First In Human Pediatric Trials and Safety Assessment for Rare and Orphan Diseases Andrew E. Mulberg, MD, FAAP Division Deputy Director OND/ODE3/DGIEP FDA

Partnership is the Key “Coming together is a beginning; keeping together is progress; working together is success.” Henry Ford Henry Ford 2

Rare Diseases: The Facts Many pediatric disorders are rare diseases Rare diseases, also referred to as orphan diseases, are defined in the United States (US) by the Orphan Drug Act (ODA) as diseases or conditions that affect fewer than 200,000 persons in the US. There are an estimated 7,000 different rare diseases that have been described which affect approximately 25 to 30 million Americans, or about 1 in 10 people in the US. Approximately 80-85% of these are genetic disorders, and about half of the affected patients are children. Pariser and Yao, Rare Diseases, Pediatric Drug Development, Mulberg AE, 2 nd ed, Wiley:

The Mission Most rare diseases are serious, life-limiting or life-threatening conditions, and only a small number have targeted therapies approved for their treatment by the US Food and Drug Administration (FDA). Develop safe and effective therapeutics to address the unmet medical need of a growing population of individuals with rare diseases 4

Clinical Development Challenges for Rare Diseases –Rare = few patients available for study Makes “getting development right” critical from the start –Chronic, progressive, serious, life-limiting and life- threatening with unmet medical need –Many different clinical presentations –Natural history often not well understood –Well defined endpoints, outcome measures/tools/ instruments, biomarkers can be lacking 5

–Establish that the drug is safe and effective for its proposed use –Obtain evidence to support drug labeling that guides providers and patients on how to use the drug for patients safely and effectively. Clinical Trial Objectives 6

Clinical and Regulatory Approaches to First In Human Trials 7

Maximum Recommended Starting Dose (MRSD) for “first-in-human” clinical trials MRSD frequently based on “no observed adverse effect levels” (NOAEL) in the tested animal species, and conversion of NOAELs 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. A NOAEL dose may not offer sufficient PDB to justify “first- in-children” clinical trial, and the MRSD may present greater risks. Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, July

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Best access to safe and effective treatment is having an approved product on the market 10

Pediatric Specific Issues Affecting FIH Considerations Protection of Vulnerable Subjects Prospect for Direct Benefit 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 11

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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) PDB is based on the "structure" of an intervention (i.e., dose, duration, method of administration, etc.), and not the investigator’s “intent” or the primary objective of the protocol. 13

† Requires review by federal panel14 Additional Safeguards 21 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)

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“First-in-Children” under 21 CFR –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. 16

Questions? Can one infer a sufficient prospect of direct benefit from animal studies alone to justify a “first- in-children” clinical trial under 21 CFR 50.52? –Nonclinical data and POC in animal models provide integral data for this paradigm potentially –These are discussions that are critical to the individual development program for rare diseases –No specific guidances can be provided –Safety is integral to any considerations of FIH pediatric trials 17

Assessment of Safety: Current Guidances ICHE1A: ICH E1 “Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life-threatening Conditions” –Usually patient should be adequate for 6 months –“100 patients exposed for a minimum of 1-year is considered to be acceptable FDA Guidance for Industry: Premarketing Risk Assessment 18

19 FDA Guidance for Industry: Premarketing Risk Assessment “The nature and extent of safety data sufficient for approval are individualized decisions based on a number of factors….In reaching a final decision on approval, both existing risk information and any outstanding questions regarding safety are considered in the risk assessment and weighed against the demonstrated benefits.”

Determining the Extent of Safety Data Collection Needed in Late Stage Premarket and Post-approval Clinical Investigations, FDA Draft Guidance, Feb 2012 The amount and types of safety data collected during clinical trials and observational safety evaluations will vary based on a range of factors, including the disease, patient population, subgroup of interest, preclinical findings, prior experience with the drug, experience with the drug class, phase of development, and study design, among other factors. 20

Determining the Extent of Safety Data Collection Needed in Late Stage Premarket and Post-approval Clinical Investigations, FDA Draft Guidance, Feb Development programs for orphan indications Orphan indications have limited patient populations available for study. Therefore, it is important in general to obtain comprehensive data on each patient to best inform product labeling. –Comprehensive data might suggest utility of baseline measurements of safety parameters (e.g., ALT, liver biopsy, etc) and protocol-specified time points for additional measurements for adequate interpretation of the treatment effects over time in all patients. 21

The Pragmatic Facts of Safety Evaluation in Rare Diseases: What Have we Learned? 22

Clinical Trial Safety Population Size– Analysis of Drug Approvals for Rare and Common Indications by FDA Center for Drug Evaluation and Research Kathryn O’Connell and Anne Pariser 23

Clinical Trial Safety Population Size– Analysis of Drug Approvals for Rare and Common Indications by FDA Center for Drug Evaluation and Research A study of the relationship between pre-marketing trial safety population size and estimated U.S. disease prevalence as compared to common disease drugs. Analysis on marketing applications approved by CDER: January 2010 and June While drugs for rare diseases have small trial safety population sizes relative to common disease drugs, a larger proportion of patients are studied relative to the number of U.S. patients with the approved indication. 24 O’Connell and Pariser, Expert Opinion on Orphan Drugs (2014) 2(9)

U.S. Prevalence Grouping Prevalence Range (number of patients) Rare Disease N=26 (%) Common Disease N=48 (%)  (4%)0 > 100 to  (15%)0 > 1000 to  10K 5 (19%)0 > 10K to  100K 14 (54%)0 > 100K to  1M 2 (8%)10 (21%) > 1M to  10M 017 (35%) > 10 M021 (44%) 26 Ref: Expert Opinion on Orphan Drugs July 2014 online doi: /

Ratio of Safety Population Size to Estimated US Prevalence %Rare Disease N=26 Common Disease N=48  (15%) > 0.01 to  (52%) > 0.1 to  1 8 (31%)15 (31%) > 1 to  (50%) 1 (2%) > 10 to  (12%)0 > 100* 2 (8%)0 27 *trial safety population>U.S. patient population due to foreign study site participants Ref: Expert Opinion on Orphan Drugs July 2014 online doi: /

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Conclusions An ethical framework must be established to allow FIH pediatric clinical trials; general principles discussed FIH trial designs must take into consideration key disease characteristics, patient demographics, and putative or known drug effects Frequent interactions are needed regarding the design and execution of FIH trials. 29