Policy and Procedures for Investigator-initiated Clinical Trials

See also:

• Investigator-Initiated Clinical Trials Program Announcement
  
• Frequently Asked Questions About Certificates of Confidentiality
• Example of consent form language describing Certificate of Confidentiality protection of privacy

Purpose

This document outlines NIDCD policy and procedures for investigator-initiated, NIH-defined phase III (see PHS 398, Rev. 5/01, for definition, at http://grants1.nih.gov/grants/funding/phs398/phs398.html) clinical trials and provides guidelines for the preparation and submission of these applications. It lists the requirements placed on the receipt, review, and funding of these applications and presents guidelines for the conduct of such trials. For information regarding the NIDCD Clinical Trial Planning grant, please see http://grants.nih.gov/grants/guide/pa-files/PAR-02-158.html.

Top

Eligibility Requirements

Applications may be submitted by domestic for-profit and non-profit organizations (including consortia of institutions), public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign organizations are not eligible to apply. Domestic applications may include international components; however, the domestic components must constitute the majority of the application. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators.

Top

Mechanisms of Support

All applications for NIDCD Investigator-Initiated Clinical Trials must be submitted as R01s. For those applications that are to be awarded $500,000 or more in direct costs in any year or support for a multi-center clinical trial, the R01 will be converted to the U01 mechanism (a cooperative agreement), indicating substantial NIDCD staff involvement, and the Terms and Conditions of Grant Award will reflect that arrangement. See below for further information.

Regardless of the mechanism of support, NIDCD staff will closely monitor progress during the Award period. This monitoring may include regular communication with the principal investigator and staff, as well as, in the case of the cooperative agreement, participation in the steering committee, data and safety monitoring committee, and related committee meetings. The level of NIDCD staff participation will be specified in the Terms and Conditions of Award.

Top

Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the PA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to the Chief, Clinical Trials, Epidemiology and Biostatistics Section, at the address indicated under "INQUIRIES".

Top

Application Procedures

The standard PHS 398 (Rev. 5/01), Grant Application Form, is used to apply for Investigator-Initiated Clinical Trials. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC-7910, Bethesda, MD 20892-7910, telephone 301-435-0714, e-mail GrantsInfo@nih.gov, and http://grants.nih.gov/grants/forms.htm. Investigators should generally adhere to the guidelines detailed in the PHS 398 application kit. As it is anticipated that applications responsive to "NIDCD Investigator-Initiated Clinical Trials" will request funds exceeding $250,000 direct costs per annum, modular grant instructions do not apply.

Applicants planning to submit an investigator-initiated application (or a group of applications for a multi-site clinical trial) requesting $500,000 or more in direct costs for any year are advised that he or she must contact the Institute or Center (IC) program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the application must obtain agreement from the IC staff that the IC will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute or Center that agreed to accept assignment of the application.

This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998, at: http://grants.nih.gov/grants/guide/notice-files/not98-030.html.

Top

Submission of Application

Receipt dates are as follows:

Note that there is only one receipt date per round for NIDCD Clinical Trial applications regardless of whether they are new, renewal, or amended. Applications received after a given receipt date will be deferred to the next review cycle.

Top

Specific Instructions

On the face page of the application, item 2, check "YES" and enter the number and title of this Program Announcement: NIDCD Investigator-Initiated Clinical Trials. Clinical trials often require the collaboration of multiple field centers, a separate data coordinating center, and one or more core facilities. The need for separate centers and cores must be carefully and completely described and justified. Separate budget justifications, facility statements, and informed consent forms must be submitted for each center. Commitment from the principal investigators and business offices of each center must be documented.

The information provided in the application should be organized in a manner that will facilitate peer review. The body of the application from the study chair must present an overview of the state of the science, current status and relevance of the trial, a discussion of the specific protocol, and the approach to data collection and analysis. It is recognized that this 25-page overview may not permit adequate detail for a complete review of the study. Therefore, details of the protocol, methods, quality control procedures, power analysis, data analysis, and similar material should appear, when needed for a thorough discussion, in well organized and referenced appendices to the study chair application. These details are not to be included in field center applications.

Single site clinical trials should include all required information (see below) in a single application. In contrast, multi-site clinical trials, comprising a study chair, field centers, a data coordinating center, and other specialized centers or core facilities, are expected to submit a family of related R01 applications, in which each individual R01 application includes the information appropriate for the anticipated role in the clinical trial effort.

A STUDY CHAIR application should include information relevant to the overall clinical trial, as well as specific information relating to the STUDY CHAIR. Accordingly, the STUDY CHAIR application should include, at a minimum:

1. an overview of the proposed clinical trial, including the rationale for the clinical trial and its significance in addressing a problem in hearing, balance, smell, taste, voice, speech, and language;
2. the appropriateness of the experimental design for testing the problem/hypothesis, the measures chosen to assess the effect of the intervention, the plans for minimizing bias, and the criteria for the study endpoints;
3. the study procedures and administrative arrangements for implementing the experimental design/protocol (a manual of procedures/operations should be included as an appendix);
4. the justification for the sample size, the availability of the patient pool, the likelihood of achieving the target sample size in a reasonable time, the reasonableness of the general statistical approach, and the procedures for quality assurance and technical monitoring of the study centers for adherence to the protocol and for data monitoring to determine whether protocol changes are needed; and
5. the scientific, clinical, and administrative qualifications of the Study Chair and other key personnel.

A FIELD CENTER Application should include:

1. the adequacy of the field center's procedures for patient recruitment, retention, and follow up; data collection and data control; quality control of clinical examinations, training, and certification of personnel, and testing and monitoring of study procedures;
2. the qualifications of all key personnel (whether compensated or not), including their experience and track record in clinical trials (NIDCD-supported and other);
3. the adequacy of the potential sources and numbers of fully-eligible patients and the documentation of any proposed collaborations; the center's recruitment and retention track record in clinical trials; the physical facilities and equipment available for the study; and
4. the appropriateness and reasonableness of all items requested relative to the center's potential for recruitment, and the overall scope of the center's proposed activities.

A DATA COORDINATING CENTER (and OTHER RESOURCE CENTER) application should include the following information:

1. the reliability and accuracy of the center's past performance and the potential of the center's future performance in clinical trials;
2. the experience of the Principal Investigator and other key personnel in conducting clinical trials;
3. the ability of the center to manage and analyze data for the clinical trial; and
4. the appropriateness of the proposed procedures for data management, data storage, and analytical activities.

Top

Application Package

The application package (consisting of a single R01 application for a single site clinical trial and a family of R01 applications for a multi-site clinical trial) must provide detailed scientific and operational plans as well as funding needs for the entire trial and data analysis period. Investigators must submit a total overall budget and a complete, itemized individual budget for each year of support requested. Separate itemized budgets must be prepared for each subcontract and/or for each center or core for each year, if multiple centers or cores are proposed. All costs requested and all changes in budgets after the first year should be clearly identified and justified. Further information concerning budget preparation may be obtained from the Chief, Grants Management Branch, NIDCD at the address indicated under "INQUIRIES".

The following sections must be included in the grant application package:

Specific Aims

• The specific aims of the trial must be clearly and concisely presented. These should include a clear specification of the primary and secondary endpoints to be measured, with a clear differentiation of the importance of various endpoints.

Significance

• The significance of the proposed clinical trial must be clearly stated. It is particularly important that there be a discussion of how the trial will test the hypothesis proposed. The application should make clear the need for the study with emphasis on how the results will advance our knowledge of theory and practice in this area. A discussion of the costs and benefits of the study should be included for evaluation of the trial's significance.

Preliminary Studies

• The studies that led to the proposed clinical trial should be presented. Data from pilot studies which show the need for and the feasibility of the trial should also be presented. Additional supporting data from other research should be included so that the approach chosen is clearly justified. Conceptualization and planning must have progressed to a stage sufficient to allow for an overall assessment of the likelihood of the success of the trial.

The NIDCD will not accept, review, or fund pilot studies in response to this program announcement. A pilot study is one whose major purpose is to demonstrate the feasibility of further studies.

Experimental Design and Methods

1. Detailed Clinical Protocol
   List the inclusion and exclusion criteria and describe the procedure to be utilized for assignment of patients to experimental conditions. Discuss in detail the study design for the intervention(s) to be used, including the rationale for the particular design chosen and procedures to assure compliance with, and standardized implementation of, the proposed protocol. Discuss potential biases in the research protocol proposed and how they will be addressed. Clinical (including behavioral), laboratory, and physiological tests and protocols should be described briefly here and in more detail in an appendix. Methods of randomization must be described and endpoints clearly defined. Assumptions and steps used to arrive at the proposed sample size must be described. Details of the sample size calculations should be presented in an appendix.
2. Patient Availability and Recruitment
   Discuss the availability of patients for the proposed study. Discuss the characteristics of this population and why it is an appropriate group to answer the question posed. Outline the approaches to be utilized for the recruitment, retention, and follow up of the required number of patients. Discuss plans for maintaining the cooperation of the study population as well as plans for addressing any anticipated changes in the composition of the study population over the course of the trial. Data should be presented supporting recruitment and retention estimates. The ability of clinical centers to recruit and retain the proposed number of subjects, including women, children, and minority subjects, must be addressed.
3. Data Management, Quality Control, and Data Analysis
   Describe the approach to data management. Include methods for monitoring the quality and consistency of the intervention(s) and data collection. Include prototypes of data collection forms in an appendix. A complete Manual of Operations (MOP) must be included in an appendix. (If unable to provide a MOP, consult NIDCD Home Page for information regarding the NIDCD Clinical Trial Planning Grant at http://grants.nih.gov/grants/guide/pa-files/PAR-02-158.html.) Describe the methods of data analysis, linking the analyses to the hypotheses to be tested. Include methods of data preparation and presentation, analytic methods, and approaches to data synthesis. Primary and secondary endpoints should be clearly defined, justified, and related to power calculations.

Human Subjects

• As of October 2000, (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html) NIH implemented a policy requiring education in the protection of human research participants for all key personnel submitting applications for grants or proposals for contracts or receiving new or non-competing awards for projects involving human research participants.

• Assurances of the protection of human participants and the biohazard safety of employees (if applicable) must be provided both for the overall study and for individual field centers. The applicant must discuss any issues that might lead to concern for the welfare of subjects. All forms to be used to obtain informed consent AT EACH CENTER must be included in an appendix. The human subjects sections of data coordinating center applications must address data security measures and confidentiality. (See PHS Form 398 for detailed instructions concerning content of the human subjects section of the application.)

Women and Minority Subjects and Minority Institution Participation

• It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purposes of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html). A complete copy of the updated Guidelines is available at: http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
  Other relevant documents may be found at:
  http://grants.nih.gov/grants/funding/women_min/women_min.htm.

• A SEPARATE section of the application should include the following: The literature and/or data sets must be reviewed to indicate to the extent possible (a) the distribution, by gender and minority status, of the US population with the disease or health problem under investigation and (b) whether the impact of the intervention may be expected to vary according to gender or minority status. Specific goals for women and minority recruitment and plans for achieving those goals must be explicitly stated. Approximate percentages of women and each minority group expected in the study sample and the basis for these estimates must be provided. Applicants should discuss proposed gender analysis and provide a justification when no data analysis by sex is proposed; scientific peer review groups will comment on the adequacy of the justification.

Inclusion of Children

• It is the policy of NIH that children (i.e. individuals under the age of 21) must be included in all human subjects research conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at: http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

• A SEPARATE section of the application should include the following: The literature and/or data sets must be reviewed to indicate to the extent possible (a) the distribution, by appropriate age groupings, of the US population with the disease or health problem under investigation and (b) whether the impact of the intervention may be expected to vary according to age. Specific goals for the recruitment of children and plans for achieving these goals must be explicitly stated. Approximate percentages of children, in appropriate age categories, expected in the study sample and the basis for these estimates must be provided. Generally, representation of children will not be considered adequate unless they occur in the study population in the same proportions as in the U.S. population having the disease entity being studied or an acceptable justification is presented (see NIH requirements available at: http://grants.nih.gov/grants/guide/notice-files/not98-024.html). Outreach and/or sampling plans to ensure adequate representation of children must be presented. Past track records in recruitment of children should be presented.

Reporting Format

• In addition to the written plans for the inclusion of women, minorities, and children in the proposed clinical study, the composition MUST be provided using the "Targeted/Planned Enrollment Format Page" and/or "Enrollment Format Page" as applicable, from the PHS 398 (rev. 5/01).

Study Organization and Administration

• Describe the organization of the study and how the trial will be managed. Include a description of the role of any internal or external advisory committees, including the data and safety monitoring committee, the responsibility and authority of the director of the data coordinating center, and policies and methods concerning masking of study results. Discuss the coordination of any centers or cores proposed. Include a complete description of any sub-contracts for personnel or facilities. Documentation of commitment, co-signed by a business official and the principal investigator at the participating center, must be included with the application. A timetable for completion of the various stages of the trial should also be included.

Investigators

• The Principal Investigator of the overall clinical trial must be an investigator with experience in the conduct of clinical trials and expertise in the content area of the trial. Such experience must be carefully documented. Biographical sketches for all key investigators must be provided. Most clinical trial designs will require a multidisciplinary team. Each center or core proposed must have a director designated. The experience of each director must be carefully documented. In addition, the authority of each center or core director within the study must be specified.

Other Support

• "Other Support" pages must be provided for all key personnel. Key personnel are individuals who contribute in a substantive way to either the scientific development or execution of the project. Key personnel will often include non-doctorate level individuals, such as nurse coordinators. Time spent on each project should be reported, regardless of whether remuneration is received for that time/effort. ALL funding in support of research endeavors should be reported. If the total effort of active and pending grants during the study period exceeds 100 percent for any key personnel, indicate clearly what adjustments will be made to which studies.

Facilities

• Clinical, data management, and laboratory facilities and required equipment should be described in detail for all participating institutions.

Budget

• A total overall budget and a complete, justified budget for each year of support must be provided. If the study involves multiple centers, an additional composite budget matrix must be provided showing the costs for each center. Separate and complete budgets must be prepared for each center. If part of the costs of the trial are to be borne by sources other than NIH, these contributions must be presented in detail along with supporting letters signed by individuals who have the authority to commit the institution. Further information concerning budget preparation can be obtained from the Chief, Grants Management Branch, NIDCD at the address indicated under "INQUIRIES".

Top

Data and Safety Monitoring

• As of the October 2000 receipt date (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html) applicants must supply a general description of the Data and Safety Monitoring Plan for all clinical trials as part of the research application. A SEPARATE section of the application should include a general description of the plan, and describe the entity that will be responsible for monitoring, and the policy and procedures for adverse event reporting. All monitoring plans must include a description of how Adverse Events will be reported to the Institutional Review Board (IRB), the NIH, the Office of Biotechnology Activities (if required), and the Food and Drug Administration in accordance with IND or IDE regulations.

• NIH requires the establishment of Data and Safety Monitoring Boards (DSMBs) for multi-site clinical trials involving interventions that entail potential risk to participants (http://grants.nih.gov/grants/guide/notice-files/not98-084.html). The purpose of this board is to provide independent advice concerning scientific issues pertaining to subject safety and data quality. In monitoring the safety of the trial, the board also may recommend termination in the event of early significance of findings or the determination of unacceptable adverse effects. The data and safety monitoring board is normally appointed in consultation with NIDCD staff and consists of individuals who are not associated with the institutions participating in the trial. Potential members of this board should NOT be named in the application. The board will report directly to the NIDCD. Further information regarding the NIH Policy for Data and Safety Monitoring can be found at: http://grants.nih.gov/grants/guide/notice-files/not98-084.html.

Top

Institute Involvement

NIDCD has determined that substantial NIDCD staff involvement is appropriate when a clinical trial application requests $500,000 or more in direct costs in one year or requests support for a multi-center clinical trial. For such clinical trial applications, the award mechanism will be a cooperative agreement (U01).

Regardless of the mechanism of support, the NIDCD staff will closely monitor progress during the award. This monitoring may include regular communications with the principal investigator and staff, as well as, in the case of the cooperative agreement, participation in the steering committee, data and safety monitoring committee, and related committee meetings. The Terms and Conditions of Award for a clinical trial will include recruitment milestones expected to be met by centers at specific time periods, accrual goals for women, children, and minorities (as appropriate), any requirements regarding minimum effort of specific investigators, and any other identified requirements for completion of the approved research. As with any award, continuation, even during the period recommended for support, is conditional upon satisfactory progress. If, at any time, recruitment falls significantly below the projected milestones for recruitment, the NIDCD will consider ending support and negotiating a phase out of the award. The NIDCD retains, as an option, periodic external peer review of progress.

Top

Possible Terms and Conditions of Award for a Cooperative Agreement

The cooperative agreement (the "U" mechanism) is an award instrument establishing an "assistance" relationship (in contrast to an "acquisition" relationship) between NIDCD and a recipient in which substantial NIDCD scientific and/or programmatic involvement with the recipient is anticipated during performance of the activity. The NIDCD goal is to support and/or stimulate the recipient's activity by involvement in and otherwise facilitating the activity in a "partner" role, but avoiding a dominant role or prime responsibility. Consistent with this concept, the dominant role and prime responsibility resides with the Study Chair, although specific tasks and activities may be shared between the awardee and NIDCD staff as noted below. The terms and conditions, below, elaborate on these actions and responsibilities, and the awardee agrees to these collaborative actions with the NIDCD Project Scientist toward achieving the project objectives. It is anticipated that these terms and conditions will enhance the relationship between NIDCD staff and the principal investigator(s), and will facilitate the successful conduct and completion of the study. The terms and conditions incorporated into the award statement and provided to the principal investigator(s) and the institutional official(s) at the time of award may vary somewhat from these possible terms and conditions according to the circumstances of the proposed project. These agreements will be in addition to, and not in lieu of, the relevant NIH procedures for grants administration. The terms will be as follows:

1. Awardee Rights and Responsibilities

A. The awardee(s) will have primary responsibility for all aspects of their study, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, dissemination of data, tools, and technologies, and collaboration with other investigators, unless otherwise provided for in these terms or by action of the Steering Committee (see 3. Collaborative Responsibilities). The awardee(s) agree to accept close coordination, cooperation, and participation of NIDCD staff in those aspects of scientific and technical management of the study as stated in these terms and conditions.

B. The clinical trial protocol will be subject to review and acceptance (in an advisory capacity only) by the Data and Safety Monitoring Committee (DSMC) (see paragraph 2.E). Upon implementation of the protocol, each field center, whether a single institution or a consortium of institutions, will follow the procedures required by the protocol regarding study conduct and monitoring, patient management, data collection, and quality control.

C. The awardee(s) will be responsible, through a Data Coordinating Center (DCC), for ensuring the provision of centralized data management and coordination assistance. The DCC is responsible for providing all data coordination and management, including quality control and analysis, using procedures and standards determined by the DCC. Specific analyses will be performed by the DCC and will be provided to the SC as the group responsible for determining which further analyses should be done. Additional analyses may be requested by the DSMC. The DCC will provide technical assistance and data management services to the field centers with respect to quality control, uniformity of data collection, management of the collective data base, and data analysis and publication. The DCC will be responsible for the acquisition and distribution of those study materials involved in the protocol. The DCC will also arrange for the appropriate approvals (when necessary) from the Food and Drug Administration (FDA) and the Bureau of Biologics (BOB) with respect to the use of investigational drugs. Any post-award changes in the selection of the facility or organization serving as the DCC will require NIDCD approval.

D. Awardees will retain custody of and have primary rights to their data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. The NIDCD Project Scientist, on behalf of the NIDCD, will have the same access, privileges, and responsibilities regarding the collaborative data as the other members of the SC (i.e., cooperative agreement awardees).

E. Support or other involvement of industry or any other third party in the study--e.g., participation by the third party; involvement of project resources or citing the name of the project or the NIDCD support; or special access to project results, data, findings, or resources--may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NIDCD.

F. The awardee(s) are expected to put all study materials and procedure manuals into the public domain. Awardees are expected to publish and publicly disseminate results, data, and other products of the study, concordant with governance policies and protocols developed by the SC and approved by the NIDCD. Review and approval by the SC will be required for all analyses prior to publication or presentation according to policies developed by the SC. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of support by the NIDCD/NIH. Analyses to be performed using the data will be determined and directed by the SC in conjunction with the DCC. Field centers wishing to perform analyses of local data must also obtain the consent of the NIDCD Project Scientist for any such analyses prior to initiation. During or within three years beyond the end date of the project period of NIDCD support, unpublished data, unpublished results, data sets not previously released, or other study materials or products are to be made available to any third party only with the approval of the SC and in accordance with paragraph 1.D. Any web site developed for dissemination of information may be linked to the NIDCD web site.

G. A change in the Study Chair, in any of the key personnel identified in the Notice of Grant Award, or in the facility serving as the DCC must have prior written approval of the NIDCD Grants Management Specialist in consultation with the NIDCD Project Scientist.

2. NIDCD Staff Responsibilities

A. An NIDCD program official will be responsible for normal stewardship of the award, as named in the notice of grant award. This program official may also serve as the Project Scientist. The NIDCD Project Scientist will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination above and beyond normal program stewardship for grants, as detailed below.

B. The NIDCD Project Scientist will serve as a voting member, and attend all meetings of the SC; he/she may serve on other study committees, when appropriate. The NIDCD Project Scientist may work with awardees on issues coming before the SC and, as appropriate, other committees, e.g., quality control, database coordination, educational and training programs, final data analysis and interpretation, data, tools, and technology dissemination, preparation of publications, and development of solutions to major problems. The NIDCD Project Scientist will participate in periodic on-site monitoring and will serve as a resource to the SC in the development of mechanisms and procedures for monitoring quality of diagnostic and therapeutic performance of the field centers.

C. The Government, through the NIDCD Project Scientist, will have access to data generated under this cooperative agreement at the end of the clinical trial. The awardee will retain custody of and have primary rights to all data developed under these awards subject to regulations regarding Government rights to access.

D. The NIDCD Project Scientist will review the progress of the study, and of each participating facility, through consideration of the annual reports, site visits, patient logs, etc. This review may include, but is not limited to, compliance with the study protocol, meeting patient enrollment targets, adherence to uniform data collection procedures, and the timeliness and quality of data reporting.

E. A Data and Safety Monitoring Committee (DSMC) will be appointed by NIDCD staff to provide independent recommendations regarding the continuation, modification, or termination of the trial based on ethical concerns or observed beneficial or adverse effects of any of the interventions under study. The DSMC membership, which must be multidisciplinary and include a biostatistician and a bioethicist, will be entirely independent of the study and will be supported by special funds set aside for that purpose in the award. Nominations for members of the DSMC may be provided by the awardees; however, authority for membership selection rests solely with the NIDCD. Conflict of interest statements, both written and oral and updated over time, will be obtained from all members of the DSMC. Individuals who have been determined by the NIDCD to have a conflict of interest will be excluded from service on the DSMC. Recommendations and summary reports of the DSMC will be forwarded to the Director, NIDCD, within one week of each review. A summary report which does not contain confidential information will be prepared by the DSMC and distributed to the Study Chair. The NIDCD is responsible for implementation of any recommendations. The DSMC will not have enforcement responsibilities.

F. The NIDCD reserves the right to terminate or curtail the study (or an individual award) in the event of (a) failure to develop or implement a mutually agreeable collaborative protocol, (b) a substantial shortfall in participant recruitment, follow-up, data reporting and dissemination, quality control, or other major breach of the protocol, (c) substantive changes in the agreed-upon protocol with which NIDCD does not concur, (d) reaching a major study endpoint substantially before schedule with persuasive statistical evidence, or (e) human subject ethical issues that may dictate a premature termination.

3. Collaborative Responsibilities

A Steering Committee (SC), composed of the principal investigator, as well as the principal investigators of the various field centers, the Data Coordinating Center (see paragraph 1.C), and of the specialized core facilities (if any), and one NIDCD representative (the Project Scientist). The NIDCD Project Scientist will have voting membership on the SC and, as appropriate, its subcommittees. The SC will have primary responsibility for facilitating the conduct and monitoring of studies and reporting study results. Awardees will be required to accept and implement the common protocol and procedures approved by the SC. As the components of the SC may be geographically dispersed, the SC should meet with monthly conference calls, supplemented as deemed necessary by face to face meetings.

4. Arbitration

Any disagreement that may arise in scientific/programmatic matters (within the scope of the award), between award recipients and the NIDCD may be brought to arbitration. An arbitration panel will be composed of four members--one selected by the SC (with the NIDCD member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NIDCD, the third member selected by the two prior members, and the fourth panelist will be a member of the National Deafness and Other Communication Disorders Advisory Council. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR part 50, Subpart D and HHS regulation at 45 CFR part 16, or the rights of NIDCD under applicable statutes, regulations and terms of the award. These special terms of award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR part 74, and other HHS, PHS, and NIH grant administration policy statements.

Top

Reporting Requirements

Recruitment progress (including recruitment of women, children, and specific minority groups), indices of quality control, and related operational features must be reported at regular intervals to the NIDCD program office. Annual and final reports are required as they are for any NIH grant.

Top

Review Considerations

Applications will be assigned on the basis of established PHS referral guidelines. Applications will be evaluated for scientific and technical merit, through special arrangement, by the Clinical Trials Review Committee of the National Heart Lung and Blood Institute, in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level of review by the appropriate national advisory council or board.

For the initial review of STUDY CHAIR application, as well as a single-site clinical trial application, the review criteria will include:

• The importance of the question(s) and the need for and significance of the trial, i.e., its potential impact. Costs and benefits of the study also will be considered.
• The technical and scientific merit of the clinical aspects of the study.
• The overall feasibility and likelihood of achieving the trial goals, and the potential for a successful trial.
• Any pilot phase experience, including evidence of patient accession and retention and the functioning of any laboratories and coordinating center.
• Adequacy of the statistical features of the study, including sample size projections and statistical power estimates, analytic methods, and use of sequential analyses of data where indicated.
• The logistical aspects of the project including the accumulation, flow, and quality control of data, proper randomization and masking procedures, the operation of any central laboratories, and plans for defining access to the data.
• The availability of participants suitable for the trial (including women, children, and minorities), the likelihood of their participation, and the likelihood of their remaining in the study until the completion of follow up.
• Reasonableness of the recruitment schedule.
• The qualifications, experience, and availability of key investigators in the content area of the trial and in the conduct of clinical trials in general.
• The adequacy of ethical and human safety issues, including current institutional human subjects review board approval(s) and forms for informed consent.
• An adequately documented working plan for the trial.
• The likelihood of successfully administering a cohesive collaborative effort, where appropriate.
• The appropriateness of the budget.

For the initial review of individual FIELD CENTERS, as well as a single-site clinical trial application, the criteria will include:

• The commitment of the institution and staff to a collaborative protocol and to the success of the study. Letters of agreement from collaborating investigators countersigned by appropriate institutional officials must be included with the application.
• The availability of subjects suitable for the trial and the likelihood of their participation, including adequacy of the outreach or sampling plan to assure adequate participation of women, children, and minorities.
• The adequacy of ethical and human safety issues and issues of the biohazard safety of employees (if applicable).
• The qualifications, experience, and availability of key investigators.
• The adequacy of the facilities, including technical resources and space.
• The appropriateness of the local organization and administration.
• The appropriateness of the budget.

For the initial review of a DATA COORDINATING CENTER, as well as a single-site clinical trial application, the criteria will include:

• The adequacy of plans for monitoring the collection, management, and statistical analysis of the data, including periodic checks of the data and reports to staff and the data and safety monitoring board.
• The involvement of coordinating center staff in the overall study design, including protocol development, and data collection, coding, quality control, and data management.
• The qualifications, experience, and availability of key investigators. The responsibility and authority of the Director of the Coordinating Center must be clearly specified.
• The adequacy of the mechanisms proposed to provide advice concerning overall policy, publications, and data and safety monitoring.
• The adequacy of the organizational and administrative structure of the proposed center.
• The adequacy and availability of the facility, including technical resources and space.
• The appropriateness of the budget.

For the initial review of any ADMINISTRATIVE CENTERS OR CORE FACILITIES, as well as a single-site clinical trial application, analogous criteria will be used, appropriate to the tasks of the centers or facilities.

All applications undergo further review by the National Deafness and Other Communication Disorders Advisory Council prior to award. The Council is responsible for the second level of review and makes recommendations to the Director of the NIDCD regarding funding. The purpose of this review is to consider the trial in the context of the overall program plans and planning activities of NIDCD. These recommendations reflect such factors as programmatic priority, balance, cost, and cost benefit of the trial.

The original and THREE copies of the completed application must be mailed to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Suite 1040-MSC-7710
Bethesda, MD 20892-7710
Bethesda, MD 20817 (for express/courier service)

In addition to the copies submitted to the Center for Scientific Review, two copies should be sent, under separate cover to:

Craig A. Jordan, Ph.D.
Chief, Scientific Review Branch
National Institute on Deafness and
   Other Communication Disorders
Executive Plaza South, Room 400-C, MSC 7180
6120 Executive Boulevard
Bethesda, MD 20892-7180
Rockville, MD 20852 (for express/courier service)

Submission of separate copies to the Chief, Scientific Review Branch, will allow more time to study the application and plan for its review.

INQUIRIES

Applicants are encouraged to contact NIDCD staff for assistance in assembling and submitting the application package.

For further information regarding programmatic issues, contact:

A. Julianna Gulya, MD
Chief, Clinical Trials, Epidemiology and Biostatistics Branch
National Institute on Deafness and
Other Communication Disorders
Executive Plaza South, 400D-7, MSC 7180
6120 Executive Boulevard
Bethesda, MD 20892-7180
Telephone: 301-435-4085
Fax: 301-402-6251
E-mail: julie_gulya@nih.gov

Revised 2002

Top

Home || Contact Us || Privacy || Public Use || Accessibility || Free Publications

National Institute on Deafness and Other Communication Disorders
National Institutes of Health
31 Center Drive, MSC 2320
Bethesda, MD USA 20892-2320
E-mail: nidcdinfo@nidcd.nih.gov

Page last updated: June 2, 2004