6:40 PM
Aug 17, 2018
 |  BioCentury  |  Regulation

Pediatric push

Why companies should invest in data, alliances to support pediatric extrapolation

FDA has endorsed extrapolation of therapeutic efficacy from adults to children for new drugs to treat partial onset seizures in a draft guidance and is now discussing in public meetings whether the approach can be extended to other indications, such as heart failure and pulmonary arterial hypertension.

Doing so on a large scale may require companies to change the way they study drugs in adult populations. Extrapolation depends upon evidence of similarity between adults and children, but sponsors do not routinely collect the necessary evidence in adult studies.

Pediatric drug approvals have lagged adult approvals despite laws and regulations intended to spur or mandate pediatric clinical research.

By law, companies must submit pediatric development plans to EMA once a drug has completed Phase I testing, and to FDA after Phase II. Japan’s PMDA does not require companies to perform pediatric studies, but offers extended market exclusivity and data protection as an incentive.

Even so, according to FDA, U.S. drug approvals for children continue to trail approvals for adults by about eight years, and off-label drug use dominates clinical practice. By some estimates, about half the drugs used in children and 90% of the drugs used in neonates have never been studied in those populations.

Reasons include difficulty recruiting enough pediatric patients for trials, the limited commercial potential of small pediatric markets, and risk-averse thinking that emphasized children’s protection to the point of excluding them from research.

“If we have to do a randomized multisite controlled trial for every single indication and every drug, we could never catch up.”

Jonathan Davis,Tufts University

Efficacy trials in children are also made difficult in some settings by incompatibility between standard endpoints and a child’s developmental abilities, or by the length of time required to assess long-term efficacy in chronic diseases with childhood onset. In neonates and preterm infants, defining outcomes measures is made difficult by the lack of consensus or guidelines on baseline parameters, such as blood pressure.

“Pediatrics were left behind for so long, and with neonates it’s much worse. If we have to do a randomized multisite controlled trial for every single indication and every drug, we could never catch up,” said neonatologist Jonathan Davis.

Davis is chief of newborn medicine and vice-chair of pediatrics at the Floating Hospital for Children at Tufts Medical Center, and professor of pediatrics at Tufts University School of Medicine.

Extrapolation can reduce or eliminate the need for clinical trials that are difficult and risky to do, but without which pediatricians are left to guess at appropriate use of drugs in children. Yet differences in disease progression and endocrine and metabolic profiles between adults and children make extrapolation tricky.

These differences also mean that determining dosing in children is not a simple matter of making adjustments based on weight.

Partial onset seizures is the first indication for which FDA has published a guidance that describes how to extrapolate efficacy in children from data collected in adults.

The draft guidance, released in February, applies to drugs already approved to treat epilepsy in adults. According to the document, the agency may approve the drugs for patients four and older based on efficacy...

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