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, the FDA “seeks to provide clarity and predictability for device sponsors and to ensure consistency within the 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.” The FDA also draws attention to the fact that the guidance does not change the regulatory threshold for valid scientific evidence.
The amount of existing scientific evidence available to substantiate submissions for pediatric medical devices is currently very limited. The 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, the 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.”
The FDA lists four main objectives for the guidance, which include:
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. The 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, the 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.
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:
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, the FDA notes that sponsors should consider all relevant biological characteristics.
When it is appropriate to extrapolate adult data, sponsors have various options for how to do so. “Available options could depend on whether a prospective study of pediatric patients is needed and feasible, and/or whether sufficiently robust pediatric data can be obtained in other ways, such as from prior studies run by the sponsor, studies in the literature, or pediatric registries.”
The FDA provides fairly explicit details regarding the options for extrapolating data. For additional information on these options and the statistical methodology involved, view the full guidance document.
According to statistic modeling, existing clinical data can be leveraged either fully or partially to support the safety and/or effectiveness of a medical device in a pediatric population.
With full data extrapolation, existing data is used as a complete substitute “for prospective pediatric clinical data in support of a determination of a reasonable assurance of effectiveness or of safety for a pediatric device. No prospective pediatric clinical data are anticipated for the endpoint being fully extrapolated.” Because of the number of potential differences between adult and pediatric patients, it is expected that full extrapolation will rarely be used to demonstrate safety.
In addition, manufacturers can also use partial data extrapolation, which is when existing adult data and pediatric data sources (or prospective pediatric clinical data) are combined (using a statistical model) to demonstrate a claim of safety and/or effectiveness. The guidance document states that “the construction of such a statistical model is anticipated to require the availability of measured variables that will help connect the adult outcomes to the pediatric outcomes. If necessary variables are not available in the data sources, partial extrapolation may not be appropriate. If the model is determined to be appropriate, then the inferences obtained from it may be used to support a pediatric indication.”
At times, existing clinical data can be used to support claims of safety, effectiveness, or both in medical devices. However, oftentimes the study endpoints used to demonstrate effectiveness are typically different from those used to demonstrate safety. Because of this, the FDA recommends that manufacturers consider whether the data will be extrapolated for safety or effectiveness (or both) independently.
Furthermore, due to the physiological differences between adults and children that may have an impact on device safety, the FDA anticipates that extrapolation for safety will be rarer than extrapolation for effectiveness.
Extrapolation, whether full or partial, adds uncertainty into the FDA’s assessment of the device’s effectiveness and safety. The extent of this uncertainty is dependent upon the differences between the two populations, as well as the quality of the data. When making benefit-risk determinations, the FDA takes this uncertainty into consideration.
As such, the FDA will only permit extrapolated data to be used when it can be done in a way that supports reasonable, scientifically sound conclusions about medical device effectiveness and safety based on valid scientific evidence.
There are a number of general factors that can aid in determining whether, and to what extent, extrapolation is necessary and appropriate.
Factors that may prevent the extrapolation of adult data include, but are not limited to:
“Factors that may limit extrapolation to a partial extent and thus require conducting a prospective study of pediatric patients include, but are not limited to, the following:
In the guidance document, the FDA states that the appropriateness of extrapolation largely depends on the following factors:
In situations where similarity and quality are both determined to be high, there is a great level of certainty that the existing data can be appropriately considered for extrapolation to the intended pediatric subpopulation. Conversely, in circumstances where neither similarity nor quality are determined to be high, it may not be appropriate to use the existing adult data for extrapolation purposes.
When determining if it is appropriate to extrapolate existing data and, if so, whether extrapolation should be full or partial, the FDA recommends using a decision tree. In the guidance, the FDA specifically states that the decision tree is intended to act only as an aid in making the final judgement. As such, “a conclusion from the decision tree that extrapolated data may be used does not necessarily mean that these data will support an approval decision for the PMA, de novo, or HDE application.”
In the guidance, the FDA provides a sample of the decision tree that sponsors should use as well as a list of the questions to consider in using the decision tree. For additional details, view the full guidance document.
In its guidance, the FDA states “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.”
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.
Furthermore, the guidance notes that sponsors can use the quantitative information that is provided by the existing adult data in one of two ways:
The statistical model that combines both the adult and pediatric data has the potential to strengthen the scientific evidence that is available to show effectiveness and/or safety among the pediatric population. This is known as “borrowing strength.” The FDA notes that the exact model used to borrow strength can vary from case to case, but regardless of the model used, the degree of leveraging depends on the similarity between borrowed data and any pediatric data that will be collected.
Furthermore, “the extent of borrowing may also be moderated by clinical judgments that are not inherently implied by the statistical modeling. This may include consideration of the quality of the data, the particulars of the populations and the studies, and whether such data are intended to demonstrate either safety or effectiveness (or both).”
The 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:
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. The 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, the 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.
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