Transcript Clinical and Research Advances in Alcoholism

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Pediatric Clinical Trials, Lessons Learned
Jennifer S. Li, MD, MHS
Professor of Pediatrics and Medicine
Division of Cardiology
Duke University School of Medicine
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Disclosures
● I have received research support from Sanofi-Aventis &
Genzyme and consulting fees from Daiichi-Sankyo,
Pfizer, and PTC Bio related to this topic.
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
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Pediatric Cardiovascular Drug Studies
● Hypertension
● Congestive heart failure
● Antiarrhythmic agents
● Antithrombotic agents
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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
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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??
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Lesson 1: Extrapolation can be useful
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Lesson 1: Extrapolation can be useful
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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
Lesson 1: Extrapolation can be useful (or
not)
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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
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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 ADPinduced 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
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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
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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)
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Lesson 3: Appropriate formulations are
important for drug delivery
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
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Lesson 3: Appropriate formulations are
important for drug delivery
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● 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
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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.
Lesson 4: Obtain clinical equipoiseexample
● 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
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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.
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Lesson 5: It’s all in the primary endpoint!
Drug
Indication
Surrogate Endpoint
ACEi, ARB, β-blockers Hypertension
BP lowering effect (DBP vs. SBP)
Statins
Hyperlipidemia
LDL lowering effect
Atorvastatin
Atherosclerosis in children with
lupus
Carotid IMT
Enalapril
Infant Single Ventricle
Growth
Mitral regurgitation post AVSD
repair
LV end-diastolic dimension Z-score
Sildenafil
Pulmonary hypertension
Exercise tolerance
Ataluren
Duchenne’s muscular dystrophy
6 min walk test
● 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
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Lesson 5: It’s all in the primary endpoint!
Drug
Indication
Milrinone
Post-op congenital HD Death, or low cardiac output syndrome requiring
additional or new pharmacologic or mechanical support
Carvedilol
Heart failure
Worsened, unchanged, or improved. Worsened defined
as death, hospitalization requiring IV meds, treatment
failure, worse HF class or global assessment score
Clopidogrel
Post-op systemic to
pulmonary artery
shunt
Death, shunt thrombosis, or intervention <120 days for a
condition of a thrombotic nature
Alglucosidase Pompe disease
alfa
Composite Endpoint
Death or need for invasive ventilation at 18 months of
age
● 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
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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 wellpowered 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
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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