What must I include in Section E: Human Subjects Research?

When preparing your application, you should know that in addition to the regular review criteria for scientific merit, reviewers use four other criteria to judge human subjects research applications:

• Risks to subjects.
• Adequacy of protection against risks.
• Potential benefits to the subjects and others.
• Importance of the knowledge to be gained.

Supplemental Instructions for Preparing the Human Subjects Section of the Research Plan is found in the PHS 398 and the SF424 and can be helpful when writing this section. It is important that you complete and submit the Targeted/Planned Enrollment Table with your application which indicates the proposed ethnic, racial and gender compositions of your study population.

Reviewers will also evaluate your plans for recruiting and retaining subjects. Trial recruitment that is slower than expected can result in prolonged trial durations, increased costs, uneven workload, and morale problems, both for trial participants and clinical research team members. Furthermore, when recruitment is so poor that it needs to be curtailed before the trial's target sample size is reached, study power is reduced and there may be a need to revise study endpoints. The Office of Research on Women's Health provides pertinent information on the recruitment and retention of women and minorities in clinical research and may be useful as you consider your plans for recruiting these special populations.

It is good to demonstrate that you have access to the population under study and to provide realistic estimates of how many in the population will meet your inclusion/exclusion criteria.  If you have done preliminary work with this same population, you may wish to describe successful strategies previously used.  You will need to describe which strategies you plan to use for identifying and enrolling participants which may include:

• Review medical records for eligible patients
• Send letters and study brochures to area health care providers to apprise them of your study and enlist their help in identifying and referring subjects
• Send letters and study brochures or make calls to potential participants
• Engage in community outreach via presentation at schools, community centers, churches or patient advocacy groups
• Utilize the media
• Develop a study web site
• Create easy to read and understand consent forms and educational brochures (See: How do I develop consent forms and who reviews them?)
• Provide adequate time to discuss the study with potential participants and answer all questions that they may have

Once enrolled into the study it is important that you have strategies outlined for retaining patients.  A brief statement as to how you plan to keep patients in the study is desirable. 

Women and Minorities
NIH requires that women and minorities be included in all research studies unless the nature of the research makes it inappropriate to do so.  You will need to provide justifications for inclusion or exclusion of these populations.  NIH provides guidance on Inclusion of Women and Minorities as Subjects in Clinical Research.  NHLBI clarifies what proportion of women and minorities is appropriate to include in your study, in a document called Questions and Answers on Inclusion of Minorities and Women in Study Populations.

The Office of Research on Women's Health provides a brief history, policy documents and outreach information on inclusion, recruitment and retention of women, men and minorities in clinical research.

Children
NIH policy mandates that children must be included in all human subjects research conducted or supported by the NIH unless there are scientific and/or ethical reasons not to include them.  NIH has developed Inclusion of Children Policy Implementation for further reference.  You may also find additional information from OHRP on Special Protections for Children as Research Subjects. 

International Subjects
The Office for Human Research Protections (OHRP) provides guidance on International Human Subjects Research Protections to help those involved in research familiarize themselves with the laws, regulations, and guidelines of particular countries where the research will be conducted.  You may go to page 5 of the document and click on a country of interest.   

Data and Safety Monitoring Plans (DSMP)
NIH policy established a requirement for Data and Safety Monitoring Plans (DSMPs) as a means of ensuring that all clinical research have a level of monitoring commensurate with scope and risk, and that this monitoring be an integral part of the research plan.  The purpose of the DSMP is to delineate how participant safety and data integrity will be monitored.  Monitoring the ongoing study plays an essential role in protecting the safety of participants and assuring the integrity of research; hence developing an effective monitoring plan is of paramount importance.

A DSMP is required for every grant application or contract proposal submitted to NHLBI that includes a clinical study.  Grants that include multiple clinical research protocols addressing separate research questions in different groups of subjects must have a DSMP for each protocol.

Peer reviewers will gauge the adequacy of your plans to protect subjects from research risk and to include required populations.  If your description is inadequate or your application does not comply with requirements, your priority score may suffer and your application may get a bar to fund.  If a grant will be funded by NHLBI, a detailed DSMP must be included as part of the formal protocol that is submitted to NHLBI Program Staff and the applicant’s IRB for approval before accrual of human subjects begins.

All clinical research that entails greater than "minimal risk" requires independent monitoring. "Minimal risk" is defined in 45 CFR 46, Section 102 (i) as: a risk where the probability and magnitude of harm or discomfort anticipated in the proposed research are not greater, in and of themselves, than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. For example, the risk of drawing a small amount of blood from a healthy individual for research purposes is no greater than doing so as part of a routine physical examination.

In the Human Subjects section of the grant application, there should be a separate subsection entitled, "Data and Safety Monitoring Plan (DSMP)".  The DSMP should provide a general description of the overall framework for data and safety monitoring. It should address the following areas:

• What will be monitored
• How often data and safety will be monitored
• Who will monitor
• Where monitoring will occur
• How the clinical study sites, research pharmacy (ies), and core laboratory(ies) will be monitored.
• How adverse events will be assessed and reported.

Monitoring requirements may differ depending on the type, complexity and phase of your clinical study.  A plan may include the following types of monitoring:

• Principal Investigator and IRB -- may be appropriate for a blood sample study.

• Independent Safety Monitor -- a physician or other expert who is independent of the study and available to review and recommend actions regarding adverse events and other safety issues.

• Independent Monitoring Committee or Safety Monitoring Committee -- a small group of independent investigators and biostatisticians who review data.

• DSMB/OSMB -- an independent committee that reviews interim safety and efficacy data and provides advice on continuing, modifying, or terminating the study.  DSMBs may be either appointed by the NHLBI or by the participating institution.  More information can be found on Establishing Data and Safety Monitoring Boards (DSMBs) and Observational Study Monitoring Boards (OSMBs)

You will work with NHLBI to make the final decision about safety monitoring before you begin your study. Please see the NIH Policy for Data and Safety Monitoring and Further Guidance on a Data and Safety Monitoring for Phase I and Phase II Trials for more information.

Data Dissemination Plan
NHLBI Policy for Distribution of Data requires that limited access data sets be prepared for selected clinical trials and epidemiology studies.  In general these may include cooperative agreements, some ancillary studies or trials/studies requesting greater than $500,000 direct costs in one year.  It is important that you read this guidance to determine if your application might fall into one of these categories and the budgetary implications of data dissemination. 

Budgetary Items
Be certain that your budget is realistic and appropriate for your project’s aims and methods.  Investigators salaries must be less than or equal to the current government cap.   Modular budgets are applicable to certain research grant applications requesting $250,000 or less per year in direct costs. Consortium/contractual F&A costs are not factored into the direct cost limit. Modular budgets are simplified and detailed categorical information should not be submitted with the application. Follow the instructions for the modular budget format in the PHS 398 form when preparing a modular budget. More information on NIH Modular Research Grant Applications is provided by OER.

The instructions for a non-modular budget can be found in the SF424 or PHS 398 or in the instructions in the RFA to which you are responding.   Non-modular budgets require much more detail about salaries, travel, equipment, patient care costs and budget justification information, among other things. 
 
Other resources:
How to Write a Human Subjects Application is an excellent tutorial presented by National Institute of Allergy and Infectious Diseases (NIAID). 

Advice to Investigators Submitting Clinical Research Applications sponsored by the Center for Scientific Review.  This site gives additional information to assist investigators in writing and submitting applications. 

Resources for Grant Applicants provides helpful writing tips, NIH terms, information for new grantees and resources for new investigators.  This source features tutorials from a number of different Institutes including NCI and NIAID.