FDA Regulatory and Compliance Monthly Recap — August 2017

• FDA outlines new approach to digital health technology regulation, plans pilot precertification program
• Draft FDA guidance offers recommendations on child-resistant packaging statements in drug labeling
• FDA finalizes guidance on voluntary qualification program for medical device development tools
• FDA issues guidance on informed consent waivers ahead of planned regulation

FDA outlines new approach to digital health technology regulation, plans pilot precertification program

In its Digital Health Innovation Action Plan, the agency outlines the guidance documents it plans to publish as it looks to implement a new approach to regulating software-based devices. It also outlines plans for a precertification program using a firm-based, rather than product-based, approach to regulatory review.

The FDA’s Center for Devices and Radiological Health (CDRH) published a Digital Health Innovation Action Plan outlining its plans for regulating digital health products while fostering innovation and protecting public health. To address the new market participants in the digital health technology space, the new innovation and manufacturing processes they bring, and advancements in medical software and technologies, the FDA is planning to implement a risk-based regulatory approach. The agency acknowledges that its traditional approach to moderate- and high-risk hardware-based devices doesn’t work as well for software-based medical technologies and that traditional premarket requirements may hinder or delay patient access.

The Action Plan outlines several steps the agency is planning to take such as issuing new guidance to implement provisions of the 21st Century Cures Act pertaining to digital health, including provisions that certain medical software – for example, software that encourages a healthy lifestyle or serves as electronic patient records – will no longer fall under the regulatory umbrella of medical devices. Planned guidance documents include:

• Draft guidance outlining the agency’s interpretation of the medical software provisions in the Cures Act and their impact on pre-existing agency policy on mobile applications, data systems, and medical image storage and communications devices, among other areas. The guidance is slated to be published by year-end.
• Draft guidance indicating that clinical decision support software will no longer be regulated by the FDA, due to be published in Q1 2018.
• Draft guidance on the agency’s oversight of products that include software functions that fall under medical device regulation and those that don’t. The FDA intends to address non-device software functions to the extent that it affects the software function subject to regulatory review (e.g., effects on safety and efficacy). The guidance is scheduled to be published in Q1 2018.
• Finalized guidance, initially published in 2016, on when 510(k) applications are required for software changes to existing devices. The agency is aiming to finalize the guidance by year-end, incorporating feedback on the draft.
• Finalized guidance on the International Medical Device Regulator Forum (IMDRF) approach to clinically assessing software as a medical device (SaMD). The FDA issued the IMDRF’s proposed document on clinical assessment of SaMD in October 2016. The IMDRF is expected to vote on the final document in September, and if the document is adopted, the FDA plans to issue final guidance.

The FDA is also reassessing its approach to digital health medical devices and is planning to implement a pilot precertification program in September to potentially replace the need for premarket submissions for certain types of products while reducing the required submission content and accelerating the review period for other products. The agency will launch a pilot program to assess the software or technology developer, rather than the product. By using such a firm-based approach, the CDRH will be able to “precertify” eligible developers who show they have a culture of quality and organizational excellence based on certain objective criteria. The program aims to determine whether a company meets the necessary quality standards to be precertified by assessing developers based on their software development, validation and maintenance practice. These precertified developers may then qualify to market lower-risk devices without FDA review or with an accelerated premarket review.

Under the program, the accelerated review could include lessened submission content and quicker review of content. Firms with a precert status may be able to collect real-world postmarket data to support the regulatory status of the product as well as new product functions. In an FAQ, the FDA indicated that the pilot won’t require a multiyear commitment from companies taking part. However, the agency was unable to offer a timeline for products that enter the pilot and receive market authorization. For companies already seeking 510(k) clearance, the agency is encouraging them to continue that process instead of taking part in the pilot. Nine companies are participating in the pilot.

Draft FDA guidance offers recommendations on child-resistant packaging statements in drug labeling

The draft addresses the information applicants, manufacturers, packagers and distributors should include in child-resistant packaging statements if they choose to include such statements in product labeling for prescription or nonprescription drug products.

The FDA published draft guidance outlining which information should be included to support child-resistant packaging (CRP) statements in drug product labeling for new drug applications (NDAs), abbreviated NDAs (ANDAs), biologic license applications (BLAs) and application supplements. The guidance includes labeling recommendations for nonprescription drug products approved under NDAs or ANDAs, as well as those marketed under the OTC Drug review.

In general, the guidance notes that if a firm decides to include labeling statements to indicate it is packaged using CRP, the CRP should be described using words because symbols and abbreviations may be misunderstood. Given that CRP statements address how a product is supplied from a manufacturer, rather than dispensed by a pharmacist, the FDA prefers the term “supplied” rather than “available.” To ensure CRP statements are not deemed false or misleading, which may render a product misbranded, the FDA notes that they should be used only when drug product packaging has been demonstrated to be in compliance with Consumer Product Safety Commission (CPSC) regulatory standards and test procedures for CRP.

The guidance outlines specific recommendations for prescription and nonprescription products, such as:

• Prescription drug products: CRP information should be provided in the section of labeling that addresses how to supply, store and handle the product and should be clearly linked to a particular package, especially in instances in which multiple packages are supplied and not all have been shown to be child-resistant. If a commercial container with a CRP is meant to be dispensed directly to patients, the CRP should be included in the patient labeling under the heading “How should I store Drug X?” and should be consistent with the CRP in the full prescribing information.
• Nonprescription drug products: Although FDA regulations don’t specify where CRP statements should be placed on labeling for nonprescription drugs, the guidance recommends that it be included under the subheading “other information” within the storage statement.

For both prescription and nonprescription drugs, the FDA notes that a CRP may be provided on carton labeling or container labels so long as there is enough space to include it alongside required information. If space allows, a firm may include a storage statement in tandem with the CRP statement to recommend the package be kept out of reach of children. Per the guidance, CRP statements for prescription drugs are best displayed on the side panels of carton labeling and container labels, near the storage information. For nonprescription drugs, the text is best placed on the principal display panels.

The guidance notes that firms should provide written verification that the CRP meets CPSC requirements and recommends they keep the data used to support CPSC standard requirements. For products approved under an NDA, BLA or ANDA, verification that the CRP meets CPSC standards should be provided in the container closure section of the electronic common technical document. If a firm decides to make changes to the package or labeling after approval, submissions for changes to add CRP statements on labeling should also provide written verification that the CRP meets CPSC standards. While there is no established process for submission of a written verification that nonprescription drug products under an OTC monograph adhere to CPSC standards, the FDA recommends that firms that decide to include a CRP statement keep the data demonstrating the packaging meets applicable standards and follow the labeling recommendations provided.

FDA finalizes guidance on voluntary qualification program for medical device development tools

The finalized guidance outlines the framework for qualification of medical device development tools and describes the factors the FDA will take into consideration when evaluating the tools. It also outlines the qualification process and provides a sample outline of qualification package contents.

The FDA finalized guidance, initially published in November 2013, on a voluntary program to qualify a medical device development tool (MDDT) used in assessing devices subject to regulation by the CDRH. The guidance outlines the framework and process for voluntary proposal and qualification of an MDDT but doesn’t address the review of tools submitted in individual premarket regulatory submissions for use with a specific medical device. The voluntary qualification program is meant to encourage the development and use of tools to accelerate device development and regulatory review.

Per the guidance, an MDDT is a scientifically valid method, material or measurement to investigate the efficacy, safety or performance of a medical device, such as clinical outcome assessments or assessments of biomarkers. These tools may be qualified for use in device investigation and to support regulatory decision-making. Qualification is designed to reflect the CDRH’s expectation that an MDDT generates results within a specific context of use that are reliable for device evaluation and to support decision-making. The guidance outlines three types of MDDT recognized by the CDRH:

1. Clinical Outcome Assessment: Made through a report by a clinician, a patient or non-clinician observer performance-based assessments. These include patient-reported, clinician-reported and observer-reported measures, primarily instruments that include a scale or score.
2. Biomarker Test: A test or instrument designed to detect or measure a biomarker, defined as a characteristic that is objectively measured and assessed as an indicator of normal biological processes, pathogenic processes or responses to a therapeutic intervention.
3. Non-Clinical Assessment Models (NAMs): Non-clinical test models or methods that measure or predict device function in in vivo device performance. These many include in vitro models, ex vivo models, animal models or computations models designed to measure or predict a parameter of interest.

The guidance indicates that the CDRH will take into consideration several factors when ascertaining whether to qualify a proposed MDDT, including:

• Whether the tool and its context of use are sufficiently described and defined: The guidance defines a context of use as a statement that completely and clearly describes the way the tool will be used and the medical product development-related purpose of that use. Per the guidance, the context of use should include a tool or product area in which the tool is proposed to be qualified, the specific output/measure of the tool, the role the tool will play in regulatory assessments and the phases of medical device development in which the tool may be used. Upon qualification, a context of use may be adjusted based on new data or changing science, so long as a new MDDT qualification package is submitted.
• The strength of the evidence demonstrating the MDDT is able to reliably and accurately measure what is intended: The evidence required to support qualification will vary based on the context of use and the type of tool, and submitters should explain how the evidence supports the proposed context of use. Per the guidance, evidence may include performance characteristics that would impact the usefulness of a tool, such as validity and performance characteristics and predictive ability.
• Whether the tool, within the specific context of use and based on the available evidence, provides advantages that outweigh potential disadvantages: The CDRH will assess the type, magnitude and likelihood of advantages and disadvantages, with emphasis on regulatory, public health and/or clinical impact. It will also explore the mitigation of potential disadvantages, the degree of certainty in the advantages and the novelty of the technology.

The draft guidance outlines the qualification process, from proposal to prequalification and qualification, and states that upon qualification for a specific context of use, the FDA will accept an MDDT’s use by any medical device sponsor for that context of use.

FDA issues guidance on informed consent waivers ahead of planned regulation

The guidance describes the FDA’s intention not to object to waivers or alterations to informed consent requirements for minimal-risk clinical studies. The agency intends to publish regulations on informed consent waivers and alterations in the future, consistent with the Cures Act and provisions in the Common Rule.

The FDA finalized guidance for sponsors, investigators and institutional review boards (IRBs) on enforcement of informed consent requirements for minimal-risk studies. The guidance follows several inquiries from sponsors and investigators about the impracticality of obtaining informed consent for minimal-risk studies. Under the 21st Century Cures Act, the Federal Food, Drug and Cosmetic Act was amended to provide the FDA with the authority to permit exceptions from informed consent for such studies when certain criteria are met. Per the amendment, the FDA may permit an exception to the requirements so long as the proposed testing poses only minimal risk to the human subjects and includes sufficient safeguards for subjects.

Generally, the FDA’s regulations pertaining to the protection of human subjects align with the Federal Policy for the Protection of Human Subjects (the Common Rule). However, the Common Rule includes a waiver of informed consent for minimal-risk studies in certain conditions, but the FDA’s regulations don’t include such a provision. The agency therefore plans to revise its informed consent regulations to add this waiver under appropriate human protection safeguards. Until such regulation is implemented, the FDA doesn’t intend to object to IRBs approving consent procedures that don’t include, or modify, “some or all of the elements of informed consent.”

The FDA also won’t object to informed consent waivers when the following are established by the IRB:

• The investigation involves no more than legally defined minimal risk to the subjects.
• The waiver or alteration won’t adversely impact the rights and welfare of the subjects.
• The study couldn’t be conducted without the waiver or alteration.
• When relevant, the subjects will be provided with additional information after participation.

Similarly, the FDA does not intend to object to a sponsor initiating, or an investigator carrying out, a minimal-risk study for which an IRB waives or modifies the informed consent requirements. The guidance will be withdrawn upon implementation of regulations on such waivers or alterations consistent with the Cures Act.