The 21st Century Cures Act encourages biomedical research investment and facilitates innovation review and approval processes, but also serves as a vehicle for a wide variety of other health-related measures, including provisions relating to FDA regulation of clinical trials. After passage by the Senate on December 7, 2016, President Barack Obama signed the bill on December 13.

Introduction

On December 7, 2016, the US Congress approved the 21st Century Cures Act, substantial legislation intended to accelerate “discovery, development and delivery” of medical therapies by encouraging biomedical research investment and facilitating innovation review and approval processes, among other things. The massive bill, however, also served as a vehicle for a variety of other health-related measures. The 21st Century Cures Act includes portions of the FDA Device Accountability Act of 2015, Promoting Biomedical Research and Public Health for Patients Act, and FDA and NIH Workforce Authorities Modernization Act. These bills were introduced, but not advanced, by the US Senate.

This On the Subject summarizes Food and Drug Administration (FDA) provisions related to clinical trials in title III of the new legislation. Other titles and FDA-related provisions will be examined in subsequent On the Subject articles over the coming days.

The prevalence of precision medicine, innovative cures and individualized patient treatments has caused FDA and other regulators to rethink traditional approaches to clinical research. Recent FDA initiatives to encourage adaptive clinical trial designs for novel therapies may signal a move toward greater flexibility regarding the types of clinical evidence and data that is adequate to support a product approval. The clinical trial portions of this legislation focus on streamlining clinical research by harmonizing human subject research protections and informed consent requirements across agencies, so that FDA’s human subject regulations are more in line with the human subject regulations of the US Department of Health and Human Services (HHS), which are known as the Common Rule. The bill also offers researchers the flexibility to use non-local institutional review boards (IRB) for investigational and humanitarian use devices and novel clinical trial designs and data in the drug and biological products approval and licensure processes.

President Barack Obama signed the Cures legislation on December 13, 2016, having previously expressed his support for the bill.

3021. Novel Clinical Trial Designs

The Cures legislation requires FDA to hold a public meeting and issue guidance to assist sponsors in incorporating complex adaptive and other novel trial designs into proposed clinical protocols and applications for new drugs and biological products. Among other items, the new guidance must address the use of such designs to demonstrate the safety and effectiveness of new drugs under the substantial evidence standard (evidence of adequate and well-controlled investigations) for FDA approval of new drugs. The guidance must also address how to submit information from modeling and simulations. This future guidance has the potential to significantly broaden the methodologies of analysis and data that may be used to support the approval and licensure of new products.

In the provision, Congress does not explicitly state whether it intends for the agency to finalize the policies set forth in the 2010 adaptive design draft guidance as-is, or if it expects the agency to make meaningful revisions to that document. However, this section of the legislation suggests that Congress expects FDA to be more flexible in evaluating the evidence of safety and effectiveness to support new drug and biological product applications. Companies with applications pending before the agency (or preparing to submit such applications) should consider leveraging the legislative language to support arguments that safety and effectiveness can be evaluated with more flexible and/or modern trial designs than FDA has traditionally required.

Additionally, sponsors and other stakeholders should consider attending the public meeting and submitting written or oral comments to inform FDA’s development of the guidance.

3023. Protection of Human Research Subjects

Effecting a change long sought by researchers, the legislation requires the HHS secretary to harmonize differences between HHS and FDA regulations for the protection of human subject (generally) and vulnerable populations (specifically). The harmonization effort may modernize the regulations to facilitate multi-site and cooperative research projects, avoid regulatory duplication and delays, protect vulnerable populations, and encourage community engagement. Additionally, the legislation encourages sponsors of research that is subject to both HHS and FDA human subject regulations to use a joint or centralized IRB review process. This provision may benefit multi-site trials by consolidating the IRB process.

This section streamlines the process by which human subject research may be reviewed and conducted. This harmonization effort will likely impact the current efforts to amend the Common Rule, which were outlined in a 2015 notice of proposed rulemaking. However, the proposed rulemaking may serve as a guidepost for the effort. For example, the proposed rulemaking would require that cooperative research or multi-site studies rely on a single IRB, with limited exceptions, which is consistent with the flexibility proposed under certain circumstances in Section 3056 of the Cures legislation (described below). The extent to which HHS will change any individual provision is unclear at this time, but potential targets are revision of the types of studies that require IRB review and oversight, allowable IRB exemptions, inconsistent definitions (e.g., research, human subject), and various aspects of the informed consent process. For example, harmonization efforts may make it easier for sponsors to obtain and use retrospective analyses of de-identified data, which have historically been exempt from the informed consent requirement under the Common Rule but not expressly exempt under FDA regulations. The possibility of establishing an analogous exemption under FDA requirements may significantly increase the extent to which sponsors rely on such analyses to support product development and other activities. Entities that perform human subject research should monitor HHS’s efforts to consult with stakeholders and the Federal Register for additional opportunities to comment on the harmonization process, rulemakings and guidance, as this section arguably provides an opportunity to broaden the exceptions to when informed consent is required for FDA-regulated clinical investigations.

3024. Informed Consent Waiver or Alteration for Clinical Investigators

The legislation allows FDA’s informed consent requirements to be waived or altered for trials of investigational drugs or devices if the proposed clinical tests pose no more than minimal risk to the human subjects and include appropriate safeguards to protect the rights, safety and welfare of the subjects. The legislation does not define the phrase “no more than minimal risk” and does not cross-reference any existing HHS or FDA regulations or guidance to provide insight as to how such language should be interpreted by the FDA. Although the phrase is not defined in the US Code, FDA has defined in 21 C.F.R. § 50.52 what constitutes a clinical investigation involving greater than minimal risk to children. Under that regulation, an IRB must find that (1) the risk is justified by the anticipated benefit to the subjects; (2) the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches; and (3) adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians as set forth in a separate FDA rule. The FDA’s interpretation of the phrase and the language on the “appropriate safeguards” required to protect human subjects will likely require a separate rulemaking or guidance, as the broad statutory language “no more than minimal risk” could be construed in many different ways.

To the extent that FDA’s interpretation of “no more than minimal risk” tracks existing HHS regulations on the protection of human research subjects, this section could potentially harmonize FDA’s informed consent requirements with existing HHS and National Institutes of Health (NIH) requirements under the Common Rule. For example, in 45 C.F.R. § 46.102, HHS defines “minimal risk” as “the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.” Additional HHS regulations discuss “minimal risk” in the context of research involving not greater than minimal risk to children, research involving greater than minimal risk that presents the prospect of direct benefit to the individual subjects, and research involving greater than minimal risk and no prospect of direct benefit, but that is likely to yield generalizable knowledge about the subject’s disorder or condition. FDA may examine the protections in these HHS regulations on “minimal risk” and “greater than minimal risk” to establish appropriate safeguards.

Depending on FDA’s interpretation of the phrase “no more than minimal risk,” stakeholders that perform, participate in, and/or evaluate investigational drug and device human subject research may have greater freedom to pursue trial designs that were previously impractical under FDA regulations. This legislative change could provide new opportunities for sponsors to use “big data,” in particular in retrospective analyses of de-identified data, in submissions to the agency, as such analyses arguably pose no more than a minimal risk to patients.

3056. Institutional Review Board Flexibility

The Cures legislation strikes references to “local” IRBs in the investigational and humanitarian device exemptions, which exempt such devices from requirements including labeling, registration, premarket approval, recordkeeping and reporting. Sponsors, investigators and others involved in a device trial or other device use (e.g., diagnosis or treatment) within the scope of the exemptions will now be allowed to engage a centralized or other non-local IRB for review and approval. This section is consistent with the trend toward centralization of IRB operations and avoidance of duplication of review, especially as associated with multi-site trials.

Sponsors should re-examine their plans for trials and centralize the IRB process insofar as use of a local IRB was intended solely to address FDA requirements. This legislative change may ease the process of beginning a clinical trial and addressing ongoing oversight of a trial. Stakeholders—including investigators, health care providers and medical centers—that administer trials or perform patient services with investigational or humanitarian devices may need to modify existing practices, policies and procedures to allow for review by non-local IRBs.