Clinical investigation is vital to the mission of NIH. The following guidelines are provided to assist investigators in the preparation of clinical applications. These suggestions are an extension, not a replacement, of instructions for completing the PHS 398 form. "Clinical studies" encompass a wide range of methodologies, and not all of these suggestions will be applicable to all clinical studies.

Specific Aims: Clearly articulate the hypotheses or objectives and specific aims of the study.

Background and Significance: Describe the scientific basis and rationale for the study. Address the following: a) the significance of the project in the context of the field; b) the clinical importance of the problem; c) the need for a clinical study; d) the potential impact of the proposed study on the understanding of the pathophysiology, etiology, or outcome of the disease; e) the potential impact on clinical practice.

Research Design and Methods: Describe the overall study design. Study groups (subjects, populations) and the rationale for their selection should be described. Description of study groups should include inclusion and exclusion criteria, potentially confounding variables, estimates of availability and accessibility, as well as recruitment strategies and the likelihood of subject accrual. Primary and secondary endpoints should be clearly defined, clinically important, and measurable. For clinical trials, if it is not included within the body of the grant application, the detailed study protocol might be submitted in the Appendix. Description of statistical analyses should include justification of sample size and power calculations. Phase III clinical trials must also include a description of plans to conduct analyses by sex/gender, racial/ethnic groups, and relevant subpopulations, when applicable. Procedures for data flow, data management, data quality, and database integrity and security should be described. If appropriate, a plan for data sharing should be included.

Human Subjects Research Section: Incomplete information concerning the use of human subjects may affect the scientific merit rating. Unless your proposed clinical studies are described by one or more of the exemptions in the human subjects regulations (45 CFR46 101 (b): see also PHS 398),the following should be addressed in a section entitled "protection of human subjects": risks to the subjects; adequacy of protection against risks; potential benefits of the proposed research to the subjects and others; importance of the knowledge to be gained. If your proposed studies are described by one or more of the exemptions, address the following in the "protection of human subjects" section: specify and justify the exemption(s) claimed; population sample; sources. Note: Prospective collection of data and/or samples does not qualify for Exemption 4. Careful attention must be paid to NIH policies on inclusion of children, women, and minority populations. Plans for inclusion and recruitment of children, women, and minorities should be addressed, and excluded populations should be justified. If the proposal involves a clinical trial, it must include a description of a Data and Safety Monitoring Plan (DSMP).

Investigators: Clinical projects often require a multidisciplinary team of investigators. The involvement and contribution of the investigators to the clinical aspects of the project should be described. The expertise of the investigators should mach the study population, e.g., investigators with pediatric expertise should be included if the study involves a pediatric population.

Environment: Describe the clinical, data management, and statistical resources that are available for the study.

Additional Resources: Investigators are encouraged to contact program staff prior to submitting an application. Additional information that may be useful is available on the following NIH web sites:

• Inclusion of Women and Minorities As Participants In Research Involving Human Subjects
• NIH instructions to peer reviewers
• Inclusion of Children Policy Implementation
• NIH Policy on Data and Safety Monitoring
• Further Guidance on Data and Safety Monitoring for Phase I and Phase II Trials
• NIH data sharing policy
• Office of Human Research Protections
• NIH Guidelines for Research Involving Recombinant DNA Molecules