Hogan Lovells Publications | Education Alert | 15 November 2016

NIH's clinical trial initiatives

Over the past few months, the National Institutes of Health (NIH) has unveiled several policies that add to the long list of regulatory obligations for research institutions. Among these policies are (i) NIH's ClinicalTrials.gov requirements; (ii) Good Clinical Practice (GCP) training; and (iii) the new Single Institutional Review Board (IRB) policy. While NIH aims to improve the transparency and effectiveness of its clinical research regime, collectively these policies put pressure on the research compliance infrastructure across a broad swath of NIH awardees, including universities, hospitals, and medical institutions. We offer below a brief summary of these developments.

NIH's ClinicalTrials.gov Policy

In September, the Department of Health and Human Services (HHS) issued a Final Rule that "clarifies and expands" the requirements for clinical trial registration and results submission on the ClinicalTrials.gov website. On the same day, NIH issued a complementary policy that supplements the obligations of NIH awardees and investigators. The expectation is that all institutions conducting clinical trials funded in whole or in part by NIH will register their NIH-funded studies at ClinicalTrials.gov and submit results information to ClinicalTrials.gov.

A summary of the HHS Final Rule is available on the Hogan Lovells website, a more detailed discussion of the Final Rule's compliance deadlines is available on the Hogan Lovells blog, and further commentary is on the NIH website.

The Final Rule requires an unprecedented level of transparency in reporting. It obligates awardees to submit for posting the full study protocol and statistical analysis plan (including amendments), and patient demographics including race and ethnicity of trial participants (if collected). The NIH Policy goes further than the HHS Final Rule; it applies to all clinical trials regardless of study phase or type of intervention, where the study is funded in whole or in part by NIH and regardless of whether it is covered by the HHS Final Rule. The NIH Policy extends to phase 1 drug and biological product trials, feasibility studies of device products, and behavioral, surgical, and other medical interventions not regulated by the Food and Drug Administration (FDA). Applicants for NIH funding must submit a plan describing how obligations under this Policy will be met.

NIH acknowledged the costs of complying with this Policy and suggested that the salaries of administrative and clerical staff that facilitate compliance could be permissible direct charges to an award, but only if these costs otherwise meet the OMB Uniform Guidance test for direct charging of administrative and clerical salaries.

Notably, noncompliance with the NIH Policy "may provide a basis for enforcement actions, including termination" and jeopardize future grant funding. NIH also says it may publicly post on the clinical trial record an awardee's omission to submit information that the Policy requires.

The HHS Final Rule is effective on 18 January 2017, after which institutions have 90 days to comply. The NIH Policy will take effect thereafter via terms and conditions inserted into the NIH award instrument.

NIH's Good Clinical Practice Training

In a surprise to the research community, in September NIH issued a mandate that all NIH-funded investigators and staff involved in the conduct, oversight, or management of clinical trials receive Good Clinical Practice (GCP) training, consistent with principles of the International Conference on Harmonisation (ICH) E6 (R2). This training is in addition to the human subjects research education already required (since June 2000) for all NIH-funded investigators and individuals responsible for the design or conduct of research involving human subjects.

NIH's GCP training requirement defines an Investigator as "The individual responsible for the conduct of the clinical trial at a trial site. If a clinical trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator." Although similar to FDA's definition of "Investigator", some have questioned why this definition differs from the definition of Investigator that NIH uses in other contexts. (For example, under the Public Health Service (PHS) Financial Conflict of Interest regulations, an investigator is defined as "the project director or principal Investigator and any other person, regardless of title or position, who is responsible for the design, conduct, or reporting of research funded by the PHS, or proposed for such funding, which may include, for example, collaborators or consultants.") The NIH GCP training requirement extends beyond investigators to "clinical trial staff" which includes research coordinators, study coordinators, research nurses, study nurses, and sub-investigators.

This training requirement—which is effective on 1 January 2017—"should be refreshed at least every three years" and trainees must retain documentation of their training. It's not yet clear whether NIH will apply the policy to all existing awards, or only to new applications submitted on 1 January and thereafter.

NIH's Single IRB Policy

For many years the government has expressed interest in reshaping the IRB landscape to streamline the clinical research review regime. A July 2011 Advanced Notice of Proposed Rulemaking (ANPRM) to revise the Common Rule proposed the use of one IRB of record for multi-site studies, subject to certain exceptions, and HHS's September 2015 Notice of Proposed Rulemaking (NPRM) followed through, mandating all domestic sites in a multi-site study to rely upon a single IRB as the IRB of record. Many institutions have experience with reliance on central IRBs, but currently most such situations are voluntary.

On 21 June 2016, NIH issued a final policy requiring a single IRB of record to be used in the review of NIH-funded non-exempt human subjects research protocols carried out at more than one site in the U.S. The policy applies to multi-site studies where each site will conduct the same protocol, whether supported through grants, cooperative agreements, contracts, or the NIH Intramural Research program.

NIH also issued a complementary table to illustrate scenarios in which direct and indirect costs could be handled in single IRB arrangements. It's not clear from this guidance that institutions will be able to recover from awards the full cost of single IRB review.

Hogan Lovells contributed to a paper titled "Central and Single IRBs Have Arrived: Is Counsel Ready?" presented at the NACUA November 2016 CLE Workshop on Academic Sponsored Research and Technology Transfer. The paper offers a broad overview of issues for academic institution counsel relative to the use of single IRBs, reliance agreements, and the allocation of responsibility between the IRB and sites.

Many organizations remain concerned about the cost and time needed to operationalize the policies, procedures, and agreements contemplated by a single IRB regime. Under NIH's Policy, an awardee institution relying on a single IRB must ensure that an IRB authorization agreement (also called a reliance agreement) is in place and maintained. This agreement must document roles and responsibilities between the institution/organization providing the IRB review and a participating site relying on it. The single IRB must carry out IRB regulatory requirements under the Common Rule and may also function as a Privacy Board to fulfill requirements of the HIPAA Privacy Rule. The single IRB also is expected to work with the awardee to facilitate communication between it and the participating sites.

Although all sites will rely on the single IRB in part, they are nonetheless responsible for meeting other regulatory obligations. These include obtaining informed consent, managing the approved protocol's implementation, and reporting unanticipated problems and study progress to the single IRB. Participating sites also must supply information needed by the single IRB to consider state/local regulatory requirements and local context issues. Nothing in the policy prevents sites from doing their own ethical review, but NIH notes that it would be against the policy's intent, and NIH will not pay for it.

Collectively, these obligations force the human research protection program to evolve and adapt—or fundamentally reorient itself—toward the single IRB concept within a compressed timeframe (25 May 2017). With the issuance of the NIH Single IRB Policy and anticipated Common Rule developments, it is important that all academic institutions engaged in clinical research take steps to gauge the infrastructure and costs necessary to implement the single IRB model. Many institutions are already considering development of new IT systems, updated policies and procedures, new staffing or training procedures, revised reliance agreements, and new relationships with commercial IRBs.

The NIH Single IRB Policy applies to: (1) all competing grant applications—new, renewal, revision, or submission—with receipt dates on or after 25 May 2017; (2) all solicitations for contracts issued on or after 25 May 2017; and (3) intramural multi-site studies submitted for initial review after 25 May 2017. Ongoing, non-competing awards are not expected to comply with the policy until the grantee submits a competing renewal application.

Hogan Lovells will continue to follow these and other NIH initiatives.

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