Device Firms: What You Should Know About The 21st Century Cures Act

By Mason Weeda

Last month, legislation that would affect, among other things, FDA’s regulation of medical devices and the manufacturers of such devices took a considerable step forward when it was introduced and then unanimously approved by the House Energy and Commerce Committee by a vote of 51-0 on May 21.  Known as the 21st Century Cures Act (“Act”), the stated aim of the legislation is to modernize and personalize health care, encourage innovation, support research, and streamline the U.S. health care system to promote the delivery of better and faster “cures” to more patients.

In support of this goal, the Act would change the review of medical devices determined to be “breakthrough,” establish a third-party option for the inspection of medical device manufacturers, make changes to certain Humanitarian Device Exemption (“HDE“) requirements, institutionalize FDA’s ongoing efforts regarding the regulation of medical software applications, and loosen some clinical investigation requirements.  Significantly, the legislation also indicates an ongoing Congressional interest in the restrictions FDA has placed on the dissemination of truthful and nonmisleading off-label information.

Breakthrough Device Pathway

The Act would support faster “cures” by creating a “priority review” pathway for those devices that meet the definition of a “breakthrough device.”  These “breakthrough devices” include those that “represent breakthrough technologies… for which no approved alternative exist,” offer “significant advantages over existing approved or cleared alternative,” and are “otherwise in the best interest of patients.”

Upon a sponsor’s request, FDA would determine whether a device meets the “breakthrough device” designation using specified criteria.  If a device receives such designation, it would be eligible for expedited review by a team of staff that will interact with the device sponsor.  During this process, the Act would require FDA to “take steps to ensure that the design of clinical trials is as efficient as practicable, such as through adoption of shorter or smaller clinical trials, application of surrogate endpoints and use of adaptive trial designs and Bayesian statistics.”  Likewise, the agency would also be required to “facilitate … expedited and efficient development and review of the device through utilization of postmarket data collection.” Although these are laudable goals, the Act does not impose any specific timelines in which an “expedited review” must be completed or otherwise quantify how much existing review times will be reduced.

Third-Party Inspections of Device Manufacturers

The Act also contains provisions that could allow FDA to conserve its inspectional assets and speed up approval of modified versions of existing devices by allowing for the use of third party inspectors to conduct the necessary establishment inspections.  The theory being that creating a “quick” method to inspect facilities in these circumstances would promote the earlier availability of improved “cures.”

Under the provisions of the Act titled “Medical Device Regulatory Process Improvements,” Congress would require FDA to establish a “third-party quality system assessment” program, where accredited third parties would inspect manufacturers for compliance with the Quality System Regulation (“QSR”) (21 C.F.R. Part 820).  However, use of such third-party inspections would be limited only to QSR inspections necessary as the result of submissions involving “device related changes” and would not be available in other types of establishment inspections.

Changes to Humanitarian Device Exemptions

This section of the Act would double the number of patients that must suffer from a disease in order for FDA to consider it a “rare disease.”    Presently, the HDE pathway is intended to incentivize and encourage the development of devices to treat “rare” diseases or conditions affecting small patient populations when the device manufacturer`s research and development costs would otherwise exceed its market returns.  It does so by significantly reducing the clinical data that would be necessary for the manufacturer to generate to support the efficacy of the device that would otherwise be required by FDA in a traditional marketing application. To qualify for an HDE, the disease or condition must presently affect fewer than 4,000 individuals in the United States per year. The Act seeks to encourage additional development making “cures” more widely available by increasing this number to 8,000 individuals.

Medical Software

In an apparent effort to “modernize” the technology involved in health care, the Act would create a definition of “health software,” which generally would not be regulated unless it:

  • is intended for use to analyze information to provide patient-specific recommended options; or
  • FDA determines that it poses a significant risk to patient safety.

This provision continues to allow FDA some flexibility as to how it may regulate software.  The Act also would require the agency to review existing regulations and guidance regarding software, including the classification of software, standards of verification and validation, review of software, and quality system for software, among others.

Clinical Trials

The Act would also make it easier for sponsors conducting clinical investigations by requiring the Department of Health and Human Services (“HHS”) to harmonize its requirements applicable to clinical investigations with FDA’s own requirements. This supports the Act’s goals by significantly reducing the regulatory burden imposed on sponsors who must presently ensure that their clinical investigations meet the often duplicitous requirements imposed by both HHS and FDA controls.  The Act also would make it easier for sponsors to meet Institutional Review Board (“IRB”) requirements by allowing the use of non-local IRBs to review medical device trials, including Investigational Device Exemptions (“IDE”) and HDEs. Permitting the use of non-local IRBs support the Act’s goal of “quicker cures” by eliminating the “log jam” and delays sometimes associated with the use (and overuse) of local IRBs by giving sponsors additional options that are potentially faster than the traditional ones.

Promotion

Lastly, and without limitation, the Act’s section on “Facilitating Responsible Communication of Scientific and Medical Developments,” provides that FDA “shall, within 18 months, issue draft guidance on facilitating the responsible dissemination of truthful and non-misleading scientific and medical information not included in the approved labeling of drugs and devices.”  This provision appears to be in response to the Coronia Case (U.S. v. Caronia, 703 F.3d 149 (2d Cir. 2012)), which holds that representatives of pharmaceutical manufacturers have a right under the First Amendment to make truthful statements regarding their products, even if such statements indirectly promote drugs for uses not approved by FDA.  The Act does not provide further direction on this topic, but Congress is clearly nudging FDA to update its position on off-label promotion which may affect medical device manufacturers.

It may be an uphill battle for Congress to agree on all topics involved in the 308 pages of 21st Century Cures Act.  However, as reported by the House Energy and Commerce Committee Press Releases, the bill appears to have support from industry and consumer groups, which may help bring Congress together.

FDA Provides Another Guidance Concerning FDA’s Use of Foreign Study Data

By Mason Weeda

FDA’s Center for Devices and Radiological Health (“CDRH”) and Center Biologics Evaluation and Research (“CBER”) recently published a new draft guidance entitled “Acceptance of Medical Device Clinical Data from Studies Conducted Outside the United States [(“OUS”)] (“Draft Guidance”) (available here). With this Draft Guidance, FDA aims to minimize the possibility for additional or duplicative U.S. studies, to harmonize global clinical trial standards, and to promote public health and innovation.

The Draft Guidance adds to a myriad of policies, statutory and regulatory provisions, and proposed rules on OUS studies, including:

  • FDCA § 569B (or 21 U.S.C. § 360bbb-8) which requires FDA to accept data from clinical investigations conducted OUS, in deciding whether to approve or clear a device. Pursuant to §569B, if FDA finds that such data are inadequate under applicable standards to support clearance or approval of the device, then FDA must provide the sponsor with written notice of the finding and FDA’s rationale.
  • 21 C.F.R. § 814.15 which provides that OUS clinical study data submitted in support of a Premarket Approval Application (“PMA”) and conducted under an Investigational Device Exemption (“IDE”) shall comply with Part 812. If an OUS study in support of a PMA is not conducted under an IDE, FDA will accept studies which have been conducted outside the United States and begun after November 18, 1986, “if the data are valid and the investigator has conducted the studies in conformance with the ‘Declaration of Helsinki’ or the laws and regulations of the country in which the research is conducted, whichever accords greater protection to the human subjects.” If relying on a study that started before November 19, 1986, FDA must be satisfied that “the data are scientifically valid and that the rights, safety, and welfare of human subjects have not been violated.” A PMA based solely on foreign clinical data and otherwise meeting the criteria for approval under this part may be approved if the foreign data are: “applicable to the U.S. population and U.S. medical practice;” “have been performed by clinical investigators of recognized competence;” and “considered valid without the need for an on-site inspection by FDA or… FDA can validate the data through an on-site inspection or other appropriate means.”
  • Proposed Rulemaking. Over two years ago, FDA published a proposed rule on “Human Subject Protection; Acceptance of Data from Clinical Studies for Medical Devices.” The proposed rule, when finalized, would require that foreign clinical studies in support of PMAs, IDEs, HDEs and 510(k)s be conducted in accordance with good clinical practice (“GCP”).
  • 2001 Guidance. In March 2001, FDA issued guidance on acceptance of foreign clinical studies titled “Guidance for Industry-Acceptance of Foreign Clinical Studies”, which describes the acceptance of foreign clinical studies in support of an application for marketing approval of human drugs, medical devices and biological products. This guidance merely clarifies that FDA incorporated the 1989 Declaration of Helsinki in its regulation governing investigational drug trials conducted in foreign countries and that it was not amending the regulation to incorporate the 2000 amendments to the Declaration.

The Draft Guidance elaborates on FDA’s regulation and provides some insight on what FDA may focus on when evaluating the adequacy of an OUS study. Not surprisingly, FDA makes it clear that sponsors should seek input from FDA prior to initiating an OUS device study to ensure that it will generate adequate and valid scientific data. The Draft Guidance essentially provides three primary considerations related to relying on OUS clinical data:

  • Differences in study populations. To the extent a device has disparate safety effects in different demographic groups, differences in the race, ethnicity, age, gender and sex of a foreign population can affect the applicability of the study to the intended U.S. population. Reporting on the representation of such groups in the device submission allows appropriate sub-group analyses. The foreign population and the intended U.S. patient populations may also differ in the prevalence of clinical factors that can affect risks of an intervention as well as clinical response.
  • Differences in clinical conditions. Differences in OUS clinical conditions versus those in the U.S. can affect the relevance of the data to the intended U.S. population. OUS countries may have different standards of care, clinical facilities, or levels of clinical skill which can cause OUS data to not be generalized to U.S. clinical practice and which can impact the data’s usefulness in supporting the safety and/or effectiveness of the device.
  • Differences in regulatory requirements. When studies conducted OUS are initiated to satisfy the requirements of foreign countries, the studies may not be designed to address the questions necessary to satisfy FDA requirements.

The Draft Guidance provides a number of useful examples that demonstrate the application of the above considerations. Although the proposed rulemaking on “Acceptance of Data from Clinical Studies for Medical Devices” is not yet final, the Draft Guidance concludes by highlighting the importance of GCP. It states that “showing compliance with GCP is one way sponsors of device applications may be able to show that their OUS data comply with applicable FDA requirements.” FDA’s requirements for IDE studies address GCPs through applicable regulations, such as 21 C.F.R. Part 50, 54, 56 and 812. The Draft Guidance also provides that FDA considers the following two standards to be GCP principles that articulate ethical and policy standards for OUS clinical trials:

  • ICH E6, “Good Clinical Practice: Consolidated Guidance,” and
  • ISO 14155 “Clinical Investigation Of Medical Devices For Human Subjects – [GCP]”

FDA is requesting comments on the Draft Guidance before it begins work on the final guidance. The Agency will be accepting comments until July 21, 2015.