NIH Clinical Trials Updates: “Putting it All Together

11/15/2017

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NIH Clinical Trials Updates: “Putting it All Together”

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Sherry Mills, MD MPHDirectorOffice of Extramural ProgramsOffice of Extramural ResearchNIH

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No policies existed to make sure that the public had access to results from unpublished NIH-funded research (BMJ 2011;344:d7292 doi: 10.1136/bmj.d7292 (Published 3 January 2012))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

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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

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What has changed?

…and what you need to do.

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GCP Training

sIRBCommon

Rule

Clinical Trial Specific FOAs

Clinical Trial Review Criteria

Expanded Registration & Reporting

Updated Application

Forms

Improved Research Enterprise

NIH Initiatives to Enhance Clinical Trial Stewardship and Human Subjects Research

New Reforms & Initiatives

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

Research that Meets the NIH Definition of a

Clinical Trial

Training in Good Clinical Practice (GCP)

Clinical trial-specific Funding Opportunity Announcements (FOAs)

New review criteria

Expanded registration and results reporting in ClinicalTrials.gov 6

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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.

Learn more at https://grants.nih.gov/policy/clinical-trials/definition.htm

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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

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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

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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

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Determine if Your Study is an NIH-defined Clinical Trial

Does your study…

1. Involve one or more human participants?

2. Prospectively assign human participant(s) to intervention(s)?

3. Intend to evaluate the effect of an intervention on human participants

4. 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

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Determine if Your Study is an NIH-defined Clinical Trial

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NIH Clinical Trial Decision Treehttps://grants.nih.gov/ct-decision/index.htm

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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)

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•NOT‐OD‐16‐148 Policy on Good Clinical Practice Training for NIH Awardees Involved in NIH‐funded Clinical Trials

Change

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

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Some GCP training options: https://nih‐extramural‐intranet.od.nih.gov/d/hs/gcptrainingFAQs on GCP:https://grants.nih.gov/grants/policy/faq_nih_good_clinical_practice.htm#5162

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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

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NOT-OD-16-147: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-147.htmlNOT-OD-17-043: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-17-043.html

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)

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Change

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Identify Appropriate FOA

FOA Title (new FOAs only) FOA Section II. Award Information

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Link to decision tool to help you determine if you are doing a clinical trial.

Changes to the Review Criteria

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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

Change

NOT-OD-17-118: New Review Criteria for Research Project Applications Involving Clinical Trials

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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

Change

NOT‐OD‐17‐062 New NIH "FORMS‐E" Grant Application Forms and InstructionsNOT‐OD‐17‐119 New “FORMS‐E” Grant Application Instructions Available

Become Familiar with new HS/CT Form

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Take a video tour of the new form.

Review High Level Summary of Form Changes: FORMS-E to learn about other form changes.

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Become Familiar with new HS/CT Form

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Review Annotated Form Set for NIH Grant Applications - FORMS-E Series

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

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Change

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Single IRB for Domestic Multi-Site Research

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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

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Single IRB for Domestic Multi-Site Research (cont’d)

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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)

Change

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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

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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

Applications/Proposals

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Budget as if no

ad hoc exception

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Expanded Registration and Reporting Requirements

Effective January 18, 2017 – All NIH-funded awardees and investigators conducting clinical trials must register and reportthe results of their trial in ClinicalTrials.gov

Relevant Policies:

FDAAA/HHS Final Rule -- Applicable Clinical Trials (ACT)

NIH Policy on Dissemination of NIH-Funded Clinical Trial Information –extends to all NIH-funded clinical trials

Learn more at https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

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Change

Expanded Registration and Reporting Requirements

In order to comply with the NIH Policy on Clinical Trial Dissemination, awardees must:

Submit a statement in the application that outlines a plan to comply with the expectations of the policy

Register the clinical trial no later than 21 days after enrolling the first participant

Update the trial with submitted information at least once a year

Submit summary results no later than one year after primary completion date

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Implementation Timeline

Where Do I Go For More Information?

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https://grants.nih.gov/policy/clinical‐trials.htm 31

Public Website on Clinical Trial Requirements


Video Overview of New Policies on Human Subjects Research

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

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Public Page Has Training Resources Too

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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

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Get Prepared!

Documents

NIH Clinical Trials Updates: “Putting it All Together