Last month, the NIH released new policies and related efforts to improve our stewardship, accountability, and transparency of clinical trials. NIH is the largest funder of clinical trials in the U.S., and these multi-faceted efforts are designed to address issues at multiple stages of the clinical trials process, from grant application through dissemination of results to the public. Although these policies and efforts were developed primarily with the traditional biomedical clinical trial in mind, they are applicable to social and behavioral trials as well. Therefore, the purpose of this rather lengthy and policy dense blog is to assist the behavioral and social sciences research community in adhering to these policies and efforts, and to highlight OBSSR’s efforts to make these policies and efforts fit better with the typical social or behavioral intervention trial. A working group of the NIH Behavioral and Social Sciences Research Coordinating Committee (BSSR-CC), led by Melissa Riddle and Stephane Philogene, is addressing various aspects of these NIH policies to determine whether additional guidance may be needed to facilitate the application of the policies to social and behavioral intervention research.
As a starting point for determining whether the policies are applicable to a social or behavioral intervention trial, it is critically important to understand what is meant by “clinical trial.” The clinical trials policies below are based on the NIH Definition of a Clinical Trial - “A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.” Understanding each component of this definition is important for determining if a behavioral or social science study meets the definition of a clinical trial.
- “Research” and “human subjects” are interpreted as per the Common Rule (45 CRF 46.102(d) and (f)). If your study is not considered “research” with human subjects as per the Common Rule (e.g., program improvement, quality assurance), then the clinical trials policy is not applicable. Note that the clinical trials definition does not distinguish between research that is exempt or no-exempt from IRB review, only that the study is considered “research” as per the Common Rule.
- “One or more” indicates that the NIH definition of a clinical trial includes N-of-1 or single case designs. Such designs are being used increasingly in clinical research and practice as new technologies provide the temporally dense longitudinal assessments needed for multiple baseline, reversal, and interrupted time series designs. As currently interpreted, these single case series designs are considered clinical trials under the current NIH clinical trials definition.
- “Prospectively assigned” refers to any pre-defined process such as randomization specified in an approved protocol that assigns participants to conditions. This applies whether the assignment is between subjects or within subjects over time. The critical aspect is that a researcher conducts a planned assignment as per study protocol. Therefore, natural experiments, including natural experiments in which some entity other than the researcher randomly assigned participants to different conditions, (e.g., lottery for housing vouchers or different types of healthcare coverage) would not be considered prospectively assigned and do not meet the clinical trial definition.
- “Intervention” is a manipulation of the participant or the participant’s environment for the purpose of modifying one or more health-related biomedical or behavioral processes/endpoints. Depending on how broadly one interprets the subsequent clause, “to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes”, this part of the clinical trials definition may include a wide range of basic behavioral and social science studies that manipulate an independent variable to observe a hypothesized modification of a behavioral process. Investigators could argue that their dependent variable is not a “health-related biomedical or behavioral outcome” but that argument also may suggest that the NIH is not the most appropriate funder of the research, so you make that argument at your own risk. While basic behavioral and social science researchers may not consider their manipulation an “intervention” or their lab research a “clinical trial,” it may be interpreted as such under this definition. Since there may be variations in how this part of the definition will be interpreted by different NIH Institutes and Centers, it is imperative that investigators discuss with program officials if and how their research may be subject to NIH clinical trials policies and efforts. The BSSR-CC working group on clinical trials will address this definitional issue, especially as it applies to basic human research not typically considered an intervention or a clinical trial and provide input to the NIH on how to interpret this definition consistently across ICs and congruent with the goals of the NIH clinical trials policies and efforts.
Case studies are available to help investigators understand whether their study is a clinical trial, and several of the cases involve behavioral interventions. See http://osp.od.nih.gov/sites/default/files/Case_Studies.pdf.
Once determined that your research meets the NIH definition of a clinical trial, behavioral and social science researchers need to know and adhere to a number of recently released NIH clinical trials policies and efforts that span from grant submission through dissemination of findings.
- Good Clinical Practice (GCP) Training: Effective January 1, 2017, investigators involved in NIH-supported clinical trials need to obtain training in Good Clinical Practice. There are many providers of this training, including many academic institutions, and the OBSSR working group is charged with identifying training programs that are particularly relevant for social and behavioral clinical trials and insuring that these GCP trainings are relevant to behavioral trialists.
- Specific FOA for Clinical Trials: Effective September 27, 2017, the NIH will require that grant applications involving clinical trials be submitted under a clinical trial-specific Funding Opportunity Announcement (FOA). This will allow NIH to identify more easily clinical trial applications and ensure that key components of clinical trial information are included and uniformly considered in review. OBSSR is working with the Centers for Scientific Review (CSR) to ensure that expertise in social and behavioral clinical trials are included in clinical trials study sections. Each NIH Institute and Center (ICs) will generate their own clinical trials FOA following an NIH-wide template to maximize communality across ICs but also allow ICs to emphasize scientific areas of interest. The BSSR-CC working group will assist the behavioral and social science program staff at each IC to ensure that scientific areas of interest include key social and behavioral trials relevant to their mission.
- Single Institutional Review Board (IRB) for Multi-site Studies: To streamline and expedite IRB review of clinical trials and other non-exempt human subjects research studies carried out in more than one domestic site, NIH released a policy establishing the expectation that a single IRB will be used for multi-site research. This policy takes effect as of May 25, 2017, but a number of studies, including the Precision Medicine Initiative Cohort Program, have already taken advantage of a single IRB via reliance agreements with the awardee institutions or sites.
- Enhanced Clinical Trial Reporting: Timely reporting of clinical trials findings is critically important. Not only does this timely reporting ensure that various stakeholders can utilize the findings from a clinical trial as soon as possible, but it also ensures that the many people who have invested in that trial, including taxpayers and study participants, get a rapid return on their investment. The Clinical Trials Registration and Results Information Submission rule requires that most clinical trials of FDA regulated products be registered in the ClinicalTrials.gov database within 21 days of enrollment of the first participant, and the submission of trial results, generally, one year after collection of the primary outcome measure(s) has been completed. A complementary NIH policy sets the same registration and reporting expectations for all NIH-funded clinical trials regardless of study phase, type of intervention, or whether they are subject to the FDA rule. Clinical trials funded by NIH that study behavioral interventions are covered by the policy. NIH also is improving the interface for ClinicalTrials.gov to make it easier to use. Further, after this policy takes effect (January 18, 2017), grant applications involving clinical trials must include a plan for how applicants will comply with the policy, and compliance will be part of the term and conditions of the award.
- Clinical Trials Protocol Template: NIH, in collaboration with the FDA, is developing a clinical trials protocol template. The FDA will be using this template for phase 2 and 3 investigational new drug or investigational device exemption clinical trials. NIH will encourage its use to organize and standardize key details that should be included in clinical trials protocols submitted to the NIH. Although this template is most consistent with the prototypic biomedical FDA trial, OBSSR provided input on the template for applicability to behavioral trials, and the BSSR-CC working group will be developing guidance for behavioral trialists on how to document the specifics of behavioral trial protocols within this template.
More information on these policies can be found through various NIH notices and blogs, as well as recent publication in JAMA. Even if policy is not your passion, I recommend that any behavioral or social science researcher who manipulates an independent variable learn about these policies. Even when in doubt, if your study constitutes a clinical trial that is subject to these NIH policies and efforts, I encourage you to adhere to them. While adhering to these policies may require additional time and effort, the intention of these policies - to ensure rigorously and appropriately conducted research, to rapidly disseminate positive and negative research findings, and to provide NIH with the tools to serve as good stewards of the research we fund – are broadly applicable principles with which we all agree.
The categories of trials that are subject to FDAAA (applicable clinical trials) are described at this website:
Image Credit/Georgi Paskov