By Kristen Booth
In 2004, the FDA issued a guidance document, entitled “Premarket Assessment of Pediatric Medical Devices.” The guidance stated that, when consistent with scientific principles, data can be extrapolated to support effectiveness and, on a limited basis, safety for premarket approval applications (PMAs). In 2014, the Agency updated that guidance to clarify that, “as with other forms of valid scientific evidence used to demonstrate effectiveness and safety for a device intended for a pediatric population, the amount and type of extrapolated data necessary to support a pediatric indication for a device varies.”
In 2007, Congress passed the Food and Drug Administration Amendments Act of 2007 (FDAAA). Included under Title III of the FDAAA is the Pediatric Medical Device Safety and Improvement Act (PMDSIA) of 2007, which specifically authorized the use of adult data in demonstrating pediatric effectiveness. Furthermore, PMDSIA also states that “data can be extrapolated from one pediatric subpopulation to another,” when appropriate.
On June 21, 2016, the FDA published a final guidance, entitled “Leveraging Existing Clinical Data for Extrapolation to Pediatric Uses of Medical Devices.” With this guidance, FDA “seeks to provide clarity and predictability for device sponsors and to ensure consistency within FDA regarding the specific criteria that should be considered when deciding whether leveraging existing clinical data to support pediatric claims is appropriate, and if so, to what extent.” FDA also draws attention to the fact that the guidance does not change the regulatory threshold for valid scientific evidence.
Background & Overview
The amount of existing scientific evidence available to substantiate submissions for pediatric medical devices is currently very limited. FDA feels that leveraging relevant and available clinical data could lead to the approval of more devices with pediatric indications, which would “increase the availability of medical devices with appropriate labeling to support safe and effective device use in pediatric patients.” Furthermore, FDA states that “this approach will potentially streamline the process for establishing a pediatric intended use claim, and enhance and encourage pediatric device development programs.”
FDA lists four main objectives for the guidance, which include:
- “Increase the availability of safe and effective pediatric devices by providing a roadmap for leveraging relevant existing clinical data for use in demonstrating a reasonable assurance of safety and effectiveness in pre-market approval applications (PMAs) and de novo requests, as well as for use in supporting approvals of humanitarian device exemptions (HDEs).
- Explain the circumstances in which it may be appropriate to leverage existing clinical data to support pediatric device indications and labeling.
- Outline the approach FDA uses to determine whether extrapolation is appropriate, and, to what extent the data can be leveraged.
- Describe statistical methodology that can be used to leverage the data in a way that increases precision for pediatric inferences.”
In the guidance document, the FDA explains how and when clinical data from another studied population may be leveraged and used to support the approval and labeling of medical devices indicated for pediatric patients. FDA also notes that the totality of the evidence must be considered in order to make decisions about the effectiveness and safety of a medical device. As such, the Agency will continue to consider clinical data in addition to other scientific evidence from assessments of device performance to determine whether or not the product’s safety and effectiveness has been adequately demonstrated.
The guidance document applies to medical devices subject to the PMA, HDE, or de novo premarket requirements where a pediatric indication is sought. “For these premarket submissions, 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, and the existing data are determined to be valid scientific evidence.” Furthermore, FDA notes that the policies outlined in the guidance do not apply to 510(k) submissions in which a pediatric indication is proposed for the device.
Definition of Pediatric Patients
According to section 520(m)(6)(E)(i) of the Federal Food, Drug, & Cosmetic Act (FD&C Act), ‘pediatric patients’ are defined “as persons aged 21 or younger at the time of their diagnosis or treatment (i.e., from birth through the 21st year of life, up to but not including the 22nd birthday).” Additionally, section 520(m)(6)(E)(ii) defines pediatric subpopulations as neonates, infants, children, and adolescents. The guidance states that “age ranges for these pediatric subpopulations are as follows:
- Neonates: from birth through the first 28 days of life
- Infants: 29 days to less than 2 years
- Children: 2 years to less than 12 years
- Adolescents: aged 12 through 21 (up to but not including the 22nd birthday)”
The Agency also notes that, despite the definitions that are provided above, extrapolation may not always follow them exactly. “For example, the course of an orthopedic disease may be determined by factors that are not categorized into the subpopulations listed above, but instead are categorized by skeletal maturity.” As such, FDA notes that sponsors should consider all relevant biological characteristics.
Why Extrapolate from Adult Data for Pediatric Use?
The ability to extrapolate adult data for pediatric use could be of benefit to pediatric patients by increasing the availability of medical devices with the appropriate labeling to support safe and effective pediatric use. FDA recognizes that “there are many potential challenges involved in conducting pediatric clinical trials to support pediatric indications for devices.” Some of these challenges include:
- “Small and diffusely scattered potential pediatric populations lead to small (trial sample sizes.)
- Challenges exist in enrollment and consent procedures, which could increase the length of time needed to conduct clinical trials.
- There are more variations in pathophysiology, physiology, anatomy, and human factors in children and within pediatric subpopulations as compared to adults.
- Reference samples to test for or determine surrogate outcome measures may require an amount of blood too voluminous to obtain safely from a neonate or small child.”
Only a small number of devices have pediatric-specific indications and labeling, which is said to be due to the challenges listed above. However, the off-label use of adult devices – those without labeling information to guide safe and effective use in children – is becoming increasingly more prevalent. FDA feels that allowing manufacturers to use existing clinical data when appropriate, it may “reduce the need to prospectively conduct large pediatric clinical trials by bolstering other scientific evidence supporting a reasonable assurance of safety and effectiveness in a pediatric population.”
Furthermore, FDA notes that by allowing the extrapolation of existing data, it could encourage manufacturers to provide performance data which supports a pediatric indication, thus reducing the unsafe off-label use of devices indicated for use in adults. Ultimately, FDA notes that informative labeling promotes safe and effective pediatric use benefits the patients.
Interested in learning more? Part two, entitled “FDA Provides Device Makers with Clarity Regarding the Use of Existing Clinical Data to Support Pediatric Claims, Part Two,” is available now with details on:
- Borrowing Strength from Adult Data
- Pediatric Extrapolation Decision Process
- Factors That Could Limit Extrapolation
- Uncertainty in Extrapolating Data
- Statistical Methodology for Extrapolation