Breakout Session VII: Research in Kids/Special Populations
Co-Moderators:
Joel E. Lavine, MD PhD
Professor and Vice-Chairman of Pediatrics
Chief of Gastroenterology, Hepatology and Nutrition
Columbia University
Kathleen B. Schwarz, MD
Professor of Pediatrics and Director Pediatric Liver Center
Johns Hopkins University School of Medicine
President of FISPGHAN (Federation of International Societies of Pediatric Gastroenterology,
Hepatology and Nutrition
Key Points 
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Issues unique to children
Assent vs. consent
Ethical issues
Retention
Collecting research specimens
The issues unique to the performance of clinical research in children are outlined in the
guidelines by Van’t Hoff et al (1) and include consent vs assent, recruitment and retention(2),
risk of bias such as by inclusion of siblings (3) , need for a DSMB, calculation of adequate
sample size, appropriate outcome measures and effects of age on biomarkers (4) and
pharmacology (5). Ethical issues include such considerations as foster children and children of
prisoners, custodial issues in the case of divorced parents, paternity questions in genetic studies,
compensation vs coercion and the collection of research specimens. There are practical issues as
well – pediatric drug formulations, transportation, and compliance/adherence.
It’s important to emphasize the many benefits of properly performed clinical pediatric research
as well as well as the challenges. Achievement of FDA approval of a pediatric indication for
drugs which can benefit children with potentially life-threatening liver diseases such as hepatitis
C (6) is an obvious reward for the investigator and patient/family unit alike. Such approval
lowers the risk of off-label use and provides drugs at a time of life when early intervention can
be the most beneficial and cost-effective. And in particular when a clinical trial is supported by
the NIDDK U01 mechanism such as PEDS C and TONIC, much knowledge can be gleaned
about disease pathophysiology (7–14.)
Case 1. A 5 year old female with vertical acquisition of HCV is brought to your clinic by
divorced parents who are interested in learning more about enrollment in your new pediatric
HCV trial. The mother is enthusiastic and the father is not. They have joint custody.
a. How do you balance these opposing sentiments?
b. How would consent and assent for the trial differ?
c. If the parents agree to enroll the child how do you monitor compliance?
Case 2. A 4 year old adopted Chinese female with HBV is brought to your clinic by her lawyer
parents who are highly motivated to enroll her in your new pediatric HBV trial which involves
swallowing a dime sized pill on a daily basis for one or more years.
a. How do you best learn if she is a suitable patient for this trial?
b. How much blood can be drawn for research at each visit?
c. How do you discuss the ethics of drawing blood for genetic studies?
Case 3. You are designing a NASH trial involving a histology based outcome that requires a
research liver biopsy on children who will be 7-17 years old, inclusive. Your design is such that
the randomized subjects receive active drug or identical placebo. The family and subjects will be
blind to treatment. You will be dispensing treatment but not allow the subject to know to what
group they are assigned. A pregnancy test is done at baseline and 24 weeks (pregnancy is an
exclusion.)
a. Will this trial design pass muster with the IRB? Why or why not?
b. What would you do if a 15 year old girl in the trial is found to be b-HCG+ at 24 week
visit?
c. If a 16 year old girl with a baby wishes to enroll in the trial, is parental consent
required?
Case 4. You are recruiting for a trial that requires 6 visits in a 6-month period, each visit
requiring one hour. A 17-year old is reluctant because of the time he must miss school. To
oblige him, and other subjects with the same concerns, you offer a recruitment incentive of
$150/visit. Another subject does not have a phone and is hard to contact. One of the subjects at
the end of the trial has left for college on the opposite coast. You offer to fly him home for
Thanksgiving in order to complete the trial.
a. Is this incentive within bounds? Why or why not?
b. Can you offer a phone or money for a “pay as you go” phone for the hard to reach
subject?
c. Can you pay for flying the subject home for Thanksgiving? Why or why not?
References
Guidelines for pediatric trials
1. Van't Hoff W, Offringa M; for the Star Child Health group
(http://www.starchildhealth.org). StaR Child Health: developing evidence-based
guidance for the design, conduct and reporting of paediatric trials.Arch Dis Child. 2014
Sep 26. pii: archdischild-2012-303094
2. Roy A, Lieb W, Garrett B, Hodik M, Klipsch A, Young M, Barton B, Schwarz KB.
Recruitment and retention strategies in a clinical trial for children with chronic hepatitis
C infection.J Pediatr Nurs. 2013 May-Jun;28(3):243-8
3. Design of the PEDS-C trial: pegylated interferon +/- ribavirin for children with chronic
hepatitis C viral infection.Murray KF, Rodrigue JR, González-Peralta RP, Shepherd J,
Barton BA, Robuck PR, Schwarz KB; PEDS-C Clinical Research Network.Clin Trials.
2007;4(6):661-73.
Importance of age-based controls and dosology
4. Rosensweig JN, Omori M, Page K, Potter CJ, Perlman EJ, Thorgeirsson SS, Schwarz
KB. Transforming growth factor-beta1 in plasma and liver of children with liver
disease.Pediatr Res. 1998 Sep;44(3):402-9.
5. Ku LC, Smith PB. Dosing in neonates: Special considerations in physiology and trial
design.Expert Rev Clin Pharmacol. 2012 Sep;5(5):525-31.
Lessons from pediatric HCV trials
6. Jonas MM, Schwarz KB, Gonzalez-Peralta R, Lobritto S, Molleston JP, Murray KF,
Rosenthal P, Wen J, Wat C, Pavlovic V, Warne C. Long-Term Growth Outcomes in
Children Treated for Chronic Hepatitis C.J Pediatr. 2014 Sep 17
7. Mohan P, Barton BA, Narkewicz MR, Molleston JP, Gonzalez-Peralta RP, Rosenthal P,
Murray KF, Haber B, Schwarz KB, Goodman ZD. Evaluating progression of liver
disease from repeat liver biopsies in children with chronic hepatitis C: a retrospective
study.Hepatology. 2013 Nov;58(5):1580-6.
8. Molleston JP, Mellman W, Narkewicz MR, Balistreri WF, Gonzalez-Peralta RP, Jonas
MM, Lobritto SJ, Mohan P, Murray KF, Njoku D, Rosenthal P, Barton BA, Talor MV,
Cheng I, Schwarz KB, Haber BA; PEDS-C Clinical Research Network. Autoantibodies
and autoimmune disease during treatment of children with chronic hepatitis C.J Pediatr
Gastroenterol Nutr. 2013 Mar;56(3):304-10
9. Jonas MM, Balistreri W, Gonzalez-Peralta RP, Haber B, Lobritto S, Mohan P, Molleston
JP, Murray KF, Narkewicz MR, Rosenthal P, Schwarz KB, Barton BA, Shepherd JA,
Mitchell PD, Duggan C. Pegylated interferon for chronic hepatitis C in children affects
growth and body composition: results from the pediatric study of hepatitis C (PEDS-C)
trial.Hepatology. 2012 Aug;56(2):523-31
10. Rodrigue JR, Balistreri W, Haber B, Jonas MM, Mohan P, Molleston JP, Murray KF,
Narkewicz MR, Rosenthal P, Smith LJ, Lobritto SJ, Schwarz KB, Robuck PR, Barton B,
González-Peralta RP. Peginterferon with or without ribavirin has minimal effect on
quality of life, behavioral/emotional, and cognitive outcomes in children.
Hepatology. 2011 May;53(5):1468-75.
11. Narkewicz MR, Rosenthal P, Schwarz KB, Drack A, Margolis T, Repka MX; PEDS-C
Study Group. Ophthalmologic complications in children with chronic hepatitis C treated
with pegylated interferon.J Pediatr Gastroenterol Nutr. 2010 Aug;51(2):183-6
12. Rodrigue JR, Balistreri W, Haber B, Jonas MM, Mohan P, Molleston JP, Murray KF,
Narkewicz MR, Rosenthal P, Smith LJ, Schwarz KB, Robuck P, Barton B, GonzálezPeralta RP. Impact of hepatitis C virus infection on children and their caregivers: quality
of life, cognitive, and emotional outcomes.J Pediatr Gastroenterol Nutr. 2009
Mar;48(3):341-7
13. Goodman ZD, Makhlouf HR, Liu L, Balistreri W, Gonzalez-Peralta RP, Haber B, Jonas
MM, Mohan P, Molleston JP, Murray KF, Narkewicz MR, Rosenthal P, Smith LJ,
Robuck PR, Schwarz KB. Pathology of chronic hepatitis C in children: liver biopsy
findings in the Peds-C Trial.Hepatology. 2008 Mar;47(3):836-43.
http://www.hhs.gov/ohrp/policy/populations/children.html
http://answers.hhs.gov/ohrp/categories/1570