Data Extrapolation to Support Pediatric Labeling

September 21, 2016
Brian D. Bollwage, JD

The FDA’s objectives regarding pediatric labeling have been misunderstood due to a confusing history on the matter. Data extrapolation can leverage an avenue for providing more comprehensive labeling for pediatric drugs.

Although the FDA has always been focused on improving drug and device instructions for the safe and effective use of drugs and devices in children, this issue has a confusing history, which has led to industry misunderstandings about the FDA’s desires regarding pediatric labeling. This blog will clarify some of these misimpressions.    A Confusing History, Condensed   Since the early 1990s, the FDA has encouraged using data extrapolation to provide more comprehensive labeling for use of drugs in pediatric patients. The 1994 Pediatric Labeling Rule created a pediatric use subsection in drug package inserts and encouraged the use of data extrapolation.   However, the FDA’s 1998 Pediatric Rule required drug manufacturers to study efficacy and safety of drugs in children or risk FDA denial. Somewhat concurrently, Congress provided incentives to encourage pediatric drug testing in the FDA Modernization Act (FDAMA) of 1997. Both encouraged pediatric clinical trials, while the FDAMA’s promise of extended exclusivity and the Pediatric Rule’s threat of NDA rejection captured much attention.   After a federal court in 2000 vacated the Pediatric Rule, Congress responded in 2003 by incorporating its relevant provisions into the Pediatric Research Equity Act (PREA) and went much further to require the conduct of clinical trials in pediatric populations. The resulting confusion led the industry to conclude, incorrectly, that efficacy trials in pediatric patients were required in order to incorporate a claim for pediatric use into product labeling.   The Actual State of Affairs   However, included in the PREA of 2003 is language that permits the FDA to accept data extrapolation in creating pediatric labeling:

  • “Where the course of the disease and the effects of the drug are sufficiently similar in adults and pediatric patients, FDA may conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled studies in adults usually supplemented with other information obtained in pediatric patients, such as pharmacokinetic studies. Studies may not be needed in each pediatric age group, if data from one age group can be extrapolated to another.”

The FDA can and does grant pediatric labeling claims for drugs based on extrapolated data. In a 2011 study looking at 166 products approved for pediatric use between 1998-2008 (Dunne J et al. Pediatrics 2011; 128; e1242), 29 used no data extrapolation, 113 relied on partial data extrapolation and 24 relied completely on extrapolated data.   It is important to note that for drugs, extrapolation is appropriate only to support a determination of efficacy. In most cases, the FDA will not accept extrapolated adult safety data.  

How to Leverage Extrapolated Data

  The FDA’s three-part test indicates that extrapolation of efficacy must be based on evidence-based assumptions:

  • Is the course of the disease sufficiently similar in adults and children?

  • Is the response to treatment sufficiently similar in adults and children?

  • Do adults and children have a sufficiently similar exposure-response relationship OR can the pediatric dose to match the adult exposure be determined in cases when certainty already exists on response?

Extrapolating Adult Data for Medical Devices

  In 2007, the Pediatric Medical Device Safety and Improvement Act, Title III of the Food and Drug Administration Amendments Act (FDAAA), authorized the use of adult data to demonstrate pediatric effectiveness. In June 2016, CDRH issued a draft guidance,

“Leveraging Existing Clinical Data for Extrapolation to Pediatric Uses of Medical Devices,”

which espouses similar principles as expressed for drugs in determining whether extrapolation is appropriate. CDRH cites three main factors to consider:

  • The similarity of the existing adult response data and/or population characteristics to the intended pediatric population

  • The quality of the adult data in terms of study design, data collection and measurement

  • Whether extrapolated data may be used to fairly and responsibly decide whether there is reasonable assurance of the safety and effectiveness (or probable benefits for humanitarian device exemptions) of a medical device

What is important is the comparison in regard to disease and response to treatment and the quality of the data relied upon. Also, extrapolation of efficacy data can only be used to support a PMA, HDE or de novo premarket application but not a 510(k).  


  The FDA’s ultimate objective, providing safe and effective treatments to patients, is supported by data extrapolation where the requisite conditions are met. There is no single approach to fit all circumstances. The FDA strongly advises researchers to consult early with the agency to determine the appropriateness and degree to which data extrapolation may be leveraged.