NIH Clinical Trial Initiatives: “Putting it All Together”

Why the changes to NIH-funded studies involving human subjects? No policies existed to make sure that the public had access to results from unpublished NIH-funded research (BMJ 2011;344:d7292 doi: 10.1136/bmj.d7292 (Published 3 January 2012)) Lack of transparency in results reporting; impedes scientific progress dishonors research participants wastes tax-payers’ research funding

Why the changes to NIH-funded studies involving human subjects? New NIH Clinical Trial Initiatives will help to : Maximize use of knowledge from clinical trials Facilitate clinical trials design and reduce duplication Promote dissemination of research information and results Foster responsible stewardship of public’s research investment

What has changed? …and what you need to do.

Improved Research Enterprise NIH Initiatives to Enhance Clinical Trial Stewardship and Human Subjects Research GCP Training Updated Application Forms sIRB Common Rule Expanded Registration & Reporting Improved Research Enterprise Clinical Trial Specific FOAs Clinical Trial Review Criteria

New Reforms & Initiatives Research that Meets the NIH Definition of a Clinical Trial All Research Involving Human Participants New forms to collect human subjects information Use of a single Institutional Review Board (IRB) for domestic multi-site studies Training in Good Clinical Practice (GCP) Clinical trial-specific Funding Opportunity Announcements (FOAs) New review criteria Expanded registration and results reporting in ClinicalTrials.gov

Know 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 other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. Before we can dive into the details, we must first understand what research falls under these reforms and how NIH defines a clinical trial. Learn more at https://grants.nih.gov/policy/clinical-trials/definition.htm

NIH Definition of a Clinical Trial Prospectively Assigned: a pre-defined process (e.g., randomization) specified in an approved protocol that stipulates the assignment of research subjects (individually or in clusters) to one or more arms (e.g., intervention, placebo, or other control) of a clinical trial. Intervention: a manipulation of the subject or subject’s environment for the purpose of modifying one or more health- related biomedical or behavioral processes and/or endpoints. Examples include: drugs/small molecules/compounds, biologics, devices procedures (e.g., surgical techniques); delivery systems (e.g., telemedicine, face-to-face interviews) strategies to change health-related behavior (e.g., diet, cognitive therapy, exercise, development of new habits) treatment strategies, prevention strategies, and diagnostic strategies

NIH Definition of a Clinical Trial Health-related Biomedical or Behavioral Outcome: the pre-specified goal(s) or condition(s) that reflect the effect of one or more interventions on human subjects’ biomedical or behavioral status or quality of life. Examples include: positive or negative changes to physiological or biological parameters (e.g., improvement of lung capacity, gene expression) positive or negative changes to psychological or neurodevelopmental parameters (e.g., mood management intervention for smokers, reading comprehension and/or information retention) positive or negative changes to disease processes positive or negative changes to health-related behaviors positive or negative changes to quality of life

NIH Definition of a Clinical Trial Definition was clarified in October 2014 Encompasses a wide range of types of trials, including: Mechanistic Exploratory Pilot/Feasibility Behavioral With broader definition, many more studies are classified as clinical trials Notice: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-015.html

Determine if Your Study is an NIH-defined Clinical Trial Does your study… Involve one or more human participants? Prospectively assign human participant(s) to intervention(s)? Intend to evaluate the effect of an intervention on human participants Have a health-related biomedical or behavioral outcome? If “yes” to ALL of these questions, your study is considered a clinical trial Clinical Trial Interactive Decision Tree: https://grants.nih.gov/ct-decision/index.htm

Determine if Your Study is an NIH-defined Clinical Trial NIH Clinical Trial Decision Tree https://grants.nih.gov/ct-decision/index.htm

Good Clinical Practice (GCP) Training Requirement Change Good Clinical Practice (GCP) Training Requirement Effective January 1, 2017 –NIH-funded clinical investigators and NIH staff who are involved in the design, conduct, oversight, or management of clinical trials are to be trained in Good Clinical Practice (GCP) NOT-OD-16-148​ Policy on Good Clinical Practice Training for NIH Awardees Involved in NIH-funded Clinical Trials

Good Clinical Practice (GCP) Requirement Receive GCP training if you are or expect to be involved in design, conduct, oversight, or management of clinical trials. Training could be: Class or course Academic training program Certification from a recognized clinical research professional organization NIH GCP training Retain documentation of training Refresh training at least every three years Some GCP training options: https://nih-extramural-intranet.od.nih.gov/d/hs/gcptraining FAQs on GCP:https://grants.nih.gov/grants/policy/faq_nih_good_clinical_practice.htm#5162 

Clinical Trial-Specific Funding Opportunities Change Clinical Trial-Specific Funding Opportunities Applications/proposals involving clinical trials (due dates on or after January 25, 2018) must be submitted to an FOA/RFP that accepts clinical trials NOT-OD-16-147: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-147.html NOT-OD-17-043: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-17-043.html

Clinical Trial-Specific Funding Opportunities Change Clinical Trial-Specific Funding Opportunities 3 Types of FOAs Clinical Trials Not Allowed – only accepting applications not proposing clinical trial(s) Clinical Trials Required – only accepting applications proposing clinical trial(s) Clinical Trials Optional – accepting applications that either propose or do not propose clinical trial(s)

Identify Appropriate FOA FOA Title (new FOAs only) FOA Section II. Award Information There are two primary places that your FOA will indicate whether it accepts clinical trials or not Link to decision tool to help you determine if you are doing a clinical trial.

Changes to the Review Criteria For Research Project (R) applications proposing clinical trials: Clinical trial-related questions in addition to standard review criteria: Significance Investigators Innovation Approach Environment Study Timeline NOT-OD-17-118: New Review Criteria for Research Project Applications Involving Clinical Trials

Changes to the Review Criteria For Career Development (K) applications proposing clinical trials: Clinical trial-related questions in addition to standard review criteria: Candidate Research Plan Mentors, co-mentors, consultants, collaborators Environment & Institutional Commitment to Candidat Study Timeline for Clinical Trials NOT-OD-17-121 New Review Criteria for Career Development Award Applications Involving Clinical Trials 

Changes to the Review Criteria For Fellowship (F) applicants proposing to gain research experience in a sponsor or co-sponsor led clinical trial: Clinical trial-related questions in addition to standard review criteria: Sponsors, Collaborators, and Consultants Research training plan NOT-OD-17-122: New Review Criteria for Ruth L. Kirschstein National Research Service Award (NRSA) Individual Fellowship Applications Involving Research Experiences in Clinical Trials

Changes to the Review Criteria For Training (T) applications if appointee(s) propose to gain research experience in a mentor or co-mentor led clinical trial: Clinical trial-related questions in addition to standard review questions: Preceptors/mentors NOT-OD-17-123: New Review Criteria for Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grants Involving Research Experiences in Clinical Trials

New Human Subjects and Clinical Trials Information Form Change New Human Subjects and Clinical Trials Information Form Required for all applications with due dates on or after January 25, 2018 Consolidates human subjects and clinical trial information into one place Expands information required for studies meeting definition of NIH clinical trial Collects information at the study level Aligns with ClinicalTrials.gov <recap benefits of new data collection strategy and close out video> NOT-OD-17-062 New NIH "FORMS-E" Grant Application Forms and Instructions NOT-OD-17-119 New “FORMS-E” Grant Application Instructions Available

Become Familiar with new HS/CT Form Take a video tour of the new form. Review High Level Summary of Form Changes: FORMS-E to learn about other form changes.

Become Familiar with new HS/CT Form Review Annotated Form Set for NIH Grant Applications - FORMS-E Series

Protocols in Applications: Appendix Policy Change Protocols in Applications: Appendix Policy Protocols only allowed in appendix when required by FOA Requirement associated with review criteria Only placed in appendix, when required by FOA Placement elsewhere results in return on application Another recent policy update that is somewhat related to this new HS/CT form is the updated appendix policy. Because the new HS/CT form will collect key elements from the protocol, the option to submit this protocol with the appendix will be removed. For Parent FOAs, our default option will be not to allow the inclusion of the protocol in the application, and if it’s included, the application will be sent back. But for IC-issued FOAs, the FOA must state that it’s a requirement to include the protocol in the appendix (not in the new HS/CT form). This requirement must also be added to the review criteria.

Single IRB for Domestic Multi-Site Research Change Single IRB for Domestic Multi-Site Research NIH-funded multi-site domestic studies involving non-exempt human subjects research are expected to use a single IRB (sIRB) Effective for applications/proposals with due dates/solicitations published on or after January 25, 2018 NOT-OD-16-094  Final NIH Policy on the Use of a Single Institutional Review Board for Multi-Site Research NOT-OD-17-076 Revision: Notice of Extension of Effective Date for Final NIH Policy on the Use of a Single Institutional Review Board for Multi-Site Research NOT-OD-16-109 Scenarios to Illustrate the Use of Direct and Indirect Costs for Single IRB Review under the NIH Policy on the Use of a Single IRB for Multi-site Research

Single IRB for Domestic Multi-Site Research (cont’d) Change Single IRB for Domestic Multi-Site Research (cont’d) Exceptions to sIRB policy include: Foreign sites Career development (K), Research Training (T), and Fellowship (F) awards Sites where review by sIRB is prohibited by federal, tribal, or state law, regulation, or policy When there is a compelling justification (very rare)

Applications/Proposals In Single IRB plan, include: Name of the sIRB (if known) Indicate that, if funded: All sites, including any added after award, agree to rely on sIRB Sites will sign reliance agreement that will include a communication plan Indicate who will maintain records of this agreement

Applications/Proposals Exceptions For legal, regulatory, or policy-based exceptions: provide specific citation and indicate which sites are impacted Special consideration, “ad hoc” exceptions, provide compelling justification Several protocols may have one sIRB plan for all If delayed onset, in justification include statement that awardee will follow the policy and will provide sIRB info prior to start Budget as if no ad hoc exception

Implementation Timeline

Where Do I Go For More Information?

Public Website on Clinical Trial Requirements https://grants.nih.gov/policy/clinical-trials.htm

Public Website on Clinical Trial Requirements Video Overview of New Policies on Human Subjects Research

Public Website on Clinical Trial Requirements https://grants.nih.gov/policy/clinical-trials.htm

Public Website on Clinical Trial Requirements https://grants.nih.gov/policy/clinical-trials.htm

Decision Tool Walks Through Questions, Links to Definition FAQs and Case Studies and Provides Advice for Picking the Right FOA

Public Page Has Training Resources Too

What You Should Do Contact a Program Officer Read/select FOA carefully Are clinical trials allowed? Additional review criteria? Protocol submission required? Apply early to FOA Read/become familiar with application instructions New Human Subjects/Clinical Trials form

Get Prepared! GCP Training Clinical Trials FOAs Single IRB Common Rule Updated Application Forms Single IRB Common Rule Expanded registration and reporting Get Prepared!