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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
http://www.brainyquote.com/quotes/authors/h/henry_ford.html
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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, 2nd ed, Wiley: 2013.
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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
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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 lifethreatening 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
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Clinical Trial Objectives
– 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.
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Clinical and Regulatory Approaches to
First In Human Trials
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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 “firstin-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 2005
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Best access to safe and effective
treatment is having an approved
product on the market
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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
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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.
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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)
† Requires review by federal panel
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“First-in-Children” under 21 CFR 50.52
– 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.
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Questions?
• Can one infer a sufficient prospect of direct
benefit from animal studies alone to justify a “firstin-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
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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 300-600 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
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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.”
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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.
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Determining the Extent of Safety Data Collection
Needed in Late Stage Premarket and Post-approval
Clinical Investigations, FDA Draft Guidance, Feb 2012
3. 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.
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The Pragmatic Facts of Safety Evaluation
in Rare Diseases:
What Have we Learned?
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• 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
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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 2013.
• 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.
O’Connell and Pariser, Expert Opinion on Orphan Drugs (2014) 2(9)
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U.S. Prevalence Grouping
Prevalence Range
(number of patients)
Rare Disease
N=26 (%)
Common Disease
N=48 (%)
100
1 (4%)
0
> 100 to  1000
4 (15%)
0
> 1000 to  10K
5 (19%)
0
> 10K to  100K
14 (54%)
0
> 100K to  1M
2 (8%)
10 (21%)
> 1M to  10M
0
17 (35%)
> 10 M
0
21 (44%)
Ref: Expert Opinion on Orphan Drugs July 2014 online doi: 10.1517/21678707.2014.935763
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Ratio of Safety Population Size
to Estimated US Prevalence
%
 0.01
> 0.01 to  0.1
> 0.1 to  1
> 1 to  10
> 10 to  100
> 100*
Rare Disease Common Disease
N=26
N=48
0
0
8 (31%)
13 (50%)
3 (12%)
2 (8%)
7 (15%)
25 (52%)
15 (31%)
1 (2%)
0
0
*trial safety population>U.S. patient population due to foreign study site participants
Ref: Expert Opinion on Orphan Drugs July 2014 online doi: 10.1517/21678707.2014.935763
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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.
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