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 Advice to Investigators Submitting Clinical Research Applications*

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:
Institute/Center Contacts and Online Resources:
Donald F. Everett
Program Director, Collaborative Clinical Research
National Eye Institute
Tel: (301) 451-2020
Web site:
Robert Musson, Ph.D.
Deputy Director DEA
National Heart, Lung, and Blood Institute
Tel: (301) 435-0266
Web site:
Meredith D. Temple-O'Connor, Ph.D.
Acting Director, Division of Interdisciplinary Training              
National Institute of Biomedical Imaging and Bioengineering
Tel: (301) 451-4792
Ivan Montoya, M.D., M.P.H.
Medications Research Grants Branch
Division of Treatment Research and Development
National Institute on Drug Abuse
Tel: (301) 443-8639
Web site:
A. Julianna Gulya, M.D.
Division of Extramural Research
National Institute on Deafness and
Other Communication Disorders
Tel: (301) 435-4085
Web site:
Richard L. Mowery, Ph.D.
Chief, Clinical, Epidemiology, and Behavioral
Research Branch
National Institute of Dental and Craniofacial Research
Tel: (301) 594-4841
Joyce A. Hunter, Ph.D.
Deputy Director, Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases          Tel: (301) 594-0056
Web site:
Kimberly Gray, Ph.D.
Health Science Administrator, Susceptibility and Population Health Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
Tel: (919) 541-0293
Alison E. Cole, Ph.D.
Program Director
National Institute of General Medical Sciences
Tel: (301) 594-3827
David Shore, M.D.
Associate Director for Clinical Research
National Institute of Mental Health
Tel: (301) 443-6776
Web site:
Scott Janis, Ph.D.
Clinical Trials
National Institute of Neurological Disorders and Stroke
Tel: (301) 496-9135
Dr. Mary E. Kerr, PhD, RN, FAAN
Deputy Director
Associate Director, for Scientific Programs
National Institute of Nursing Research
Tel: (301) 496-8230

* NIH Definition of Clinical Research
1. Patient-oriented research. Research conducted with human subjects (or on material of human origin such as tissues, specimens, and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects. Excluded from this definition are in vitro studies that utilize human tissues that cannot be linked to a living individual. Patient-oriented research includes: (a) mechanisms of human disease, (b) therapeutic interventions, (c) clinical trials, or (d) development of new technologies.
2. Epidemiologic and behavioral studies,
3. Outcomes research and health services research.