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Regulatory Update, June 2016

Wednesday, June 1, 2016

FDA Proposed Rule on Administrative Actions for IRB Noncompliance

In the April 4, 2016, Federal Register, the FDA proposed amending the regulations describing lesser administrative actions that may be imposed on an Institutional Re­view Board (IRB) that has failed to comply with applicable IRB regulations. The FDA is taking this action to ensure clarity and ac­curacy of the regulations. The FDA is pro­posing to amend language in 21 CFR 56.120 (b) that describes lesser administrative ac­tions the FDA may impose on an IRB until the IRB takes appropriate action to correct noncompliance identified during an FDA inspection of the IRB. This revision would state that the FDA has authority to require the IRB withhold approval of new FDA-regulated studies conducted at the institu­tion or reviewed by the IRB, to direct the IRB that no new subjects may be enrolled in ongoing studies and to terminate ongoing studies, provided that doing so would not endanger study subjects. Disqualification of the IRB would be used only if the non­compliance adversely affects the validity of the data or the rights or safety of the human subjects and lesser actions (e.g., warnings or rejection of data from individual clinical in­vestigations) have not been or probably will not be adequate in achieving compliance.

To explain its reasoning for justifying this revision, the FDA stated that its longstand­ing interpretation of the regulations was that the FDA could impose these restrictions on a noncompliant IRB until the IRB took ap­propriate corrective action, but the text of the regulations suggested that the FDA would withhold approval of studies rather than the IRB. This proposed rule would clarify that the IRB or the parent institution takes re­sponsibility for suspending the stated activi­ties until the IRB has taken appropriate cor­rective action to address its noncompliance.

The revision clearly states that the FDA is authorized to notify others about the IRB’s noncompliance. The FDA may notify rel­evant State and Federal regulatory agencies when warranted to ensure that organiza­tions with a need to know about the IRB’s apparent noncompliance are appropriately informed.

This proposed rule accompanies a “direct final rule,” which becomes effective August 17, 2016, and was published in the final rules section of the same issue of the Federal Reg­ister. Both rules are substantively identi­cal. The proposed rule allows for the usual public comment period while the FDA prepares to implement the direct final rule. If the FDA receives a significant adverse comment, it will withdraw the direct final rule but continue with the proposed rule. A significant adverse comment is one that ex­plains why the rule would be inappropriate (including challenges to the rule’s underly­ing premise or approach), or would be inef­fective or unacceptable without a change. In determining whether an adverse comment is significant and warrants withdrawing a direct final rule, the FDA considers whether the comment raises an issue serious enough to warrant the usual notice-and-comment process.

Interested parties may submit electronic or written comments on this proposed rule or its companion direct final rule by June 20, 2016. Submit electronic comments at http://www.regulations.gov/. Submit writ­ten comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD 20852. Identify com­ments with Docket No. FDA-2015-N-5052.

The FDA also has instructions on how to submit confidential information. If those instructions are not followed, any submit­ted confidential information will be made public.

FDA Draft Guidance on IDE Clinical Considerations for Neurological Devices

In the March 7, 2016, Federal Register, the FDA announced the availability of the draft guidance titled, “Clinical Considerations for Investigational Device Exemptions (IDEs) for Neurological Devices Targeting Disease Pro­gression and Clinical Outcomes.” The Center for Devices and Radiological Health (CDRH) developed this draft guidance to assist sponsors who intend to submit an IDE to FDA to con­duct clinical trials on medical devices targeting neurological disease progression and clinically meaningful patient centered outcomes. The FDA believes that neurological devices intend­ed to slow disease progression and improve clinical outcomes that are meaningful may represent a revolutionary option for patients.

The FDA developed this draft guidance to assist sponsors who intend to submit an IDE to the FDA to conduct clinical trials on medical devices targeting neurological disease progres­sion and clinically meaningful patient centered outcomes. The draft guidance is intended to aid industry and the FDA staff in considering the benefits and risks of medical devices that target either the cause or progression of the neurolog­ical disorder or condition such as Alzheimer’s disease, Parkinson’s disease or Primary Dys­tonia, rather than their symptoms. This draft guidance is intended to apply to neurological medical devices that are designed to slow, stop or reverse the progression of disease and result in clinically meaningful patient outcomes. This draft guidance provides general study design considerations for clinical trials that investigate neurological devices using biological markers and clinical outcome assessments.

Interested parties should submit comments on this draft guidance by June 6, 2016, to ensure that the FDA considers those comments before it begins work on the final version.

Submit comments as instructed above and identify them with Docket No. FDA- 2016-D-0539.

FDA Draft Guidance on FMT Enforcement Discretion

In the March 1, 2016, Federal Register, the FDA announced the availability of the draft guidance document titled, “Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Thera­pies; Draft Guidance for Industry.” The draft provides members of the medical and scientific community and other interested persons with notice that, when made final, the FDA intends to exercise enforcement discretion, under lim­ited conditions, regarding the investigational new drug (IND) requirements for the use of fecal microbiota for transplantation (FMT) to treat C. difficile infection not responding to standard therapies. The draft guidance re­places the draft guidance of the same title dated March 2014 and, when made final, is intended to supersede the document of the same title dated July 2013.

The FDA intends to exercise this enforce­ment discretion, provided that:

  • The licensed healthcare provider treating the patient obtains adequate consent from the patient or his or her legally authorized representative for the use of FMT products. The consent should include, at a minimum, a statement that the use of FMT products to treat C. difficile is investigational and a dis­cussion of its reasonably foreseeable risks.
  • The FMT product is not obtained from a stool bank.
  • The stool donor and stool are qualified by screening and testing performed under the direction of the licensed healthcare provider for the purpose of providing the FMT prod­uct for treatment of the patient.

The FDA has developed this policy to en­sure that patients with C. difficile infection not responding to standard therapies may have access to this treatment, while addressing and controlling the risks that centralized manufac­turing in stool banks presents to subjects. The FDA intends for this to be an interim policy while it develops a comprehensive approach for the study and use of FMT products under an IND.

In the draft guidance, the FDA provides that the stool bank sponsor may request a waiver of certain IND regulations relating to the ob­ligations of investigators and sub-investigators (e.g., certain sections of the Statement of In­vestigator Form FDA 1572 that may not be applicable to FMT provided to the healthcare provider to treat their patients). The FDA is re­questing comments on which IND regulations are appropriate to waive. In particular, the FDA is requesting comments on the requirement for IRB review of the use of FMT to treat patients with C. difficile infection not responding to standard therapies when the FMT is provided by a stool bank.

In the draft guidance, the FDA proposes a revised policy with regard to patient access to FMT. The provision that the donor be known either to the patient or to the treating licensed healthcare provider, a concept that was used in the March 2014 draft guidance, was subject to difficulties in interpretation, and the revised approach more accurately reflects the FDA’s to mitigate risk, based on the number of patients exposed to a particular donor or manufactur­ing practice rather than the risk inherent from any one donor. Although the FDA acknowl­edges that directed donations present different risks than stool bank donations, the number of persons exposed through a directed donation will be limited. The FDA also requests com­ments on this revised policy.

The Regulatory Update is excerpted from Re­search Practitioner, Volume 17 Number 03, May-June 2016.

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