A new supplemental proposed regulation and related draft guidance document released by the US Food and Drug Administration (FDA) both aim to clarify what is expected of sponsors submitting medical device applications, which are now required to provide information regarding the pediatric subpopulations that suffer from the disease or condition their product is intended to treat.
In 2007, Congress passed the FDA Amendments Act, a massive piece of legislation that channeled a significant amount of energy into commitments meant to make products safer for consumers to use.
On the pharmaceutical side of the legislation, that meant the enactment of Risk Evaluation and Mitigation Strategies (REMS), which include elements to ensure that products are used as intended by regulators and manufacturers.
On the device side, that meant section 515A of FDAAA, which requires any sponsor of a premarket approval application (PMA), PMA supplement, humanitarian device exemption (HDE) or product development protocol (PDP) to submit to FDA information regarding how many children suffer from the disease their product is intended to treat.
FDA defines pediatric populations as including neonates (0-28 days), infants (<2 years), children (2-12 years of age) and adolescents under 21 years of age. In other words, if a product can treat a person under the age of 21, it falls under section 515A of FDAAA.
"The application or protocol described … shall include, with respect to the device for which approval is sought and if readily available: (A) a description of any pediatric subpopulations that suffer from the disease or condition that the device is intended to treat, diagnose, or cure; and (B) the number of affected pediatric patients," the law states.
The goal of section 515A is relatively straightforward: Products that are likely to be used by children should have information regarding special accommodations for their safe use in pediatric subpopulations. Those concerns have historically been primarily associated with pharmaceutical products due to their potential to be metabolized differently by children, but FDAAA expanded those concerns to devices as well, and called on regulators to develop plans to expand pediatric medical device research and development.
Section 515A calls on manufacturers to submit to FDA data that might be used to support its safety and efficacy in children.
"If the course of the disease or condition and the effects of the device are sufficiently similar in adults and pediatric patients, the [FDA] may conclude that adult data may be used to support a determination of a reasonable assurance of effectiveness in pediatric populations, as appropriate," section 515A explains. Additionally, data about subpopulations may be extrapolated to one another.
Despite the law being implemented nearly half a decade ago, FDA said in a concurrent notice that it had several difficulties proposing and passing a regulation to fully implement section 515A into law as the result of several comments that called into question the very way in which it set about trying to regulate.
Those comments, it said, argued that the regulation as written in 2010 would have exceeded FDA's regulatory authority, but that it already had the ability to regulate pediatric information through its basic authority per 21 CFR 814.42(e)(2) to "refuse to file any PMA application that does not contain required elements."
Those comments sent FDA back to the regulatory drawing board, which it has now returned from with a supplemental notice of proposed rulemaking released 19 February 2013.
The rule, it writes, is intended to fully implement section 505A and codify a definition of "readily-available information," as well as associated penalties for failure to include that information.
New Definitions and Requirements
FDA explains in its accompanying draft guidance that it takes the term to mean, "Information that is available in the public domain … available through commonly used public resources for conducting biomedical, regulatory and medical product research."
These sources, it says, might include medical journals, statistical registries maintained by federal agencies, meta-analyses maintained by groups like Cochrane, information from clinicaltrials.gov, large surveys, patient registries and other clinical databases.
Unacceptable sources of data will include internal marketing surveys, sales records, R&D reports, private consultations with experts and unpublished presentations, FDA wrote. In other words, anything that isn't publicly available.
So what pediatric use information needs to be included in those submissions? FDA explained in the draft guidance that sponsors should collect all relevant information in a separate section of their application entitled "515A Pediatric Device Use Information."
That section will consist of two major elements: a description of the uses of the device and an estimate of the number of pediatric patients it affects in the US. This information should be contained in tabular form, along with a brief narrative summary of the disease itself.
Example of Pediatric Summary Table
Pediatric subpopulation /
Specific device /
This device is indicated for use as an adjunct to medical therapy in the management of pediatric and adult patients with the following clinical conditions:
Congestive heart failure related to [rare congenital disease, e.g., Duchenne's muscular dystrophy]
Widget Model M-111
Harsh Consequences for Failure to Comply
Consequences of not producing that information are also explored in FDA's proposed rulemaking.
For sponsors, the penalties are potentially severe and indirectly costly. "If the applicant does not submit the information required by section 515A(a) of the FD&C Act, FDA may not approve the application until the applicant provides the required information," FDA explained.
If FDA finds that an application is missing the pediatric section during the course of its normal review, it says it will contact the applicant and ask it to amend the application to include the required information.
If FDA does not detect this omission until the end of the review, it said it would send sponsors an "approvable letter" placing final approval on hold until section 515A data is submitted to the agency for review.
Sponsors with other deficiencies that could still obtain approval will be sent a "major deficiency" letter explaining the effect of the missing 515A data in addition to other deficiencies, FDA said.
Comments on the amended regulation and draft guidance are due to FDA on 22 April 2013.