During this presentation, Dr. Charlene Sanders and Angi Robinson 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.

1. 2 0 11 P E D I AT R I C C L I N I C A L R E S E A R C H W E B I N A R
SERIES
Pediatric Considerations beyond
Assent
Presented by
May 11, 2011 Charlene Sanders, M.D. and Angi
Robinson

2. Charlene Sanders, M.D.
 Vice President, Global Regulatory Affairs and Pediatric
Strategic Consulting
 15+ years of regulatory and medical affairs experience
– Regulatory portfolio includes NDA approvals for 15
programs which incorporated pediatric protocol design,
pediatric clinical study development, PREA discussions
and/or pediatric related safety issues
 25+ years of clinical patient care management
experience
 Trained in pediatrics and completed post-doctoral
2011 PEDIATRICspecialty fellowship training in primary and critical care
CLINICAL RESEARCH WEBINAR SERIES

3. Angi Robinson
 Director, Clinical Trials Management
 10 years of pediatric clinical research
experience in pharma and government
 Completed a six-year contract as the
BPCA-CC for the NICHD/NIH; PM for the
first study launched under the BPCA in
Pediatric Sedation in the ICU
 Global Project Director for Good Clinical
Practice Journal's (GCPj) 2008 Clinical
Research Team of the Year
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

4. Research is Making a
Difference
4
Pediatric research has resulted in:
 More than 350 products labeled with new
pediatric information
 More than 130 products with pediatric focused
post labeling safety reviews
D. Murphy, MD, FAAP, In Search of Pediatric Information: Where Is It at FDA?, 2010 DIA Annual
Meeting, Washington, D.C.
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

5. Ethical Considerations
5
 Ethics of conducting pediatric research has not been
studied as extensively as ethics of adult research
 Need for special protections in vulnerable populations is
mandated by regulations, enacted by:
– IRB assessment of research risk category
– Attention to Assent/Parental Permission process
– DSMBs ( Data Safety Monitoring Boards)
– Assurance of treatment continuity after clinical study
– Use of placebos (to be discussed later)
 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
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

6. Ethical Questions to Consider
6
Is it ethical to enroll children in:
 Poorly designed studies?
– According to FDA, 50% of all pediatric studies are not interpretable
 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
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

7. Potential Ethical Conflicts in Pediatric
Research
Weighing of ethical principles is integral part of process
7
Autonomy, Self-
Beneficence
Determination
Potential or real benefit to child vs.
Child’s dissent
Justice
Beneficence
vs. Potential costs or harms
Potential or real benefit to child
to other family members
Beneficence, Justice
Possibility of obtaining Non-maleficence
vs.
information that could benefit Potential risk to child
many
Non-maleficence
Privacy, Confidentiality
Potential harm from
Drug testing, vs.
researcher
pregnancy testing results
not reporting risky behavior
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

8. 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
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

9. Pediatric Subpopulations
Each age group is considered an
indication
9
Pre-term Newborns Infants & toddlers Children Adolescents
newborn 27 days 28 days to 23 2 to 11 years 12 to 16-18 years
s months
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

10. Age Appropriate Formulations
10
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
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

11. Age Appropriate Formulations
11
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
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

12. Drug Administration
Considerations
12
Dosing is more difficult to manage than in an adult
population:
 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:
 If during the day and there are school-age children, schools
will need to be able to appropriately store the IP, administer it,
and document dosing
 Strict dosing times may be difficult to adhere to
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

13. Designing and Executing Pediatric
Trials
13
Key factors (―PIE‖):
Protocol
Need scientifically rigorous protocols that are also
feasible for the child/parent
Investigative sites
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
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

14. Pediatric Study Design
Considerations
Scientifically Feasible for the
rigorous child/parent
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

15. Study Design
15
Why up to 50% of pediatric studies fail
 Small sample size, low enrollment
 Endpoints that are not well defined or pediatric
relevant
 PK–PD correlations that are not established
 Incorrectly identified dosages for efficacy studies
 Feasibility issues
 Ethical constraints in protocol development
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

16. Pediatric Study Design
16
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
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

17. Child Friendly Study
Procedures
17
 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
 Handle pregnancy testing in minors with care
 Consider not only the child but also the parents and
2011 siblings when planning the frequency and length of
PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

18. Traditional vs. Population PK
Sampling
18
 Traditional PK approach is to conduct a study of single or
multiple doses of the drug in a small number of subjects
with relatively frequent blood sampling
 Population PK approach requires a larger number of
subjects and utilizes infrequent or sparse 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
Guidance for Industry: E11 Clinical Investigation
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES of Medicinal Products in the Pediatric Population,

19. FDA Guidance for Pediatric
Studies
Pediatric Study Decision Tree - Integration of
19
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
• Conduct safety/efficacy similar concentration-
trials response (C-R)
NO in pediatrics and adults?
NO
YE
Is there a PD measurement S
that can be used to predict • Conduct PK studies to
efficacy? achieve levels similar to
adults
YE
• Conduct safety trials
• Conduct PK studies to get
S
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 Design, Data Analysis, and Regulatory
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

20. Use of Placebo
20
 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
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

21. Use of Placebo
21
It is important to minimize placebo exposure:
 Number of subjects
 Study duration
 Randomization ratio
 Need pre-defined discontinuation criteria
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

22. Pediatric Specific
Endpoints/Follow-up
22
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
Behavioral and Psychological Maturation/Milestones
 Child Behavioral Checklist (CBCL)
 Quality of Life, school performance, etc.
 Infants and young children – mental, motor and behavioral
development
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

23. Duration of Treatment,
Follow-up, and Retention
23
 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
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

24. Pediatric Investigative Site
Selection
Operational Medical
consider
Factors Factors
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

25. Operational Considerations for
Pediatric Investigative Site
25
Selection
 In general, use same principles as selecting sites for
adult trials:
– Expertise and experience
– Therapeutic area
– Clinical research
– Pediatric studies
– Adequate number of appropriate patients
– Easier to recruit from and gain trust of families who know
PI/SC/nurse than referrals
– Degree of interest expressed by the site
 Facilities need appropriate equipment and activities and
that can accommodate children/families
 Consider using a Pediatric Research Network
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

26. Medical Considerations for
Pediatric Investigative Site
26
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
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

27. Pediatric Enrollment and
Retention
Patient really means family
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

28. Enrollment Strategies
28
 Remember that ethical decision-making in pediatric
research is not always the same as it is for adult
research
 Conduct studies in familiar environments such as
hospital or clinic where participants normally receive
their care
 Studies have shown that most parents/guardians gave
consent for their child to learn more about their child’s
disease
 References typically through a primary care provider or
another physician
 Family counseling by independent advisor
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

29. Enrollment Strategies
29
Each age group has it own issues with enrollment
 Teenage girls may decline to participate once they learn
that a pregnancy test is required
 The use of cartoons to explain the study may be useful
for younger patients
– Some countries are requiring pictorial information sheets
for young children
 Time missed from school may be important
– Not an issue with the very young
Assume about 50% of approached families will agree
to participate
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

30. Enrollment Strategies
30
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 to patients/parents
– Reimbursements for travel expenses may be better
approach
– AAP recommends to not disclose payment/reimbursement
information to children until they have completed the study
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

31. Retention Strategies
31
 Provide resource materials for patients and
families
 Make sure the stipend is appropriate and that
families are compensated for expenses
associated with their child’s participation
 Appointment reminder and missed appointment
postcards, emails or text messages
 Close, ongoing assessment of discontinuation
reasons
– One-page retention questionnaire to help
determine reason for withdraws
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

32. Retention Strategies
32
 Consider appropriate strategies for the different age groups
– Example: For adolescents, consider a study subject blog; this
group
loves technology and it is appealing to communicate with other
kids around the country who also have the same condition
 Depending on indication, conduct a webcast with famous
person with condition including education segment and ability to
submit questions
 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
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
it not only possible, but FUN!!

33. ―Patient‖ really means ―Family‖
33
Parents/guardians are vital to retention and
compliance – you need to have their support for
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
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

34. ―Patient‖ really means ―Family‖
34
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
Plan to address this with:
 Secure area for siblings to wait
 Personnel available to ―babysit‖ younger children during study
visit
 DVD player with children’s movies/shows
 Snacks for longer visits
 Making siblings feel welcome and parents comfortable with
2011 their decision to bring them along
PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

35. 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
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
Maximize compliance/retention using child-specific

36. Past Webinars
36
Recordings available
at www.premier-research.com/webinars
▪ Developing a Feasible Pediatric Plan for PREA/PMDSIA
Compliance
Speaker: Charlene Sanders, M.D.
▪ Planning your Paediatric Investigation Plan (PIP) Submission in
Europe
Speaker: Susan Bhatti, Ph.D.
▪ Guidelines for Effective and Appropriate Pediatric Assent and
Parental Permission
Speakers: Angi Robinson and Elizabeth Jay, RN, MA
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

37. Questions?
Charlene Sanders, M.D.
Vice President,
Global Regulatory Affairs and Pediatric Strategic Consulting
charlene.sanders@premier-research.com
Angi Robinson
Director, Clinical Trials Management
angi.robinson@premier-research.com
Centre Square West
1500 Market Street, Suite 3500
Philadelphia, PA 19102
Telephone: 215.282.5500
2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES