in research that is both scientifically necessary and ethically sound. • Children are widely considered to be vulnerable persons who, as research participants, require additional (or special) safeguards beyond those afforded to competent adult persons.

3. Additional Safeguards21 CFR 50, Subpart D • Not involving greater than minimal risk (§50.51) • Greater than minimal risk but presenting the prospect of direct benefit to individual subjects (§50.52) • Greater than minimal risk, no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about subjects’ disorder or condition (§50.53) • Not otherwise approvable that present an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children (§50.54)† • Requirements for permission by parents or guardians and for assent by children (§50.55) † Requires review by federal panel

4. Minimal Risk • 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. 21 CFR 56.102(i)

5. Additional Protections for Children Risks are reasonable in relation to anticipated benefits, if any, to subjects and importance of knowledge that may reasonably be expected to result 21 CFR 56.111 Research involving children either must be restricted to “minimal”/“minor increase over minimal” risk absent potential for direct benefit to the child, or 21 CFR 50.51/50.53 must present risks justified by anticipated direct benefits to the child, and which are as favorable as any available alternatives. 21 CFR 50.52

6. Basic Ethical Framework • Children should only be enrolled in a clinical trial if the scientific and/or public health objective(s) can not be met through enrolling subjects who can provide informed consent personally (i.e., adults). • Absent a prospect of direct therapeutic benefit to the children enrolled in a clinical trial, the risks to which those children would be exposed must be “low” (i.e., knowledge does not justify more than “low” risk). • Children should not be placed at a disadvantage after being enrolled in a clinical trial, either through exposure to excessive risks or by failing to get necessary health care.

7. Topics • Scientific Necessity (Principle 1) • Establishing the Appropriate Balance of Risk and Potential Benefit • Limiting Non-therapeutic Risk Exposure (Principle 2) • Sufficient Prospect of Direct Benefit to Justify Risks (Principle 3) • “First-in-children” studies • Component analysis (avoid “fallacy of the package deal”) • Choice of Control Group (placebo; sham surgery) • Referral for Review under 21 CFR 50.54 • Preliminary Impressions from CBER BIMO Review

8. 1. Principle of Scientific Necessity Children should not be enrolled in a clinical investigation unless necessary to answer an important scientific question about the health and welfare of children. Practical application: determine the type and timing of clinical studies required for establishing "safe and effective" pediatric use of drugs/biologics Objective: “public health benefit” for children (i.e., licensure) Equitable selection (prima facie obligation) Subjects capable of informed consent (i.e., adults) should be enrolled prior to children Do not enroll children unless essential (i.e., no other option, whether animal or adult human). REBUTTAL: life-threatening disease absent suitable alternatives. Minimize Risks and Equitable Selection [US 21 CFR 56.111(a)(1) and (b)]

9. Different Pathways to Pediatric Licensure • Product is being developed for a pediatric indication alone (i.e., no adult indication exists). • Challenge: developing sufficient preclinical data† to support the initiation of pediatric clinical trials. • Product is being developed for both a pediatric and adult indication (goal: concurrent licensure). • Sequential Development (linear or staggered) • The results (efficacy and/or safety) of adult studies are necessary to inform pediatric development. • Parallel Development • Pediatric and adult development may proceed together, based on data supporting the initiation of pediatric clinical trials. † Safety data from adult studies/post-marketing use for another indication may exist.

10. Linking Science and Ethics • The challenge is to establish sufficient data using either preclinical animal models or adult human clinical trials† to conclude that: • Absent a sufficient prospect of direct benefit, administration of the investigational product to children presents an acceptably “low” risk, or… • 21 CFR 50.51/50.53 • Administration of the investigational product to children presents a sufficient prospect of direct benefit to justify the risks. • 21 CFR 50.52 † Data also may come from post-marketing pediatric (i.e., "off label") and/or adult data

11. Topics • Scientific Necessity (Principle 1) • Establishing the Appropriate Balance of Risk and Potential Benefit • Limiting Non-therapeutic Risk Exposure (Principle 2) • Sufficient Prospect of Direct Benefit to Justify Risks (Principle 3) • “First-in-children” studies • Component analysis (avoid “fallacy of the package deal”) • Choice of Control Group (placebo; sham surgery) • Referral for Review under 21 CFR 50.54 • Preliminary Impressions from CBER BIMO Review

12. Minor Increase over Minimal Risk • Any clinical investigation in which more than minimal risk to children is presented by an intervention or procedure that does not hold out the prospect of direct benefit for the individual subject may enroll children as subjects only if the • Risk represents a minor increase over minimal risk; • Presents experiences to subjects reasonably commensurate with those inherent in their actual or expected medical, …psychological, [or] social… situations; • Likely to yield generalizable knowledge about the subjects’ disorder or condition that is of vital importance for the understanding or amelioration of [that] disorder or condition; and • Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians. 21 CFR 50.53

13. “Normal” or “routine” risks? The US National Commission defined “minimal risk” as those risks “normally encountered in the daily lives, or in the routine medical or psychological examination, of healthy children.” Although the phrase “of healthy children” was deleted from the current definition, most ethicists and US federal panels (e.g., SACHRP, IOM) agree with this limitation. Administration of experimental drug/biological products is neither “normal” or “routine” and is thus not “minimal” risk. Interventions/procedures that do not present a prospect of direct benefit must present a “low” (e.g., minor increase over minimal) risk, and thus must be limited to children with a “disorder or condition” (absent a federal exception). National Commission - Introduction, Report on Research Involving Children (1978)

14. How is “disorder or condition” defined? The US federal research regulations offer no definition of either “disorder” or “condition.” A Proposed Definition “A specific (or set of specific)… characteristic(s) that an established body of scientific evidence or clinical knowledge has shown to negatively affect children’s health and well-being or to increase their risk of developing a health problem in the future.” Institute of Medicine (US): Recommendation 4.3† Key Concept: “at risk” for disorder or disease. † IOM, Ethical Conduct of Clinical Research Involving Children (2004)

15. “Low Risk” Non-Therapeutic Trials • Non-therapeutic trials may be conducted in subjects with consent of a legally authorized representative provided the following conditions are fulfilled: • Objectives of trial can not be met by means of trial in subjects who can give informed consent personally (i.e., scientific necessity). • Foreseeable risks to subjects are low. • Negative impact on subject’s well-being minimized and low. • Trial not prohibited by law. • Approval of IRB/IEC. • Such trials, unless an exception is justified†, should be conducted in patients having disease or condition for which investigational product is intended. • ICH Good Clinical Practice Guidelines 4.8.14 † US regulations allow for limited exception (21 CFR 50.54) after review by federal panel and approval by DHHS and/or FDA.

16. Topics • Scientific Necessity (Principle 1) • Establishing the Appropriate Balance of Risk and Potential Benefit • Limiting Non-therapeutic Risk Exposure (Principle 2) • Sufficient Prospect of Direct Benefit to Justify Risks (Principle 3) • “First-in-children” studies • Component analysis (avoid “fallacy of the package deal”) • Choice of Control Group (placebo; sham surgery) • Referral for Review under 21 CFR 50.54 • Preliminary Impressions from CBER BIMO Review

17. Greater than “Low” Risk Research • “Children should not be placed at a disadvantage after being enrolled in a clinical trial, either through exposure to excessive risks or by failing to get necessary health care.” • Any clinical investigation [presenting] more than minimal risk to children… by an intervention [with] the prospect of direct benefit… may involve children as subjects only if: • risk justified by anticipated benefit to subjects; • relation of anticipated benefit to risk as favorable to subjects as… available alternative approaches. • US Regulations at 21 CFR 50.52 • Challenge: “First-in-Children” Studies • Can one infer a sufficient prospect of direct benefit from animal studies alone to justify a “first-in-children” clinical trial?

18. Prospect of Direct Benefit (PDB) A “benefit” is “direct” if it: Accrues to individual subject enrolled in clinical trial; Results from research intervention being studied (and not from other clinical interventions included in protocol) Word “benefit” often modified by “clinical” to indicate that “direct benefit” relates to health of enrolled subject. PDB is based on “structure” of an intervention (i.e., dose, duration, method of administration, etc.), and not the investigator’s “intent” or protocol objective(s). Direct benefit is an attribute of the intervention or procedure and not of the overall research protocol and/or objective(s). 18

19. Prospect of Direct Benefit (PDB) Evidence for PDB must be “weaker” than evidence for “efficacy.” PDB may be based on surrogate endpoint (e.g., immune response) if sufficient evidence exists linking chosen surrogate to clinical efficacy. Need empirical evidence of sufficient “prospect of direct benefit” to justify exposure to the risks. Risk/benefit evaluation is a complex quantitative and qualitative judgment that is similar to clinical practice Contextual justification of risk by PDB can include: Importance of “direct benefit” to subject Possibility of avoiding greater harm from disease Justification set in context of disease severity (e.g., degree of disability, life-threatening) and availability of alternative treatments. Should have “as good a chance for benefit as the clinical alternatives” Whether experimental intervention offers PDB separate from whether PDB of sufficient probability, magnitude and type to justify the anticipated risks of the intervention, given the overall clinical context. 19

20. Proposal: Sliding Threshold • Data (whether animal or human adult) necessary to establish sufficient prospect of direct benefit (PDB) to justify the risks varies with the severity of the disease and the adequacy of alternate treatments. • Structure (generally insufficient for PDB) • Function (based on mechanism of action) • Molecular target (receptor); Biomarker (RNA/protein); Physiologic pathway (metabolic product) • Transgenic Technology (human target + mouse) • Clinical Disease Model • Surrogate endpoints • Clinical endpoint (e.g., survival) (FDA "Animal Rule")

21. Starting Dose for “first-in-human” clinical trials • MRSD† frequently based on “no observed adverse effect levels” (NOAEL) in the tested animal species, and conversion of NOAEL to a human equivalent dose with the application of a safety factor. • Risk/potential benefit for NOAEL “safe starting dose” may not be equivalent to MRSD dose associated with greatest efficacy in animal studies. • Challenge: NOAEL dose may not offer sufficient PDB to justify “first-in-children” clinical trial, and the MRSD may present greater risks. † Maximum Recommended Starting Dose

22. Component Analysis Research protocols may combine non-therapeutic interventions with other interventions that either: (1) offer (as a research intervention) a prospect of direct benefit to the enrolled child, or (2) would be considered part of necessary health care for that child. The risks of an experimental intervention must be justified by the prospect of direct benefit from that same intervention (or absent direct benefit, be restricted to “low” risk), and not the possible direct benefit of other interventions or procedures included in the protocol. This approach is often called “component analysis” and is meant to avoid what has been called the “fallacy of the package deal.” Possible exception: the risks of diagnostic procedures that do not provide direct benefit but which are necessary to answer the scientific question associated with the experimental intervention may be justified by the prospect of direct benefit of that specific intervention. 22

23. Impact on Use of Controls in Pediatrics • Placebo • Placebo does not offer a prospect of direct benefit • Risk of placebo generally “minimal” (if chosen well) • Risk of placebo control group related to risk of harm from not receiving “proven” or “effective” treatment • Thus, risk of withholding proven effective treatment must be no more than a “minor increase over minimal risk” (21 CFR 50.53) • Sham Procedures • Do not offer a prospect of direct benefit • Thus, risk of sham procedure must be no more than a “minor increase over minimal risk” (21 CFR 50.53)

24. Topics • Scientific Necessity (Principle 1) • Establishing the Appropriate Balance of Risk and Potential Benefit • Limiting Non-therapeutic Risk Exposure (Principle 2) • Sufficient Prospect of Direct Benefit to Justify Risks (Principle 3) • “First-in-children” studies • Component analysis (avoid “fallacy of the package deal”) • Choice of Control Group (placebo; sham surgery) • Referral for Review under 21 CFR 50.54 • Preliminary Impressions from CBER BIMO Review

25. IRB Referrals under Subpart D • If an IRB does not believe that a clinical investigation involving children as subjects meets the requirements of §50.51, §50.52, or §50.53, the FDA-regulated clinical investigation may proceed only if: • The IRB finds and documents that the clinical investigation presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; and • The Commissioner of Food and Drugs, after consultation with a panel of experts in pertinent disciplines (for example: science, medicine, education, ethics, law) and following opportunity for public review and comment, determines that the clinical investigation can proceed under either §50.51, §50.52, §50.53, or §50.54. References to 21 CFR 50, Subpart D

26. Charter • The Pediatric Advisory Committee (PAC) advises and makes recommendations to the FDA Commissioner regarding… research involving children as subjects as specified in 21 CFR 50.54. • PAC advises and makes recommendations to the Secretary directly or… through the Commissioner on research involving children as subjects that is conducted or supported by DHHS as specified in 45 CFR 46.407. • A permanent Pediatric Ethics Subcommittee (PES) of the PAC advises and makes recommendations to the PAC on… IRB referrals related to clinical investigations involving children as subjects as specified in 21 CFR 50.54, and IRB referrals that involve both FDA regulated products under 21 CFR 50.54 and research involving children as subjects that is conducted or supported by DHHS as specified in 45 CFR 46.407. • The PES will consist of two or more members of the parent PAC and additional experts (e.g., science, medicine, education, ethics and law) to address specific issues within their respective areas of expertise. http://www.fda.gov/oc/advisory/OCPedsCharter2008.html

27. Required Findings under 21 CFR 50.54 • Either the clinical investigation in fact satisfies the conditions of §50.51, §50.52, or §50.53, as applicable, or • All of the following conditions are met: • The clinical investigation presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; • The clinical investigation will be conducted in accordance with sound ethical principles; and • Adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians as set forth in §50.55. 21 CFR 50.54

28. Guidance • Food and Drug Administration • Guidance for Clinical Investigators, Institutional Review Boards and Sponsors Process for Handling Referrals to FDA under 21 CFR 50.54. • Federal Register (Dec. 22, 2006, Volume 71, pp. 77034-77035) • http://www.fda.gov/OHRMS/DOCKETS/98fr/06d-0172-gdl0002.pdf • Office for Human Research Protections (OHRP) • Children Involved as Subjects in Research: Guidance on the HHS 45 CFR 46.407 Review Process. • Date: May 26, 2005 • http://www.hhs.gov/ohrp/children/Guidance_407Process.pdf

29. Topics • Scientific Necessity (Principle 1) • Establishing the Appropriate Balance of Risk and Potential Benefit • Limiting Non-therapeutic Risk Exposure (Principle 2) • Sufficient Prospect of Direct Benefit to Justify Risks (Principle 3) • “First-in-children” studies • Component analysis (avoid “fallacy of the package deal”) • Choice of Control Group (placebo; sham surgery) • Referral for Review under 21 CFR 50.54 • Preliminary Impressions from CBER BIMO Review

30. FDA Inspection of IRBs • FDA inspected 24 IRBs representing 45 IND/IDEs and 52+ protocols • Detailed ethics review of 33 consent/assent forms and associated IRB minutes performed • Most studies approved under 21 CFR 50.52 (prospect of direct benefit) • CFs generally had detailed discussion of procedures and risks, did not promise benefit, and adequately differentiated research from clinical care

31. Consent Review • Benefits • Usually framed as disease improvement, without information about probability • Language regarding “hope” common, e.g. “we hope that this treatment will improve your condition, but cannot be sure” • Research versus Clinical Care • In some studies, the only research intervention was cell sorting prior to a BMT with transplant of an enriched or depleted subpopulation • Risks and procedures of standard portions of the BMT still included in consent documents

32. Enhancing Consent Forms • Does the use of the term “hope” in early phase consent forms accurately convey the likelihood of benefit to parents of children with serious medical conditions? • Should information about procedures that are unmodified by the research (e.g. BMT preparative regimens) be included in consent forms? • To what extent do either of these approaches exacerbate the potential for “therapeutic misconception”?

33. Basic Ethical Framework Scientific Necessity • Children should only be enrolled in a clinical trial if the scientific and/or public health objective(s) can not be met through enrolling subjects who can provide informed consent personally (i.e., adults). Appropriate Balance of Risk and Potential Benefit • Absent a prospect of direct therapeutic benefit to the children enrolled in a clinical trial, the risks to which those children would be exposed must be “low” (i.e., knowledge does not justify more than “low” risk). • Children should not be placed at a disadvantage after being enrolled in a clinical trial, either through exposure to excessive risks or by failing to get necessary health care.

34. Thank you. 34