The Food and Drug Administration released the revised draft guidance entitled ‘‘Leveraging Existing Clinical Data for Extrapolation to Pediatric Uses of Medical Devices” on June 21, 2016 (Docket No. FDA–2015–D–1376). This guidance explains the circumstances in which appropriate extrapolation of medical device data (either from adults or a different pediatric subpopulation) to support pediatric device indications in premarket approval applications (PMAs), humanitarian device exemptions (HDEs), and de novo requests. Extrapolation may be appropriate when there are few differences in safety or effectiveness of the proposed device when used in adults as compared to the intended pediatric populations and the adult data are of high quality for borrowing. Extrapolation enables a sponsor to leverage adult data to support demonstration of a reasonable assurance of effectiveness and possibly the safety of a medical device for pediatric use.
It may be appropriate to extrapolate existing clinical data when the course of the disease or condition and effects of the device are sufficiently similar in adults and pediatric patients. Extrapolation should be limited to circumstances in which endpoints used in the adult data sources are relevant to the pediatric population, and the quality of the data is high. It is important to note that extrapolation for effectiveness and for safety are considered separately.
Title III of Food and Drug Administration Amendments Act of 2007 (FDAAA) is the Pediatric Medical Device Safety and Improvement Act (PMDSIA) of 2007. PMDSIA specifically authorized the use of adult data to demonstrate pediatric effectiveness. “If the course of the disease or condition and the effects of the device are sufficiently similar in adults and pediatric patients, the Secretary may conclude that adult data may be used to support a determination of a reasonable assurance of effectiveness in pediatric populations, as appropriate.”1
While PMDSIA addresses the extrapolation of existing data to support a determination of a reasonable assurance of effectiveness, it does not address safety data. However, there may be specific cases where it will be appropriate to consider extrapolation of existing clinical safety data to support or enhance evidence for pediatric indications for medical devices, including the effects of the device under consideration are identical when used in pediatric and adult populations and the course of the disease or condition and associated risk factors are the same between the two populations. When appropriate, data can be extrapolated from one pediatric subpopulation to another.1
Because the mechanism of action for devices is often well-characterized and often fairly localized, non-clinical forms of scientific evidence may provide information about device performance characteristics related to safe device functioning (for example: preclinical testing, engineering models, computer modeling, or other nonclinical data). The potential availability of these types of data for medical devices provides further support for the use of extrapolated clinical data to demonstrate safety in pediatric patients.1
In HDEs, extrapolation of data to demonstrate probable benefit of medical devices may be appropriate given the rarity of the diseases and/or conditions that are addressed by medical devices. When existing clinical data are relevant and appropriate for leveraging, the amount of prospective clinical data in the pediatric population needed to demonstrate a reasonable assurance of effectiveness and/or safety (or that probable benefits outweigh risks, for HDEs) may be reduced.1
Extrapolation of Clinical Data for Drug Products
Under PREA, if the course of the disease and the effects of the drug are sufficiently similar in adults and pediatric patients, the 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 [section 505B(a)(2)(B)(i) of the FD&C Act]. Thus, if similarity in disease process and the benefits of the drug are demonstrated between a pediatric population and adults, a drug may be considered to be effective in the pediatric population when the effectiveness has been demonstrated in adults.2
Extrapolation of data from adults to the pediatric population under PREA refers only to efficacy and not to safety or dosing. Note that the pharmacokinetics of a drug in the pediatric population will usually be required. Since each drug product and the target disease is unique, demonstration of similarity in the disease process between adults and the pediatric population may need to include the analysis of the pathophysiology, nature of the disease, mechanism of action of the drug, and maturity of the target organ(s) and/or enzyme systems in the pediatric population.
PREA also authorizes the extrapolation from one pediatric age group to another pediatric age group. It states, “A study may not be needed in each pediatric age group if data from one age group can be extrapolated to another age group” [section 505B(a)(2)(B)(ii) of the FD&C Act]. As noted, pediatric studies in one age group may not be required as long as the expected therapeutic benefits can be demonstrated to be similar to the beneficial effects observed in another age group. As with the process of extrapolation of the adult data, it necessarily depends on the similarity in disease process and the benefits of the drug. However, extrapolation of safety data is allowed between pediatric populations. In addition, the extrapolation may be supplemented with data to define dosing and safety for the relevant pediatric age groups.2
- CDRH, Guidance for Industry and Food and Drug Administration Staff, Leveraging Existing Clinical Data for Extrapolation to Pediatric Uses of Medical Devices. June 21, 2016. http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm444591.pdf
- CDER, Guidance for Industry, How to Comply with the Pediatric Research Equity Act, Draft Guidance. September 2005. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm079756.pdf