Implementation of Policies for Human Intervention Studies

IMPLEMENTATION OF POLICIES FOR HUMAN INTERVENTION STUDIES

INTRODUCTION

The following policies are based on two goals:

1. Protecting the safety of participants in intervention studies.

This goal applies to any study whether or not the study is a Phase III trial or a more limited intervention study. Policies to achieve it are described in the "Data and Safety Monitoring Policies" section.

2. Assuring that trials likely to affect clinical or public health

practice (Phase III trials) are soundly conducted and analyzed. This goal serves to prevent implementation of non-efficacious or harmful interventions (or failure to implement efficacious interventions) in practice, based on the results of a trial. A NIH-defined Phase III Clinical Trial, (page 29 of the PHS 398 form, rev. 4/98), is any broadly based prospective study evaluating an experimental intervention with a control or standard, or comparing two or more existing treatments or interventions where the outcome of the study is likely to contribute to change in either standard of care or public health policy.

The following policies describe NIA requirements for extramurally supported projects. They apply immediately to all projects to be submitted. They do not replace existing NIH grant policy or policies of DHHS/NIH regulations on protection of human subjects, policies and guidelines for conduct of clinical research, inclusion of women and minorities, research project administration, reporting, and financial management, or requirements of local Institutional Review Boards (IRBs). DHHS regulations for the protection of human subjects are described in 45 CFR46. The implementation of these regulations for PHS research grants involving human subjects is found in the PHS 398 form (rev. 4/98), available on the NIH home page ( http://www.nih.gov/grants/forms.htm ).

Applicants should also be aware of NIH policy "Guidance on Reporting Adverse Events to Institutional Review Boards for NIH-Supported Multicenter Clinical Trials" (NIH Guide for Grants and Contracts, June 11, 1999), "NIH Policy on Data and Safety Monitoring" (NIH Guide for Grants and Contracts, June 10, 1998), and "Further Guidance on a Data and Safety Monitoring for Phase I and Phase II Trials" (NIH Guide for Grants and Contracts, June 5, 2000).

This NIA policy document describes further steps to be taken to ensure the protection of human subjects when the study involves a potentially harmful intervention, and for other Phase III studies to ensure that participants receive an appropriate share of the benefits. In individual cases, the NIA may find it beneficial to have additional levels of involvement or oversight beyond those described in these policies.

DATA AND SAFETY MONITORING POLICIES

Applications for any intervention study should state (per the instructions for the "Human Subjects" section of the PHS-398 form) whether or not the proposed study intervention could have harmful effects, and the basis for that opinion. After review of the application by an Initial Review Group (IRG) and the Institutional Review Board's (IRB) review and approval, the Program Administrator will review the risks of the intervention. If the proposal for a study with a potentially hazardous intervention does not include the required information for such studies (described below), NIA will not fund the project until this information is received, reviewed, and approved by a designated Program Administrator. The Program Administrator may obtain additional consultation from NIH staff, or members of the National Advisory Council on Aging (NACA).

The following requirements apply to all studies employing interventions.

In each of the following sections ("Requirements for Investigators", "Requirements of a Data Safety Monitoring Board (DSMB)", and "Requirements of Program Administrators") the first part describes requirements for all such trials and the second part describes additional requirements for Phase III trials.

REQUIREMENTS FOR INVESTIGATORS

• All applications must describe a data and safety monitoring plan and management of monitoring procedures.
  
• In general, proposals to NIA for human intervention studies should include plans for a DSMB if the proposed study meets any of the following criteria:

  a. Is a Phase III clinical trial

  b. Is a multi-site clinical trial

  c. Has a high risk intervention

  d. Has over one hundred participants

Applicants for studies that do not meet the above criteria for having a DSMB may still propose to have a DSMB if they feel it would be useful for their study.

• All studies should have a structured adverse event determination, monitoring and reporting system, including standardized forms and protocols for referring and/or treating subjects experiencing adverse events.
  
• The proposed schedule for reporting adverse events to the DSMB (if one is established), the IRB (or IRBs in the case of multi-site studies), the Program Administrator, and/or the FDA should be described. The proposed schedule should include a system for sending DSMB's reports regarding safety issues (see section "Requirements of Data and Safety Monitoring Boards") to the study Principal Investigator (PI). In multi-site studies the study PI is responsible for sending these DSMB reports to individual site PIs, who in turn are required to distribute these reports to their local IRBs.
  
• Investigators must ensure that the NIH is informed of actions, if any, taken by the IRB as a result of their continuing review.
  
• Applications must include the proposed human subjects consent form and describe procedures for protection of human subjects.
  
• All masked studies should describe a randomization scheme, and specific criteria and procedures for unmasking. If a DSMB is not proposed, the application should also designate individuals with access to unmasked data.
  
• If the applicants believe that an independent DSMB is required for adequate subject safety, the application should indicate the proposed frequency of meetings for the DSMB, and include a proposed list of data items to be provided to the DSMB and estimates for DSMB-related expenses in the proposed project budget. Applicants should NOT nominate specific individuals for the DSMB in the application. If notified by the Program Administrator that the project is likely to be funded, the investigators should then nominate prospective DSMB members, including such information on the nominated DSMB member as: CV, a list from each of the nominated DSMB members of their current affiliations with pharmaceutical and biotechnology companies including the name of the company and the type of affiliation (e.g.stockholder, consultant), as well as any other relationship that could be perceived as a conflict of interest related to the study and associated with commercial interests. These nominations are subject to approval by the Director of the NIA. (DSMB members should have no direct involvment with the study or conflict of interest with investigators conducting the study.) If applicants have not proposed a DSMB, but prior to funding of the proposed project the Program Administrator believes an independent DSMB is required, applicants will make arrangements for a DSMB as described in section "REQUIREMENTS FOR PROGRAM ADMINISTRATORS."
  
• If the proposed project has additional clinical sites besides that of the Principal Investigator, the application should also describe procedures by which the PI will notify sites of any problems as identified by the DSMB if one is established.

• In specific cases where the funding IC is the sponsor of the test agent, i.e., holder of the Investigational New Drug (IND) application, investigators must submit individual adverse event reports to the IC (as sponsor) in accordance with FDA regulations.

ADDITIONAL REQUIREMENTS FOR INVESTIGATORS FOR PHASE III TRIALS

Applications for any intervention study should state in the "Research Plan section" of the PHS-398 form whether or not the proposed study meets NIH's criteria for a NIH-defined Phase III trial and the basis for that opinion. After review of the application by an IRG, the NIA Program Administrator will review this information. If the proposal for a study deemed by NIA to be a Phase III trial does not include the required information for such studies (described below), NIA will not fund the project until this information is received and reviewed by the Program Administrator. The Program Administrator may obtain additional consultation from IRG members (acting through the appropriate SRA), NIH staff, or members of the National Advisory Council on Aging (NACA).

Proposals for Phase III trials must include:

• Plans for establishment of an independent DSMB.
  
• A data processing and analysis unit or function administered by a designated individual other than the Principal Investigator(s)of the trial. (In the case of multiple-award studies, the designated individual may be the Principal Investigator of an administratively separate award). This individual may report to the Principal Investigator or, in multiple-award studies, may report to the steering committee, of which the Program Administrator is a member.

In all cases, all data from this unit must be directly available to the Program Administrator and the DSMB upon request.

• Protocols for quality assurance/quality control, data management, and analysis.
  
• Plans for notifying subjects of trial results after the conclusion of the trial and providing the subjects' health providers with the appropriate information from the trial, as needed, concerning the individual subject (e.g., cessation of drugs, changes in dosage, etc.).

Though a detailed Manual of Procedures is not required in the application submitted to peer review, the applicant should prepare the Manual of Procedures for review and approval by the DSMB and Program Administrator, prior to implementation of the trial.

REQUIREMENTS FOR DATA and SAFETY MONITORING BOARDS (DSMBs)

If a DSMB is established, its initial tasks are to review the protocol with regard to subject safety (including identification and formatting of data to be regularly reported to the DSMB); identify needs for protocol modification; identify that the study protocol insures adherence to human subject protection policies; and, after receipt of a satisfactory protocol, recommend subject recruitment be initiated.

DSMB meetings will be open only to NIA staff and designated individuals who have been approved to have access to unmasked data. The DSMB must meet on a regular schedule (not less than twice a year) over the course of study (with additional meetings as needed)to:

• Review data (including masked data) over the course of the trial relating to efficacy, recruitment, randomization, compliance, retention, protocol adherence, trials operating procedures, form completion, intervention effects, gender and minority inclusion and subject safety.
  
• Identify problems relating to safety over the course of the study. Inform study PI via written report, who in turn will ensure that all clinical site PIs receive this report.
  
• Identify needs for additional data relevant to safety issues and request these data from the study investigators.
  
• Propose appropriate analyses and periodically review developing data on safety and endpoints.
  
• Make recommendations on continuation of the study, in regard to recruitment, treatment effects, retention, compliance, and safety issues.
  
• Send the Program Administrator and PI written reports following each D SMB meeting and additionally, as needed, on all issues reviewed by the DSMB. The PI will then send the report to their IRB.
  
• If there is more than one clinical site the study PI is responsible for sending the reports to individual site PIs, who in turn are required to distribute the report to their local IRBs, as detailed in the NIH "Guidance on Reporting Adverse Events to Institutional Review Boards for NIH-Supported Multicenter Clinical Trials" (NIH Guide for Grants and Contracts, June 11, 1999).

ADDITIONAL REQUIREMENTS FOR THE DSMB FOR PHASE III TRIALS

• The initial task of the DSMB is to review the entire study protocol, the Manual of Procedures, and the informed consent form with regard to recruitment, randomization, intervention, subject safety, data management, plans for auditing of primary subject records, and quality control and analysis, and to identify needed modifications. The DSMB shall then identify the relevant data parameters and the format of the information to be regularly reported. If the need for modifications to the protocol, Manual of Procedures, consent form, etc., is indicated by the DSMB and/or the program administrator, the DSMB shall postpone its recommendation for the initiation of subject recruitment until after the receipt of satisfactory revised protocol(s), etc.
  
• Review masked or unmasked outcome data as needed and appropriate over the course of the trial.
  
• At each meeting, consider the rationale for continuation of the study, with respect to progress of randomization, retention, protocol adherence, data management, safety issues, and outcome data, if relevant, and make a recommendation for or against continuation of the trial.
  
• Provide advice on issues regarding data discrepancies found by the data auditing system or other sources. If this advice is requested by the Project Office/Program Administrator, it should be provided by the DSMB in writing within two weeks of the date of this request.
  
• Review manuscripts of trial results prior to submission for publication. (The NIA Program Administrator may require that the DSMB approval of the manuscript be obtained before submission.)

REQUIREMENTS FOR PROGRAM ADMINISTRATOR

For applications receiving a peer review rating that is potentially in the fundable range, the Program Administrator will review the risks of the intervention. If the information required in applications for studies havingpotentially harmful interventions is not included in the application, the Program Administrator will notify the applicant of what items are missing and indicate that NIA will not fund the project until this information is received, reviewed, and approved by the Program Administrator. The Program Administrator may obtain additional consultation from NIH staff, or members of the National Advisory Council on Aging (NACA).

If the NIA plans to fund the proposed project, and the applicant has not proposed a DSMB, the Program Administrator will determine whether or not a DSMB is required for adequate subject safety. If a DSMB is required, the Program Administrator will request the applicant to indicate the proposed frequency of meetings for a D SMB; to submit a proposed list of data items to be provided to the D SMB; to nominate a DSMB of no less than three persons (including such information on the nominated DSMB member as: CV, a list from each of the nominated DSMB members of their current affiliations with pharmaceutical and biotechnology companies including the name of the company and the type of affiliation (e.g.stockholder, consultant), as well as any other relationship that could be perceived as a conflict of interest related to the study and associated with commercial interests). These nominations are subject to the approval by the Director of the NIA. Applicants should also submit a proposed supplemental budget for travel and administrative expenses for the DSMB. The NIA will reserve the right to appoint additional members to the DSMB to include scientific expertise in topic areas relevant to the trial such as biostatistics, ethics, or patient advocacy.

For awards that are to be funded, the Program Administrator will:

• Review and approve data and safety monitoring plans

• Verify that applicants have sent a detailed monitoring plan to IRB or IRBs involved in study.

• Include a condition in the Notice of Grant Award stating that the awardee's site cannot recruit participants until both NIA program staff and the awardee's IRB have approved the monitoring plan; and that NIA program staff have also documentation of the IRB's approval of that site's monitoring plan.
  
• Institute any other appropriate terms in the award needed for subject safety (e.g. data reporting formats and schedules, restrictions on expenditure of funds pending completion of particular activities, etc.).

For funded awards, the Program Administrator will:

• Review regular reports of data (including unmasked data if needed) on adverse events.
  
• Request additional data from investigators as needed on safety issues arising over the course of the study.
  
• Upon receipt of noncompeting renewal applications (and more frequently if necessary), review rationale for continuation of study, and terminate award if recommended by the DSMB and/or the Director of NIA (e.g., inadequate recruitment, retention or compliance, or excessive adverse events).

For studies with DSMBs, the Program Administrator will also:

• Include in the Notice of Grant Award a condition stating that the awardee cannot recruit participants until the NIA Program Administrator approves the protocol based on recommendations of the DSMB.
  
• Review DSMB reports.
  
• As needed, request that the DSMB provide advice to the study on trial protocol and safety issues arising over course of study, and continuation or termination of the study.
  
• Facilitate implementation of DSMB recommendations by the Institute.

The Program Administrator may serve as a non-voting, ex officio member of the DSMB.

ADDITIONAL REQUIREMENTS FOR THE PROGRAM ADMINISTRATOR FOR PHASE III TRIALS

After review of the application by an IRG, the Program Administrator will confirm whether or not the study is a NIH-defined Phase III trial. If the information required in applications for Phase III trials (described above) is not included in the application, the Program Administrator will notify the applicant of what items are missing and indicate that NIA will not fund the project until this information is reviewed and approved by the Program Administrator. The Program Administrator may obtain additional consultation from NIH staff, or members of the National Advisory Council on Aging (NACA).

• Institute any appropriate terms in the award needed for subject safety, satisfactory data management, quality, and analysis; recruitment and protocol adherence (e.g., data reporting formats and schedules, restrictions on expenditure of funds pending completion of particular activities, etc.).
  
• Review regular reports of relevant masked group data on treatment effects.
  
• Request additional data from investigators as needed on safety issues, data management, quality, and analysis; recruitment, retention, and protocol adherence issues arising over course of study.
  
• As needed, request that the DSMB provide advice to the study on trial protocol and safety issues; data management, quality, and analysis; recruitment, retention, and protocol adherence issues arising over the course of the study and continuation or termination of the study.
  
• Acknowledge reports of serious data discrepancies found by the DSMB, or other sources within two weeks of the receipt of this information by the Project Officer/Program Administrator. This acknowledgment should be in writing and include a plan describing the steps that are to be taken next, and should be sent to the Principal Investigator, the Chair of the DSMB, and the Director of NIA.
  
• Assure preparation and dissemination of a clinical alert in the event of a clinically significant finding. This dissemination should also include informing the subjects of this clinical alert and providing them and their health provider with as complete information as possible that may affect the subjects' well-being.

• Reserve the option, at any point in the trial, to obtain an independent audit of a sample of primary subject records for comparison with the trial's regular audit reports. Auditors so engaged will report directly to NIA and be reimbursed directly by NIA, i.e., reimbursement will not be drawn from the award for the trial, and costs of such audits will not be borne by the awardee institution(s).
  
• The NIA Program Administrator may reserve the option to obtain prior review by the DSMB of manuscripts reporting major outcomes before submission of such manuscripts for publication.

PEER REVIEW OF APPLICATIONS TO NIA FOR PHASE III TRIALS

Applications will be reviewed by an IRG. The review will specifically address the adequacy of plans, budgeting, and staffing to implement the requirements listed under "REQUIREMENTS FOR INVESTIGATORS".

INQUIRIES

The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries are encouraged and may be directed to the NIA program staff member with whom the applicant/grantee has been in contact or, if there are general issues of policy, please contact:

Dr. Miriam Kelty
Office of Extramural Affairs
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C218 MSC 9205
Bethesda, MD 20892-9205
Telephone: (301) 496-9322

Email: MK46U@NIH.GOV