IMPLEMENTATION OF POLICIES FOR HUMAN INTERVENTION STUDIES NIH GUIDE, Volume 25, Number 33, October 4, 1996 P.T. 34 Keywords: Clinical Medicine, General Human Subjects Policy Safety National Institute on Aging INTRODUCTION The following policies are based on two goals: Protecting the safety of participants in intervention studies. This goal applies to any study including an intervention that could have harmful effects, whether or not the study is a Phase III trial or a more limited intervention study. Policies to achieve it are described in the "Safety Policies" section. Assuring that trials likely to affect clinical or public health practice (Phase III trials) are soundly conducted and analyzed. This goal serves to prevent inappropriate implementation of non-efficacious or harmful interventions (or inappropriate failure to implement efficacious interventions) in practice, based on the results of a trial. Policies to achieve it are in the "Data Integrity/Quality Control Policies for Phase III Trials" section. These policies describe NIA requirements for extramurally supported projects. They apply to all new projects to be submitted for the June 1, 1996 receipt deadline and all subsequent deadlines. They do not replace existing 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. 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. 5/95), available on the NIH home page (HTTP://www.nih.gov). 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. SAFETY 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), 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 and reviewed by the Program Administrator. The Program Administrator may obtain additional consultation from IRG members (acting through the appropriate Scientific Review Administrator [SRA]), NIH staff or members of the National Advisory Council on Aging (NACA). The following requirements apply to studies employing interventions that could have significant harmful effects: Requirements for Investigators (design and plans for implementation must be included in application): 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 Safety Monitoring Board (if one is established), the Program Administrator and/or the FDA should be described. The proposed human subjects consent form should be included in the application. All masked studies should describe randomization scheme, and specific criteria and procedures for unmasking. If a Safety Monitoring Board (SMB) is not proposed, the application should also designate individuals for access to unmasked data. If the applicants believe that an independent Safety Monitoring Board is required for adequate subject safety, the application should indicate the proposed frequency of meetings for the SMB, and include a proposed list of data items to be provided to the SMB and estimates for SMB-related expenses in the proposed project budget. Applicants should NOT nominate specific individuals for the SMB in the application. If notified by the Program Administrator that the project is likely to be funded, the investigators should then nominate prospective SMB members, subject to approval by the Director of the NIA. If applicants have not proposed an SMB, but prior to funding of the proposed project, the Program Administrator believes an independent SMB is required, applicants will make arrangements for an SMB as described on page 3 (Requirements for Program Administrators). Responsibilities of Safety Monitoring Boards (SMBs). If an SMB 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 SMB); identify needs for protocol modification; and, after receipt of a satisfactory protocol, recommend to the NIA initiation of expenditure of project funds. Subsequently, it must meet on a regular schedule (not less than twice a year) over the course of study (with additional meetings as needed) to: o Review data (including masked data) relating to recruitment, randomization, compliance, retention, protocol adherence, trials operating procedures, form completion, intervention effects, and subject safety. o Identify problems relating to safety over the course of the study. o Identify needs for additional data relevant to safety issues and request these data from the study investigators. o Propose appropriate analyses and periodically review developing data on safety and endpoints o Make recommendations on continuation of the study, in regard to recruitment, retention, compliance and safety issues. o Send the Program Administrator written reports following each SMB meeting, and additionally as needed, on all issues reviewed by the SMB. 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 having potentially hazardous interventions (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 received, reviewed and approved 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). If the NIA plans to fund the proposed project, and the applicant has not proposed a SMB, the Program Administrator will determine whether or not an SMB is required for adequate subject safety. If an SMB is required, the Program Administrator will request the applicant to indicate the proposed frequency of meetings for an SMB; to submit a proposed list of data items to be provided to the SMB; to nominate an SMB of no less than three persons subject to approval by the Director of NIA; and to submit a proposed supplemental budget for travel and administrative expenses for the SMB. The NIA will reserve the right to appoint additional members to the SMB to include scientific expertise in topic areas relevant to the trial such as biostatistics, ethics, or patient advocacy. For funded awards, the Program Administrator will: o Institute any 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.). o Review regular reports of data (including masked data if needed) on adverse events. o Request additional data from investigators as needed on safety issues arising over the course of the study. o Upon receipt of noncompeting renewal applications (and more frequently if necessary), review rationale for continuation of study, and terminate award if recommended by the SMB and/or the Director of NIA (e.g., inadequate recruitment, retention or compliance, or excessive adverse events). For studies with SMBs, the Program Administrator will also: o Review proposed membership of SMB before approving initiation of expenditure of award funds. o Review SMB reports. o Request advice of SMB as needed on study protocol and safety issues arising over course of study, and advisability of terminating the study. o Facilitate implementation of SMB recommendations by the Institute DATA INTEGRITY/QUALITY CONTROL POLICIES FOR PHASE III STUDIES A Phase III Clinical Trial, as defined on page 29 of the PHS 398 form (rev. 5/95), 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. 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 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). The following requirements apply to Phase III trials: Requirements for Investigators (design and plans for implementation must be included in the application). The proposed trial must include: o Explicit criteria and procedures for defining, determining, and reporting intervention-related outcomes. o 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. o An independent Data and Safety Monitoring Board (DSMB). 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, subject to approval by the Director of NIA. o The proposed human subjects consent form. o Protocols for quality assurance/quality control, data management, and analysis. o 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 Data and Safety Monitoring Board and Program Administrator should be described. o Specific criteria and procedures for unmasking (if the study is masked). o Plans for independent auditing of primary subject records over the course of the trial to verify conformance with eligibility criteria, recruitment and outcome data, adverse events, etc., and reporting discrepancies to the Principal Investigator, the DSMB, and the Program Administrator. These plans should provide for reporting serious discrepancies within two weeks of their discovery. o A detailed Manual of Procedures. This is not required in the application submitted to peer review. If an award is made, the applicant should prepare the Manual of Procedures for review by the Data and Safety Monitoring Board and Program Administrator, prior to implementation of the trial. o Plans for notifying subjects of trial results after the conclusion of the trial. Responsibilities of the Data and Safety Monitoring Board (DSMB). The DSMB will report to the Director of the NIA. 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, 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., are indicated by the DSMB and/or the program administrator, the DSMB shall postpone its recommendation (to the NIA and the grantee) for the initiation of expenditure of project funds until after the receipt of satisfactory revised protocol(s), etc. DSMB meetings will be open only to NIA staff and designated individuals who have been approved to have access to unmasked data. The DSMB shall meet on a regular schedule over the course of study (at least twice a year), with additional meetings as needed, to: o Review data (including masked data) over the course of the trial relating to recruitment, randomization, compliance, retention, protocol adherence, intervention effects, data management and quality assurance/quality control, and subject safety. o Identify any problems relating to the above issues. o Identify needs for additional data, and request these data from the study investigators. o Review unmasked outcome data as needed and appropriate over the course of the trial. o 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 recommendation for or against continuation of the trial. o 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 in writing within two weeks of the date of this request. o Send written reports following each DSMB meeting on all issues reviewed by the DSMB as needed to the Program Administrator and Director of NIA o Review manuscripts of trial results prior to submission for publication (at the request of the program administrator) Requirements for the Program Administrator: After review of the application by an IRG, the Program Administrator will assess whether the study meets NIH criteria for a 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 IRG members (acting through the appropriate SRA), NIH staff, or members of the National Advisory Council on Aging (NACA). For Phase III trial awards, the Program Administrator may: o Review proposed membership of DSMB and recommend endorsement by the Director of NIA before approving initiation of expenditure of award funds. o 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.). o Review regular reports of relevant masked group data on treatment effects. o Review DSMB reports. o 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. o Request advice of the DSMB as needed 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 on the advisability of continuing the study. o Convey DSMB recommendations and requests to the Principal Investigator(s) o Acknowledge reports of serious data discrepancies found by the data auditing system, the DSMB, or other sources within two weeks of the receipt of this information by the Project Office/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. In addition, in instances of reported fraud or abuse, standing NIH policies apply. o Upon receipt of noncompeting renewal applications and DSMB recommendations (and more frequently if necessary), review rationale for continuation of study, and terminate award if indicated (e.g., inadequate recruitment, retention or protocol adherence or excessive adverse events). o Prepare clinical alert in the event of a clinically significant finding which should be disseminated immediately. o 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). o Reserve the option to obtain prior review by the DSMB of manuscripts reporting major outcomes before submission of such manuscripts for publication The Program Administrator may serve as a non-voting, ex officio member of the DSMB. Peer Review of Applications to NIA for Phase III Trials. Applications will be reviewed by an IRG, which includes several members with expertise in clinical trials methodology (including Phase III trials) as well as several members with expertise in the particular topic(s) of the trial. 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: Dr. Robin A. Barr or 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: RB42H@NIH.GOV Email: MK46U@NIH.GOV .
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