The industry recognizes the importance of ensuring the safety and well‐being of children involved in research studies. Medical and regulatory bodies have worked to provide a framework to support appropriately designed studies through regulations and guidance documents in this vulnerable population. However, it is crucial to understand the nuances associated with pediatric trials, for the site, patient and family, in order to manage them to successful completion. During the 2012 ACRP Annual Meeting, Dr. Charlene Sanders and Angi Robinson from Premier Research reviewed topics including the evaluation of study design considerations such as duration of treatment, required assessments, use of placebo, and inclusion of specific age groups; selection of appropriate sites for pediatric trials and the unique needs of these sites; identification of pediatric recruitment/retention hurdles and site specific strategies to overcome these as well as a reflection on ethical concerns related to pediatric research. For more information, go to http://www.premier-research.com/pediatrics.

1. Successful Pediatric Studies:
Key Study Design and Site Selection Considerations
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April 14, 2012 4:15 PM – 5:15 PM

2. Successful Pediatric Studies:
Key Study Design and
Site Selection Considerations
Presented by
Charlene Sanders, M.D. and Angi Robinson
Premier Research
April 14, 2012
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3. Disclosure
We have no relevant financial relationship
in relation to this educational activity
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4. Research is Making a Difference
Pediatric research has resulted in:
More than
products labeled with
new pediatric information
More than
products with pediatric focused
post labeling safety reviews
Source: FDA website accessed on February 29, 2012
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5. What Makes
Pediatrics Different?
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6. Pediatrics does not deal with
miniature men and women, with
reduced doses and the same
class of diseases in smaller
bodies, but ... it has its own
independent range and horizon
and gives as much to general
medicine as it receives from it
- Abraham Jacobi, 1889
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7. Pediatric Subpopulations
Each age group is considered an indication
Pre-term Newborns Infants & toddlers Children Adolescents
newborns 27 days 28 days to 23 months 2 to 11 years 12 to 16-18 years
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8. Age Appropriate Formulations
Consider age, physical development, illness, dosage, dosing
frequency, treatment duration, and route of administration
Need pediatric formulations that are:
• Easy to both administer and swallow
• Acceptable in taste and volume
• Appropriate in dosage and strength
• Tolerable with minimal and safe excipients
• Adequate bioavailability
• Less frequent administration
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9. Age Appropriate Formulations
Children will refuse an unpleasant formulation
Foster compliance by delivering formulations with an
acceptable taste
Poor compliance increases the risk of therapeutic failure
and emergence of resistances
Need to ensure safe and precise administration
Foster compliance with an easy administration
Provide appropriate dosing/administration devices
Important to have child-proof container for product
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10. Plant the SEED to Succeed!
Scientifically meaningful
Need scientifically rigorous protocols
Ethical
Need special protections with this vulnerable populations
Enrollable
Need protocols that are patient and family friendly
Directed
Need appropriate sites and targeted patient recruitment strategies
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11. Scientifically Meaningful
Study Design
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12. Study Design
Why up to 50% of pediatric studies fail:
Not well defined PK–PD
Small sample
or pediatric correlations that
size, low
relevant are not
enrollment
endpoints established
Incorrectly Ethical
identified Feasibility constraints in
dosages for issues protocol
efficacy studies development
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13. Pediatric Study Design
Protocols need to be designed specifically for the
population and not simply re-worked from adult protocols
→ Design must be customized for the specific populations
→ Primary endpoint in children may be different or even
inappropriate in adults
→ Developmental variability should be considered in inclusion
criteria, sample size calculations, and analysis
→ Study design must be realistic for families to commit
Unsuitable designs will lead to slow enrollment and low
retention resulting in higher costs and approval delays
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14. Traditional vs. Population PK Sampling
Traditional PK Population PK
Approach is to conduct a study Approach requires a larger
of single or multiple doses of number of subjects and
the drug in a small number of utilizes infrequent or sparse
subjects with relatively sampling
frequent blood sampling
While current FDA and ICH recommendations do not indicate
which method should be used, they do describe the population
PK methodology as a useful technique to minimize the number
of samples obtained from each patient
14 Guidance for Industry: E11 Clinical Investigation of Medicinal Products in the Pediatric Population, Dec 2000.

15. FDA Guidance for Pediatric Studies
Pediatric Study Decision Tree - Integration of PK-PD
Reasonable to assume (pediatrics vs. adults)
• Similar disease progression?
• Similar response to intervention?
NO YES TO BOTH
• Conduct PK studies Reasonable to assume similar
• Conduct safety/efficacy trials concentration-response (C-R)
in pediatrics and adults?
NO NO
YES
Is there a PD measurement that
can be used to predict efficacy? • Conduct PK studies to achieve
levels similar to adults
YES • Conduct safety trials
• Conduct PK studies to get
C-R for PD measurement
• Conduct PK studies to achieve
target concentrations based
on C-R
• Conduct safety trials Guidance for Industry: Exposure-Response Relationships — Study
15 Design, Data Analysis, and Regulatory Applications, April 2003.

16. Use of Placebo
Use of placebo typically more restricted
in pediatric trials simply because
children cannot consent
While not ideal, the use of a placebo may
be acceptable if there is no approved or
adequately studied therapies
Placebo use has to be justified
scientifically and ethically
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17. Use of Placebo
It is important to minimize placebo exposure:
Number of Study
subjects duration
Need
Randomization pre-defined
ratio discontinuation
criteria
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18. Pediatric Specific Endpoints/Follow-up
Physiological Measures and Benchmarks
• Weight
• Height
• Thyroid hormone, Insulin-like growth factor-1 (IGF-1)
• Skeletal growth
• Sexual maturation
Development and Cognitive function
(short and long-term effects)
• Attention, memory and learning
• Language skill
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19. Pediatric Specific Endpoints/Follow-up
Behavioral and Psychological Maturation/Milestones
• Child Behavioral Checklist (CBCL)
• Quality of Life, school performance, etc.
• Infants and young children – mental, motor and behavioral
development
• Neonates – known complications and effects of prematurity
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20. Duration of Treatment,
Follow-up, and Retention
→ Long-term treatment or recurrent treatment may
necessitate:
– Tracking of growth and development changes
– Potential need for patient to sign multiple assent
forms/consent form over time
→ Outline process for study drug delivery during school
days, with alternate caregivers, etc…
→ Working parents and school attendance issues will
present additional practical problems
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21. Ethical Considerations
and Special Protections
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22. Special Protections in Pediatric Research
Need for special protections in vulnerable populations
is mandated by regulations, enacted by:
Assent/
IRB assessment Data Safety
Parental
of research risk Monitoring
Permission
category Boards (DSMBs)
process
Treatment
Limiting use of
continuity after
placebos
clinical study
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23. Ethical Considerations
Ethics of conducting pediatric research
has not been studied as extensively as
ethics of adult research
Pediatric research means decision-
making for another and involves more
than just the patient
Potential risks and inconvenience are
accepted by parent, but may affect child,
siblings, and parents
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24. Ethical Questions to Consider
Is it ethical to enroll children in:
Poorly designed studies?
– According to FDA, 50% of all pediatric studies are not
interpretable
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25. Ethical Questions to Consider
Is it ethical to enroll children in:
Studies without the possibility of direct benefit?
– Normally only allowed if risk is low
– Should have access to necessary health care after being
enrolled in a clinical trial
– Rules and definitions differ by country
• Non-therapeutic studies in children are not allowed in
some countries
• Definition of low risk varies by country
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26. Potential Ethical Conflicts in Pediatric Research
Weighing of ethical principles is integral part of process
Beneficence Autonomy, Self-Determination
Potential or real benefit to child vs. Child’s dissent
Justice
Beneficence
Potential or real benefit to child
vs. Potential costs or harms
to other family members
Beneficence, Justice
Non-maleficence
Possibility of obtaining information vs. Potential risk to child
that could benefit many
Privacy, Confidentiality Non-maleficence
Drug testing, vs. Potential harm from researcher
pregnancy testing results not reporting risky behavior
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27. Enrollable Protocols
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28. Child Friendly Study Procedures
Minimize intensity and frequency of the study assessments
• Limit number and volume of blood draws – coincide the
collection of protocol-specified blood samples with routine
clinical samples
• Limit invasive procedure as much as possible
Minimize pain and distress
• Use topical anesthesia, butterfly needles, pediatric sampling
tubes
• Indwelling catheters rather than repeated venipunctures for
blood sampling
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29. Child Friendly Study Procedures
In addition:
• Handle pregnancy testing in minors with care
• Consider not only the child but also the parents and
siblings when planning the frequency and length of
visits/assessments
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30. Drug Administration Considerations
Dosing is more difficult to manage than in adults:
• Often based on experience in adults and weight/BSA
• Titration rates and AE monitoring need to be carefully evaluated
• Administration of investigational product can pose problems
Timing of dosing can also be a challenge:
• Issues with dosing in school-age children
• Strict dosing times may be difficult to adhere to
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31. Directed and Executable
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32. Operational Considerations for
Pediatric Investigative Site Selection
In general, use same principles as selecting sites for adult trials:
Access to
Degree of
Expertise and adequate interest
number of
experience expressed
appropriate by the site
patients
Facilities need
appropriate Consider using
equipment/ a Pediatric
activities to Research
accommodate Network
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children/families

33. Medical Considerations for
Pediatric Investigative Site Selection
• Absolutely MUST have person experienced in pediatric
lab draws
• Depending on protocol, may also need personnel
with expertise in catheterizing small children,
pediatric IV starts, placing pediatric NG tubes, etc.
• Sites that are not pediatric based must have access to
resources needed for the pediatric population
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34. Enrollment Strategies
Conduct studies in familiar environments
such as hospital or clinic where
participants normally receive their care
Support on site and off site activities
Be mindful of age specific issues
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35. Enrollment Strategies
Each age group has it own issues with enrollment
Babies and toddlers Consider naptimes
Young children The use of cartoons to explain the study
may be useful for younger patients (some
countries are requiring pictorial
information sheets for young children)
School age Time missed from school may be
important factor
Teenagers Teenage girls may decline to participate
once they learn that a pregnancy test is
required
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36. Enrollment Strategies
Avoid coercion or even its appearance
Advertisements
• Consider different media – TV, radio, internet, parenting
publications, etc.
• Ads need to target the parent, not the child
• Not always appropriate
Payments
• Reimbursements for travel expenses may be better approach
• AAP recommends to not disclose payment/reimbursement
information to children until they have completed the study
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37. Enrollment Strategies
Siblings are frequently brought along to study
appointments distracting both the parents and patients
This can cause:
• Missed reporting of AEs and con meds
• Potentially incorrect responses on
questionnaires
• Early termination if siblings are not made
to feel welcome
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38. Enrollment Strategies
Plan to address this with:
1 Secure area for siblings to wait
Personnel or family/friends available to “babysit”
2 younger children during study visits
3 DVD player with children’s movies/shows
4 Snacks for longer visits
Making siblings feel welcome and parents
5 comfortable with their decision to bring them
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39. Pediatric Assent/Parental Permission
Plan in advance whether and how pediatric assent will
be solicited and have trained personnel obtain this
Considerations for forms:
• In most cases it is appropriate to have one
or more assent forms separate from
parental permission form
• Assent forms need to be aimed at the
appropriate reading grade level for the
youngest person who will sign
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40. Retention Strategies
Make sure stipend is
Provide resource appropriate and families
materials for patients are compensated for
and families expenses associated with
child’s participation
Appointment reminder Close, ongoing review of
and missed appointment discontinuation reasons
postcards, emails or (one-page retention
questionnaire to help determine
text messages reason for withdraws)
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41. Retention Strategies
Consider appropriate strategies for the different age
groups and indications
Example: For adolescents, Example: Depending on
consider a study subject indication, conduct a
blog; this group loves webcast with famous
technology and it is person with condition
appealing to communicate including education
with other kids around segment and ability to
the country who also have submit questions
the same condition
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42. Retention Strategies
Incentive/Rewards
• For milestone achievements, depending on age consider
reward certificate with 10 free music downloads or movie
theatre passes
• Organizer folder/portfolio with place to carry medication to
and from visits that includes calendar with stickers for
appointments as well as books and materials to educate on
condition and making living with it not only possible, but
FUN!!
• Family incentives such as a refrigerator magnet with notepad
or calendar
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43. Retention Strategies
Parent/guardian support is vital to retention and
compliance with visits and drug administration
Must remove barriers to trial participation including:
• Clear instructions for drug administration and compliance
• Difficult visit schedules – include appropriate windows
• Scheduling – parent’s job, school attendance, nap times
• Transportation costs
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44. Take Home Message
With experience, pediatric studies can be easy as PIE
Protocol
Need scientifically rigorous protocols that are also child/parent friendly
Investigators
Choose sites that can handle issues unique to pediatric studies
Enrollment and retention
Develop parent-targeted recruiting/enrollment strategies
Maximize compliance/retention using child-specific strategies
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45. Charlene Sanders, M.D.
Vice President, Global Regulatory Affairs
& Pediatric Strategic Consulting
Email: charlene.sanders@premier-research.com
Phone: 215.282.5500
Angi Robinson
Executive Director, Clinical Trials Management
Email: angi.robinson@premier-research.com
Phone: 215.282.5500
www.premier-research.com
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