Pediatric Clinical Trials, Lessons Learned

1. Pediatric Clinical Trials, Lessons Learned Jennifer S. Li, MD, MHS Professor of Pediatrics and Medicine Division of Cardiology Duke University School of Medicine

2. Disclosures I have received research support from Sanofi-Aventis & Genzyme and consulting fees from Daiichi-Sankyo, Pfizer, and PTC Bio related to this topic.

3. Off-Label Use of Cardiovascular Medications in Children Hospitalized With Congenital and Acquired Heart Disease Pasquali S K et al. Circ Cardiovasc Qual Outcomes 2008;1:74-83

4. Pediatric Cardiovascular Drug Studies • Hypertension • Congestive heart failure • Antiarrhythmic agents • Antithrombotic agents

5. Challenges in Pediatric Trials • Relative rarity of specific diseases • disease heterogeneity • incompletely defined natural history • Lack of research infrastructure • Ethical issues in pediatric research • Children cannot give consent • Benefits must outweigh risk • Difficulty in identifying valid clinical endpoints • Large amount of clinical practice variation

6. Pediatric Trials • Many initiatives • FDA—BPCA, PREA, FDAAA • NIH Pediatric Networks—NHLBI Pediatric Heart Network • Patterns emerging of: • Failure to see dose-response • Failure to demonstrate efficacy • Lessons learned??

7. Lesson 1: Extrapolation can be useful

8. Lesson 1: Extrapolation can be useful

9. Lesson 1: Extrapolation can be useful (or not) • Epidemiology of conditions in adults vs. children • Thrombosis--atrial fibrillation vs. single ventricle • Heart failure--ischemia vs. structural disease • Systemic hypertension--primary vs. mixed etiologies

10. Lesson 1: Extrapolation can be useful (or not)

11. Lesson 2: PK/PD studies are important precursors to efficacy studies • Developmental changes in children • Absorption, distribution, binding, clearance of drugs are age-dependent • Pitfalls when using extrapolated dosing

12. Lesson 2: PK/PD studies are important precursors to efficacy studies • Clopidogrel in adults • 75 mg/day provides a mean 30-50% inhibition of 5 μmol/L ADP-induced platelet aggregation • Treats and prevents major CV events • Extrapolation of dose ~ 1 mg/kg/day • PICOLO PD study—Children ages 0-24 months (Li et al, Circulation 2008) • 0.2 mg/kg/day achieves a mean 30-50% inhibition of 5 μmol/L ADP induced platelet aggregation • Platelets of children are hyporesponsive to activation markers with ↓ aggregation, ↓ granule secretion and ↓expression of activation markers in response to ADP, collagen • Impaired receptor mediated signal transduction in thromboxane synthesis, G protein mediated response, and intracellular Ca mobilization

13. Lesson 2: PK/PD studies are important precursors to efficacy studies • ACCP guidelines for recommended prophylactic doses of LMWH/enoxaparin based on extrapolation of dose from adult data • 0.75 mg/kg bid for neonates • 0.50 mg/kg bid for children > 2 mos • To achieve anti-activated factor X (Xa) levels of 0.5-1 and 0.1-0.3 U/ml respectively • Recent study (Ignjatovic et al, BJH 2010) • 299 children, 59% with DVT • Those <1 yr of age require ~1.5 mg/kg with frequent dose changes to achieve target therapeutic range

14. Lesson 2: PK/PD studies are important precursors to efficacy studies • Use preliminary PK/PD studies to guide dose selection • Sub-therapeutic dosing will lead to an efficacy study with no effect • Over-dosing may lead to an increase in adverse events • PK/PD information to see a positive slope in a dose response curves (hypertension) • Closely spaced dosages will may yield overlapping exposures among dose groups • If overlap is substantial, the dose response could appear flat and fail to demonstrate a dose response relationship (amlodipine, fosinopril, irbesartan)

15. Lesson 3: Appropriate formulations are important for drug delivery PICOLO

16. Lesson 3: Appropriate formulations are important for drug delivery • Liquid formulations allow for more precise dosing per kg • Crushed tablets suspended in aqueous medium are bitter • Ideal oral drug for children should be effective, well tolerated, have good stability, and have good palatability with acceptable taste, after-taste and smell • Excipients • bulk materials, flavorings, sweeteners and coloring agents • add desirable color, mask the unpleasant taste and smell, and facilitate a uniform mixture of the active ingredient • Stability and bioequivalence testing of liquid formulations require additional time and expense

17. Lesson 3: Appropriate formulations are important for drug delivery • Many failed antihypertensive studies (amlodipine, fosinopril, irbesartan) did not develop a liquid formulation with resulted in imprecise dosing throughout the trials. • PICOLO study (clopidogrel) • Extemporaneous solution • Very bitter and stability of only several days • Carvedilol • Combination liquid and pill

18. Lesson 4: Obtain clinical equipoise • The ethics of clinical research require equipoise • state of uncertainty on the part of the clinical investigator regarding the comparative therapeutic merits of each arm in a trial • Equipoise required for colleagues, referring physicians and parents as well • Parents often have therapeutic bias • Will hesitate to enroll their children in RCT with placebo arm when they are aware that the active agent is readily available for adults or off-label.

19. Lesson 4: Obtain clinical equipoise-example • Conflicting data reported from trials of ACE inhibitors for MR in both adults and children • Pediatric Heart Network ACE Inhibition in Mitral Regurgitation Study • Enalapril vs. placebo in children after AVSD repair with at least moderate MR and LV dilation • Of 139 subjects with at least mild to moderate MR on a screening echo, 47 were already on ACEi

20. Lesson 5: It is all in the primary endpoint! • Impractical to conduct a pediatric clinical trial with a statistically significant number of hard clinical endpoints • Surrogate endpoint • A laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint • Composite endpoint • Multiple single endpoints that are combined; the composite event rate is a measure of effect from a combined set of variables.

21. Lesson 5: It’s all in the primary endpoint! • Knowledge of the natural history with regard to surrogate endpoint and its relationship to the clinically meaningful endpoint is vital • Ability to accurately obtain the test

22. Lesson 5: It’s all in the primary endpoint! • Mostly a combination of a hard endpoint and soft components • Addresses broader aspects of a multi-faceted disease • Soft endpoints are subject to ascertainment ambiguity and clinical practice variation between centers

23. Conclusions • Pediatric drug trials are usually conducted after a product has been developed for adults and information from adult trials can be used to design pediatric trials. • Pediatric drug trials are technically challenging, yet well-powered safety and efficacy trials are critically important for child health • Results of negative studies provide important information • Issues such as lack of a liquid formulation, failure to incorporate PK into dosing, lack of equipoise, and the uncertain validation of surrogate and composite primary endpoints have led to difficulties observed in several pediatric trials

24. Future directions • Development of exposure-response models with existing adult and pediatric data to perform clinical trial simulations of pediatric studies and explore trial design and analysis options • Better use of pediatric registries to define the natural history • Better use of surveys to define clinical practice variation • Improved multi-center collaborative efforts