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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