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• Introduction
• Submission Requirements at the Time of Proposal
• Submission Requirements Prior to Study in a Clinical Trial
• Ongoing Reporting Requirements
• NCCAM Terms of Award for Clinical Trials: Checklist
• NCCAM Contacts
• Other Applicable Regulations and Guidelines

Introduction

Background
The National Center for Complementary and Alternative Medicine (NCCAM) supports clinical trials and other clinical studies of complementary and alternative medicine (CAM) agents. NCCAM must ensure compliance with Federal regulations to protect the safety of trial/study participants, and to ensure that trials/studies are conducted sufficiently well to justify expenditures of Federal funds. To assist NCCAM in properly monitoring such research, additional information is required for submission with a competitive grant application and the annual progress report. The additional NCCAM requirements are consistent with and complementary to the requirements stated in the instructions for the grant applications PHS 398 or SF424 (R&R) and progress report (non-competitive renewal, PHS 2590, and NCCAM Requests for Proposals (RFPs), Requests for Applications (RFAs), Program Announcements (PAs), and other terms and conditions of grant awards. If these requirements conflict with specific requirements written into a Cooperative Agreement or contract, the requirements of the Cooperative Agreement or contract apply.

Applicability
The NCCAM Terms of Awards for Clinical Trials ("Terms") apply to all NCCAM-supported trials of therapeutic or preventive interventions involving human subjects ("clinical trials"). When the award supports more than one clinical trial, the Terms apply to each of the clinical trials. These Terms apply to any CAM domain that may be the subject of the trial: biologically based therapies including homeopathy, alternative medical systems, manipulative and body-based methods, and energy therapies. (See nccam.nih.gov/health/whatiscam/#4 for a description of CAM domains.)

The Terms will become effective December 1, 2002, and will apply to all monetary awards made after that date, for example, all FY 2003 and subsequent clinical trials..

Procedures To Protect the Safety of Trial Participants
Federal and international standards to protect clinical trial participants are summarized in the U.S. Food and Drug Administration (FDA) document E6 Good Clinical Practice: Consolidated Guidance (ICH April 1996). This document is available at fda.gov/cder. Good Clinical Practices (GCP) are standards for the design, conduct, recording, monitoring, analysis, and reporting of clinical trials that best assure that the safety of trial subjects are protected and that the data are credible. Grantees show that the standards have been met through documents submitted prior to, during, and after the trial.

GCP standards in use by other NIH Institutes and Centers and applicable to NCCAM have been presented to and agreed upon by the National Advisory Council on Complementary and Alternative Medicine.

Documents needed prior to accrual of patients into the trial:
• The final protocol, consent form, and case report forms.
• Notice that an Institutional Review Board has approved the protocol and consent form for the trial, and the FDA has not put a clinical hold on the trial.
• Documentation of a Data Safety and Monitoring Plan (DSMP) by which the drug/pharmacy, clinical laboratory, efficacy data, and safety data are monitored.
• Data verification plan.

Documents needed during the trial:
• Revisions of the documents submitted before the trial.
• Documentation that the DSMP is being implemented.

Documents needed after the trial:
• Final DSMP report.

Other clinical information needed:
• · A targeted/planned enrollment plan and an accrual plan are needed prior to accrual.
• · Demonstration that the plans are being met is required during the trial.
  Principal investigators of some NCCAM clinical trials/studies will be asked to provide updates on recruitment and retention on a quarterly basis (R21) or on a semi-annual basis (R01) to demonstrate that the enrollment/accrual plan is succeeding.

Awardee's Responsibilities
The Terms describe the awardee's responsibilities for submitting required documentation related to the progress of clinical trials to NCCAM (and to other NIH offices, as applicable) at specific times. The Terms will be attached to the notice of grant (or cooperative agreement/contract) award. It is the awardee's responsibility to submit the required documentation to NCCAM according to these timelines. Lack of compliance with the Terms will be grounds for termination of the award at the first appropriate opportunity. To help assist awardees in meeting these deadlines, there is a checklist of submission and ongoing reporting requirements at the end of this document.

All clinical research conducted in the United States supported by NCCAM must comply with state and local regulations. All clinical research supported by NCCAM, but conducted outside of the United States, must also comply with the local regulations of the host country. If regulations differ between authorities, the more restrictive regulation applies.

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Submission Requirements at the Time of Proposal

NIH Form 398 or Grants.gov form SF424 (R&R), as required, containing Research Plan, Data Safety and Monitoring Plan, and Risks to Human Subjects
Instructions for NIH form 398 may be found at grants.nih.gov/grants/funding/phs398/phs398.html.
Instructions for the SF424 (R&R) may be found at grants.nih.gov/grants/funding/424/

The Research Plan, Data Safety and Monitoring Plan, and Risks to Human Subjects information requested as part of both of these application packages addresses many but not all of the considerations needed in a Protocol, DSMP, and Consent Form, as outlined in E6 Good Clinical Practice: Consolidated Guidance. Grant applicants may choose to submit a Protocol, DSMP, and Consent Form according to E6 Good Clinical Practice: Consolidated Guidance as part of the grant application, or after favorable review of the grant application.

Targeted Enrollment Table
A Targeted/Planned Enrollment Table must be submitted with the grant application. The table includes projected demographic information of the study population. The format for this table is located at grants.nih.gov/grants/funding/phs398/enrollment.pdf (for PHS398) or at grants.nih.gov/grants/funding/424/SF424R-R_enrollment.doc for the SF424.

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Submission Requirements Prior to Study in a Clinical Trial

Prior to conducting the study, the awardee submits the following to the responsible NCCAM Program Officer for review and approval:

1. Clinical Protocol and Consent For
The awardee submits the Institutional Review Board (IRB) approved protocol and consent form identified by version number and/or date.

The general elements of a GCP clinical protocol and consent form are described in sections 6 and 4.8, respectively, of the document E6 Good Clinical Practice: Consolidated Guidance. The protocol and consent form should include the elements listed below, if appropriate to the particular trial and if they are in agreement with site-specific requirements of the awardee.

2. Data and Safety Monitoring Plan

Specifics of a data safety and monitoring plan
Data and safety monitoring is intended to provide an independent review of the conduct of the pharmacy, of the clinical laboratory and other tests, and of data related to efficacy and safety. The specific subjects to be covered in the data and safety monitoring plan include many of the elements in section 8 of the document E6 Good Clinical Practice: Consolidated Guidance.


• Pharmacy plan (for trials of biologically based therapies): certificate of analysis of investigational product and instructions for shipping, handling, and storing investigational product. The review of the pharmacy plan may include advice on product selection and on the parameters needed in the certificate of analysis.
  
  
• Laboratory plan: normal values for medical, laboratory, or technical procedures and assurance that medical, laboratory, or technical personnel can accurately perform tests.
  
  
• Efficacy plan: entering data into case report forms and monitoring of case report forms to determine that entered data reflects data in original source documents.
  
  
• Safety plan (for trials of more than minimal risk--see below): entering data into case report forms; monitoring of case report forms to determine that entered data reflects data in original source documents; and review procedures and stopping rules for adverse effects and serious adverse effects. Review of the efficacy and safety plans may include advice on dosing regimens.
  
  
Review of adverse events in trials of more than minimal risk
Independent review of adverse events is essential for all clinical trials that may involve more than a minimal risk. A risk is minimal when the probability and magnitude of harm or discomfort anticipated in the proposed research are not greater than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.



For trials of more than minimal risk, the body that reviews adverse events could be



• an Independent Safety Monitor, a physician or other appropriate expert, independent of the study, who is available in real time to review and recommend appropriate action regarding adverse events and other safety issues
  
  
• an Independent Monitoring Committee, a small group of independent investigators and biostatisticians who review safety data
  
  
• a Data and Safety Monitoring Board (DSMB), an independent committee charged with reviewing safety and trial progress and providing advice with respect to study continuation, modification, and/or termination. All phase III clinical trials must be reviewed by a DSMB
  
  
Data safety and monitoring plan approval
Discussions with the responsible NCCAM Program Officer are encouraged, particularly with respect to the choice of body that reviews adverse events and whether the awardee or NCCAM monitors the case report forms. Whatever body reviews adverse events, a description of the monitor/board, its charter and/or operating procedures (including proposed meeting schedule), and roster and curriculum vitaes of all members must be submitted for approval.

3. Institutional Review Board (IRB) Approval
The awardee is responsible for submitting all IRB notifications of protocol and consent form approval to the responsible NCCAM Program Officer, including the name of the IRB and the Office for Human Research Protections (OHRP) IRB registration number and the OHRP Federal Wide Assurance (FWA) site number. If there are other institutions involved in the research, for example, a multi-center study, the protocol should be reviewed and approved by each center's IRB or have written assurance that a central IRB has jurisdiction. Written documentation of approval from each IRB must be provided to the NCCAM and must include a copy of the IRB approved protocol and informed consent document, identified by version number and/or date, and dates during which it is valid.

Some countries may have a national IRB for which protocol and informed consent approval may be required. This approval process may be in addition to, or in lieu of, local IRB approval. For countries with multiple levels of IRB review, written documentation of protocol and consent form approval from each IRB must be provided to the NCCAM.

4. Investigational New Drug (IND) Requirements
Consistent with PHS 398, clinical trial protocols involving biologically based interventions must be submitted to the FDA for the FDA's determination as to whether an IND is needed. If an IND is needed, it must be obtained from the FDA. Exceptions to the need for an IND must be granted in writing by the FDA, or an FDA contact must be supplied so that NCCAM can verify the exception. The FDA published Botanical Drug Products: Draft Guidance (Aug 2000) regarding the need for and content of an IND for botanical drugs. It is available at fda.gov/cder.

NCCAM does not have a policy with respect to INDs for clinical trials involving non-biologically based interventions.

If the proposed clinical trial will be performed under an IND, the awardee must provide NCCAM with the name and institution of the IND sponsor, the date the IND was filed with the FDA, the FDA IND number, any written comments from the FDA, and the written responses to those comments. In addition, risk information, such as an Investigator's brochure, or information obtained through published literature review or other venue, should be submitted.

The awardee must wait 30 days from FDA receipt of the initial IND application prior to initiating the clinical trial. The awardee must notify NCCAM if FDA places the study on clinical hold and provide the NCCAM with any written comments from the FDA, written responses to the comments, and documentation in writing that the hold has been lifted.

For foreign studies, the awardee must provide NCCAM with written documentation from the foreign regulatory body that the awardee is in compliance with that country's regulations.

5. Other Relevant Requirements

Requirements for training in human subjects protections
The awardee is responsible for submitting written documentation to NCCAM that the awardee and all study staff responsible for the design and/or conduct of the research have received training in the protection of human subjects. The NIH provides an online tutorial titled, "Human Participant Protections Education for Research Teams," available at cme.nci.nih.gov. Other non-NIH-supported training programs are also available.

Accrual plan
Awardees must submit the anticipated rate of accrual of human subjects. Reporting on accrual will be at 3 to 6 month intervals for trials of 3 years or less, at 6 to 12 month intervals for trials of greater than 3 years, or as otherwise directed by a DSMB or the NCCAM Program Officer.

Other requirements
Other requirements may be determined on a case-by-case basis. NCCAM and the awardee must document the requests for, and compliance with, any additional requirements.

NCCAM response times
NCCAM staff comments will be forwarded to the awardee within 1 month of receipt of the above information. The awardee must address in writing all safety, regulatory, ethical, conflict of interest, and other concerns raised by NCCAM staff to the satisfaction of NCCAM before participant enrollment can begin. Any changes to the protocol must be reviewed and approved by the IRB prior to participant enrollment.

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Ongoing Reporting Requirements

Institutional Review Board Actions
Unless otherwise directed, the awardee is responsible for submitting to NCCAM all IRB notifications of protocol renewal, amendments, suspensions, and termination.

The responsible IRB(s) conduct continuing review of research at intervals appropriate to the degree of risk, but not less than once per year, as described in the Code of Federal Regulations: Title 45 Public Welfare, Part 46 Protection of Human Subjects (45 CFR 46.109).

Annual review
The awardee is required to submit, at least annually, to the responsible NCCAM Program Officer (and Contracting Officer, if applicable) documentation of the continuing IRB review. The submission will include:


• a copy of the IRB letter of renewal, in which the approved protocol and informed consent document are identified by version number and/or date
  
  
• dates during which the protocol and informed consent are valid
  
  
Amendments, suspension, and termination
The awardee must submit to the responsible NCCAM Program Officer (and Contracting Officer, if applicable) written documentation of any changes in IRB approval status, including:


• all amendments or changes to the protocol, other than minor corrections, identified by version number and/or date. (Except in the case of imminent danger to participants, changes to the protocol must be approved by the IRB prior to clinical implementation.)
  
  
• all changes in informed consent documents, other than minor corrections, identified by version number and/or date. (Changes must be approved by the IRB prior to clinical implementation.)
  
  
• temporary suspension or permanent termination of patient accrual
  
  
• temporary suspension or termination of the protocol
  
  
• any change in IRB approval status
  
  
• any other problems or issues that could affect the participants of the study.
  
  
Notification of any of the above changes must be made within 3 working days by e-mail or fax, followed by a letter co-signed by the Principal Investigator and the institutional business official, detailing the change of status notification to the IRB and a copy of IRB responses.

Data and Safety Monitoring Reviews
When a monitor or monitoring board is organized by the awardee, the awardee submits written summaries of all reviews conducted by the monitoring group to the responsible NCCAM Program Officer within 30 days of reviews or meetings. If reviews are frequent, quarterly reports are sufficient.

Safety Reporting Requirements

IND reporting
The awardee must notify the responsible NCCAM Program Officer in writing if the FDA places the study on clinical hold at any time while the clinical trial is being conducted.

IND safety reporting
Under an IND, the sponsor is required to provide the FDA with safety reports of serious adverse events. According to the Terms, the awardee must submit copies to the responsible NCCAM Program Officer as follows:


• 7-day IND Safety Reports (unexpected fatal or life-threatening adverse experiences), a copy of the report sent to the FDA must be submitted to the NCCAM Program Officer within 24 hours of FDA notification
  
  
• 15-day IND Safety Reports (any other serious and unexpected adverse event, including animal findings, that suggest a significant risk for human subjects), a copy of the report submitted to the FDA must be submitted to the NCCAM Program Officer within 24 hours of FDA notification
  
  
• Other adverse events documented during the course of the trial should be included in the annual IND report.
  
  
In case of specific problems or issues, the NCCAM Program Officer will contact the awardee within 10 working days, by e-mail or FAX, followed within 30 calendar days by an official letter to the Principal Investigator, with a copy to the institution's office of sponsored programs, describing issues and appropriate actions to be discussed.

Safety reporting for research not performed under an IND
Final decisions regarding ongoing safety reporting requirements for research not performed under an IND will be made jointly by NCCAM and the awardee.

Requirements for Training in Human Subjects Protections
The awardee is responsible for submitting documentation in the annual progress report that newly hired study staff responsible for the design and/or conduct of the research have received training in the protection of human subjects.

Inclusion Enrollment Reports
The Inclusion Enrollment Report includes cumulative accrual and demographic information for human subjects enrolled in the clinical research protocol. This report must be submitted annually at the same time as the annual progress report. The Inclusion Enrollment Report (Form PHS 398/2590) is located at grants.nih.gov/grants/funding/phs398/398_forms.pdf.

Awardees are expected to maintain the rate of accrual as stated in the initial accrual plan. Please contact the NCCAM Project Officer if enrollment is less than initially planned. If enrollment is markedly less than initially planned (50% to 67%), appropriate steps may be taken to ensure enrollment compliance and/or awards may be terminated, unless awardees can reasonably assure NCCAM that enrollment will increase.

Other Requirements
After the last trial subject has finished followup, a final monitoring report is to be submitted.

Other requirements may be determined on a case-by-case basis. NCCAM and the awardee must document requests for, and compliance with, additional requirements.

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NCCAM Terms of Award for Clinical Trials: Checklist

This summary checklist is a reminder of information that must be submitted to NCCAM.

Documents Required at Time of Competitive Application and Proposal:

• PHS398 or SF424 (R&R), containing Research Plan, Monitoring Plan (if more than minimal risk), and Risks to Human Subjects
  
  
• Targeted/Planned Enrollment Table

Documents Required Prior to Study Enrollment:

With each of the following documents, please provide a cover page with the following identifying information:

• Principal Investigator (phone/fax/e-mail)
• Date of Submission of Document
• Grant (or cooperative agreement/contract) Number
• Site Name
• Address
• Protocol Title
• OHRP IRB Registration Number and Name

1. IRB documents and Protocol/Consent Form, identified by version number and/or date (attach the following for each investigative site/IRB):



• IRB name
  
  
• FWA (Federal Wide Assurance) number for institution/site
  
  
• IRB OHRP registration number
  
  
• IRB notification of protocol and consent form approval
  
  
• IRB approved protocol
  
  
• IRB approved consent forms identified by dates during which they are valid
  
  
2. Data Safety and Monitoring Plan
   
   
3. Additional Information for Clinical Trials with INDs:*
   
   
• Name, Institution, and Address of IND Sponsor
  
  
• FDA IND Number (attach copy of letter from FDA) and Date IND was filed
  
  
• FDA Correspondence (attach copies of all written communication with the FDA)
  
  
• Risk Information (Investigator's brochure, etc.)
  
  
*For trials without INDs, supply risk information.


4. Documentation of Training in Human Subjects Protections
   
   
5. Accrual plan
   
   

Ongoing Reporting Requirements:

With each of the following documents, please provide a cover page with the following identifying information:

• Principal Investigator (phone/fax/e-mail)
• Date of Submission of Document
• Grant (or cooperative agreement/contract) Number
• Site Name
• Address
• Protocol Title
• OHRP IRB Registration Number and Name

1. Documentation of IRB continuing reviews (attach the following for each investigative site):
   
   
   • IRB OHRP registration number
     
     
   • OHRP Federal Wide Assurance (FWA) number for site
     
     
   • IRB continuing review and approval of protocol and consent form, identified by version number and/or date and dates during which it is valid
     
     
   • Documents related to protocol amendments, suspensions, or termination.
     
     
   Please note that for the duration of the award it is the responsibility of the awardee to notify NCCAM of subsequent protocol amendments or changes in IRB approval status within 3 working days of IRB decision. Documents related to an amended protocol must be submitted to the NCCAM prior to implementing changes (except in the case of imminent danger to participants).
   
   
2. Data and Safety Monitoring Reviews or Summaries (submit within 30 days of review or meeting)
   
   
3. IND Safety Reports
   
   
   • For 7-day reports, send copy to NCCAM Program Officer within 24 hours of FDA notification
     
     
   • For 15-day reports, send copy to NCCAM Program Officer within 24 hours of FDA notification
     
     
   • Report adverse events not included in expedited reports in the annual IND report
     
     
4. Training in human subjects protections for new study staff, if applicable, submit with each annual progress report
   
   
5. Inclusion Enrollment Reports, submit with each annual progress report
   
   

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NCCAM Contacts

General inquiries related to this notice, and inquiries prior to submission of a grant (or cooperative agreement/contract):

Director, Office of Clinical and Regulatory Affairs (OCRA), NCCAM, NIH
Phone: 301-594-7105
E-mail: bermanjo@mail.nih.gov

Inquiries related to a specific grant (or cooperative agreement/contract):
Inquiries should be directed to the assigned NCCAM Program Officer.

Document submission:
All information and documentation required by the NCCAM Terms of Award for Clinical Trials must be forwarded by the responsible institutional official, electronically or by mail, to the NCCAM Grants Management Officer, who will distribute copies to the responsible Program Officer and to Director OCRA.

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Other Applicable Regulations and Guidelines

NCCAM-supported clinical research must adhere to all applicable clinical research and human subject protection regulations and guidelines including those of the Office for Human Research Protections (OHRP), U.S. Department of Health and Human Services. All clinical research supported by NCCAM must comply with OHRP requirements for human subject protection, informed consent, IRB registration, assurances, and responsibilities, including ongoing review. For more information please visit the OHRP at www.hhs.gov/ohrp.

FDA's Information Sheet, Guidance for Institutional Review Boards and Clinical Investigators (1998), which represents the agency's current guidance on protection of human subjects of research, can be found at www.fda.gov/oc/ohrt/irbs/default.htm.

All NCCAM-supported clinical trials that are conducted under a FDA IND application must comply with relevant Parts of CFR Title 21, specifically:

• Part 50, "Protection of human subjects"
  
  
• Part 54, "Financial disclosure by clinical investigators"
  
  
• Part 56, "Institutional review boards"
  
  
• Part 312, "Investigational new drug application"

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