1.  Acceptance of Data from Clinical Studies

On February 25, 2013, the U.S. Food and Drug Administration (FDA) issued a proposed rule amending its regulations to update the standards for FDA acceptance of data from clinical studies.  FDA is proposing to amend these regulations so that acceptance of data from clinical studies is consistent across all types of device submissions.  FDA believes that the proposed rule will ensure protection of human subjects and quality and integrity of data obtained from such studies, while also being flexible enough to account for the differences in clinical research throughout different countries.

The proposed rule would require clinical studies conducted outside the United States in support of investigational device exemption (IDE) applications, premarket notification (510(k)) submissions, premarket approval (PMA) applications, product development protocols (PDPs) and humanitarian device exemption (HDE) applications to be conducted in accordance with good clinical practices (GCPs).  This includes the review and approval of the study by an independent ethics committee (IEC) and obtaining and documenting the freely given informed consent of subjects (except in life-threatening situations).  In addition, a statement would be required assuring the availability of the study data to FDA for validation through an onsite inspection if FDA deems it necessary.  There is also a requirement regarding the retention of records for up to two years.

Currently, FDA regulations for 510(k) submissions and IDE applications do not address these requirements.  Therefore, the proposed rule would incorporate GCPs into the existing 510(K) and IDE regulations regarding FDA acceptance of data from studies conducted outside the United States (these changes would simultaneously address requirements for FDA acceptance of data from clinical studies conducted inside the United States).  With respect to PMAs, the proposed rule would also amend regulations to require the acceptance of data from outside the United States to be in compliance with GCPs (whereas previously, they were required to be in compliance with the Declaration of Helinski).

FDA will be accepting electronic or written comments on the proposed rule by May 28, 2013.  The proposed effect date for the final rule would be 180 days after publication of the final rule in the Federal Register.

2.  Distinguishing Medical Device Recalls from Product Enhancements

On February 22, 2013, FDA issued a Draft Guidance, “Distinguishing Medical Device Recalls from Product Enhancements and Associated Reporting Requirements,” in order to clarify when a potential change to a device constitutes a medical device recall and to distinguish these from instances that constitute mere “product enhancements.”  The Draft Guidance explains how to differentiate between a device recall and a product enhancement and describes the respective reporting requirements for each.

Recall regulations require removal or correction of a marketed product by the manufacturer to correct a product defect or performance failure that renders the product violative and poses a public health risk. In these instances, manufacturers are required to comply with the recall reporting requirements under 21 C.F.R. Part 806, including a correction and removal report (“806 report”). “Recalls” do not include “market withdrawals” or “stock recoveries” (those terms are defined in 21 C.F.R. Parts 7 and 806). The purpose of this Draft Guidance is to clarify that recalls also do not include “product enhancements.”

Although FDA regulations do not define “product enhancement,” for the purposes of the Draft Guidance, FDA defines a product enhancement as a change or improvement to a non-violative device as part of continuous device improvement activities. This includes changes designed to better meet the needs of the user, changes that make the product easier to manufacture and aesthetic changes that do not affect its use. The key distinguishing factor between a product enhancement and a recall is that a product enhancement is not a change to remedy a violation of the Federal Food, Drug and Cosmetic Act (FCDA).

In order to determine whether the change to the device does not reach the higher threshold of a product recall, the manufacturer must determine whether the device can be marketed without change and still be in compliance with FDA regulations. A “Recall Decision Making Flow Chart” is provided (Draft Guidance at 8). Manufacturers should ask themselves the following three questions (before making a change):

  1. Is the device failing to perform as intended or failing to meet any specification?
  2. Is the device labeling false, misleading or otherwise inaccurate?
  3. Is the device otherwise out of compliance with FDA regulations?

If the answer is affirmative for any of these questions, the change would constitute a product recall; however, if the answer is negative for all three questions, the change constitutes a mere product enhancement. Once a manufacturer has determined that the change is a product enhancement, the Draft Guidance explains that the 806 report is still required if the correction or removal is initiated “to reduce a risk to health posed by the device” (e.g., a design change to improve a product’s safety profile) unless all the information has previously been provided under FDA’s medical device reporting requirements.

The Federal Register notice states that comments should be submitted by May 23, 2013.

3.  Providing Information about Pediatric Uses

On February 19, 2013, FDA also issued a supplemental notice of proposed rulemaking, along with a Draft Guidance, “Providing Information about Pediatric Uses of Medical Devices Under Section 515A of the Federal Food, Drug, and Cosmetic Act,” requiring certain submissions for medical devices to include “readily available pediatric use information.” The proposed rule would require any request for a HDE, any PMA or supplement, or any PDP to include any publicly available information about any pediatric subpopulation that suffers from the disease or condition that the device is intended to treat, diagnose or cure, and the number of pediatric patients affected by the disease or condition.

The rule defines pediatric patients as persons 21 years of age and younger at the time of their diagnosis or treatment and includes the following subpopulations: neonates (birth to 28 days), infants (29 days to 2 years), children (2-12 years) and adolescents (12-21 years). The pediatric use information requirement would be met by providing information available in the public domain (e.g., research published in peer-reviewed medical journals) on U.S. subjects. Data on non-U.S. subjects should only be used in the absence of readily available information on U.S. subjects. The pediatric use information submission should briefly describe in narrative form the natural history of the disease or condition and include a description of the proposed indications for the device, as well as an estimate of the number of affected pediatric patients in the United States that suffer from the disease or condition that the device is intended to treat, diagnose or cure. The Guidance provides a table for how this information should be presented (Draft Guidance at 7).

FDA stated in its Draft Guidance that it will use this information to comply with the statutory requirement to provide an annual report to Congress that includes the number of devices approved that year for these pediatric populations. This is another reason why FDA requests “publicly available information;” since this information will be presented to Congress, FDA explicitly instructs sponsors to exclude proprietary, trade secret and commercial confidential information. The Agency also indicated that it would like to use this information to determine unmet pediatric needs in medical device development so that the Agency can coordinate with industry, stakeholders and FDA staff to promote development and proper labeling of pediatric devices. Of course, providing this information will not be sufficient to establish the safety and effectiveness of a device for a new pediatric indication.

This supplemental notice of proposed rulemaking is FDA’s second attempt to issue pediatric submission requirements. On April 1, 2010, FDA first issued a proposed rule along with a direct final rule, but later withdrew the direct final rule after receiving “significant adverse comments.” FDA will be accepting electronic or written comments on the newest proposed rule by April 22, 2013.

4. Registration and Listing Of Contract Manufacturers

A reminder that starting in Fiscal Year (FY) 2013 (which began on October 1, 2012), FDA made changes to the registration and listing requirements for medical devices. These changes, required as part of the enactment of the Food and Drug Administration Safety and Innovation Act (FDASIA), expanded the entities for which FDA establishment registrations must be filed to include all contract manufacturers of finished devices, regardless of whether they put the device into commercial distribution. A notice of changes for FY 2013 and a full listing of which entities must register, list and pay the establishment registration fee, can be found on FDA’s website.