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What must I include in "Protection of Human Subjects"?

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.

Part II: Supplemental Instructions for Preparing the Protection of Human Subjects Section of the Research Plan is found in the PHS 

Public Health Service (PHS)
governmental division comprised of agencies related to health and human services such Agency for Healthcare Research and Quality (AHRQ), Centers for Medicare & Medicaid Services ( CMS ), Food and Drug Administration (FDA), and National Institutes of Health (NIH) to name a few. DHHS Homepage
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

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 

National Institutes of Health (NIH)
the United State's medical research agency, a federal government agency composed of diverse Institutes and Centers that conduct and support biomedical and behavioral research. NIH Homepage.
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 

Human Subject
Legally defined term for living persons about whom an investigator obtains specimens or data through direct interaction 
Interaction
any communication or other interpersonal contact between an investigator and a human subject. For more information, go to definitions in 45 CFR 46.102 and full 45 CFR 46.
or intervention or through identifiable, private information. Regulations include but are not limited to human organs, tissues, body fluids, and recorded information. Term is defined differently by FDA.
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 
Office for Human Research Protections (OHRP)
HHS office overseeing human subject protection for HHS-supported research. OHRP protects the rights, welfare, and well-being of subjects involved in research conducted or supported by HHS and helps ensure that such research is carried out in accordance with the regulations described in 45 CFR 46. OHRP Homepage.
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 

Data and Safety Monitoring Plan (DSMP)
designed by the investigator and approved by Program Staff to ensure safety of human subjects and integrity of data. (see Data and Safety Monitoring Policy image of word document icon (120 KB))
)
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 

Proposal
a written offer by an individual or non-federal organization to enter into a contract, consisting of a technical and a business proposal which includes a description of the project and its costs, and the methods, personnel, and facilities to carry it out.
submitted to NHLBI 
National Heart, Lung, Blood Institute (NHLBI)
a NIH Institute that provides leadership for a national program in diseases of the heart, lung, and blood as well as blood resources, sleep disorders and the Woman's Health Initiative. NHLBI Homepage.
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 

Bar to fund
block to an award of a grant application until problems are resolved, for example, due to insufficient protection of human subjects or research animals.
.  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 
Institutional Review Board (IRB)
a board or committee designated by an institution to ensure the protection of rights and welfare of human research subjects and reporting to the Office for Human Research Protection (OHRP). IRBs make ongoing independent determinations to approve, require modifications in, or disapprove research protocols based on whether human subjects are adequately protected. Also known as Research Ethics Boards (REB) or Ethics Committee (EC).
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:

  • 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 
    Data and Safety Monitoring Board (DSMB)
    an independent committee that reviews clinical trial progress and safety, and advises the appointing body whether to continue, modify, or terminate a trial. This is sometimes called a Data Monitoring Committee (DMC). (see Data and Safety Monitoring Policy image of word document icon (120 KB))
    / OSMB 
    Observational and Safety Monitoring Boards (OSMB)
    independent monitoring group whose principal role is to regularly monitor regularly data from large or complex observational studies and to review and assess the performance of its operations. Whether an OSMB is needed is determined on a case-by-case basis by NHLBI.
    -- 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 ( OSMB )

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 

Phase I Clinical Trial
testing in a small group of people (e.g. 20-80) to determine efficacy and evaluate safety (e.g., determine a safe dosage range and identify side effects).
and Phase II 
Phase II Clinical Trial
study in a larger group of people (several hundred) to determine efficacy and further evaluate safety.
Trials for more information.

Data Sharing
Information about sharing your data can be found at the NIH Data Sharing Policy Site. NHLBI 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 

Direct Costs
costs in a grant or contract identified with a project or program which may include salaries, travel, supplies, patient care costs, consultant services and others.
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 

Grant
financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity. A grant is used whenever the NIH Institute or Center anticipates no substantial programmatic involvement with the recipient during performance of the financially assisted activities.
Applications is provided by OER 
Office of Extramural Research (OER)
a NIH office that supports extramural research by providing policy and guidance to the NIH ICs that award grants and assisting investigators through the process of attaining grants funding and helping them understand and navigate through federal policies and procedures. OER Homepage
.

The instructions for a non-modular budget can be found in the SF424 or PHS 398 or in the instructions in the RFA 

Requests for Applications (RFA)
initiatives sponsored by one or more NIH institutes or centers that stimulate research by requesting grant applications in a well-defined scientific area.
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:
Human Subjects Application and Grant Handbook is an excellent tutorial presented by National Institute of Allergy and Infectious Diseases (NIAID). 

Advice to Investigators Submitting Clinical Research 

Clinical Research
patient-oriented research (human subjects, tissues, specimens, and cognitive phenomena), including epidemiologic and behavioral studies, outcomes research, and health services research in which a researcher directly interacts with human subjects.
Applications sponsored by the Center for Scientific Review.  This site gives additional information to assist investigators in writing and submitting applications. 



Page Last Updated: February 2011
Content Manager: ClinicalResearchPolicyManager@nhlbi.nih.gov

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