Data and Safety Monitoring Policy

National Heart, Lung, and Blood Institute
National Institutes of Health

October 31, 2008

Purpose and Scope:

This policy sets forth the National Heart, Lung, and Blood Institute (NHLBI) requirements for data and safety monitoring (DSM) for all human subjects research funded in whole or in part by NHLBI extramural programs. Effective October 1, 2008, this policy is incorporated as part of the terms and conditions for all awards. Release of funds for human subjects research activities is contingent upon compliance with this DSM policy.

Policy:

1. Data and safety monitoring is a critical component of all human subjects research; the level of monitoring should be commensurate with the complexity of the study and the level of risk to study participants.
   
   
2. All human subjects research requires Institutional Review Board (IRB) approval. IRBs have the prime responsibility for oversight of all clinical research conducted at their institutions.
   
   
3. Certification of IRB approval of the protocol must be sent (preferably electronically) to NHLBI before a proposed human subjects research project may begin and should include the following elements:
   1. Application grant number or contract number
   2. Title of research project
   3. Principal investigator (PI) name
   4. Date of IRB approval or exemption
   5. Appropriate signatures (e.g., IRB chair, Authorized Organizational Representative)
   6. For studies with multiple protocols, the IRB identification number and approval date associated with each protocol
   NOTE:
   The awardee is responsible for ensuring that all of its sites engaged in research involving human subjects have IRB approval and an appropriate assurance approved by the Office of Human Research Protections (OHRP).
   
   
4. In addition, an IRB-approved data and safety monitoring (DSM) plan must be sent (preferably electronically) to NHLBI for
   1. All clinical trials regardless of phase, and
   2. All clinical research with greater than minimal risk.
   NOTE:
   If an IRB-approved DSM plan is not received, NHLBI may request certification that the proposed research is neither a clinical trial nor a study that involves greater than minimal risk to participants. Such certification must be countersigned by the Authorized Organizational Representative (AOR) and submitted to the designated NHLBI Grants Management Officer (GMO) or Contracting Officer (CO) for review and acceptance prior to commencement of human subjects research. Principal investigators (PIs) with questions about the adequacy or appropriateness of their DSM plans are encouraged to consult with their Program Official or Project Officer (PO) before submission to the IRB.
   
   
5. The DSM plan describes oversight and monitoring to ensure the safety of participants and the integrity of the data. DSM plans should address the following essential elements:
   1. Monitoring entity or who will monitor the study—e.g., PI, independent monitoring group, data and safety monitoring board (DSMB) or observational study monitoring board (OSMB). For example, for studies with low risk, monitoring by the principal investigator and the IRB may suffice; for higher risk studies, a DSMB may be required.
   2. Procedures for 1) monitoring study safety, 2) minimizing research-associated risk, 3) protecting the confidentiality of participant data, and 4) identifying, reviewing, and reporting adverse events and unanticipated problems to the IRB, NHLBI, and FDA (if applicable). For further information, see:
      • NIH Guidance on Reporting Adverse Events to Institutional Review Boards for NIH-Supported Multicenter Clinical Trials (http://grants1.nih.gov/grants/guide/notice-files/not99-107.html)
      • OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events (http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm)
      • NHLBI Adverse Events and Unanticipated Problems Reporting and Management (Interim Policy) http://public.nhlbi.nih.gov/ocr/home/GetPolicy.aspx?id=16.
   3. For multi-site studies, procedures to ensure compliance with the monitoring plan and reporting requirements across study sites.
      
      
6. An independent DSMB is generally required for phase III clinical trials. A DSMB or OSMB may be required for the following:
   1. Phase I or phase II clinical trials that have multiple sites, are blinded, or include high-risk interventions or vulnerable populations.
   2. Clinical research involving high-risk procedures/tests or vulnerable populations.
   NOTE: PIs are encouraged to consult with their PO for assistance in determining whether a DSMB/OSMB is required for a given study. For further information, see NIH Policy for Data and Safety Monitoring (http://grants.nih.gov/grants/guide/notice-files/not98-084.html) and Further Guidance on Data and Safety Monitoring for Phase I and Phase II Trials (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html).
   
   
7. The PI must provide timely reporting to the PO of the following:
   1. Unanticipated problems or unexpected serious adverse events that may be related to the study protocol.
   2. IRB-approved protocol or consent form revisions that indicate a change in risk for participants.
   3. A summary of recommendations made by the DSMB/OSMB or other monitoring entity and (if applicable) the action plan for response.
   4. Notice of any actions taken by the IRB or regulatory bodies regarding the research and any responses to those actions.
   NOTE: All personal identifiers must be removed from any documents sent to NHLBI.
   
8. In annual progress reports, PIs should address the following:
   1. Adherence to the DSM plan.
   2. A summary of any DSM issues that have occurred during the previous year.
   3. Any changes in the human subjects research or to the DSM plan that affect risk. Modifications to the human subjects research or DSM plan should be submitted to the NHLBI GMO or CO prior to implementation of the change in study practice.
   4. New and continuing IRB approvals.

DSM Decision Flowchart for Research Involving Humans or Human-Derived Materials

References:

Code of Federal Regulations, Title 45 - Public Welfare, Department of Health and Human Services, Part 46 - Protection of Human Subjects, 6/23/2005: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm.

Grants.gov Application Guide SF424 (R&R), Part II: Supplemental Instructions for Preparing the Human Participants Section of the Research Plan, 1/15/2008: http://grants1.nih.gov/grants/funding/424/index.htm.

NIH Policy for Data and Safety Monitoring, 6/10/1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html.

NIH Further Guidance on Data and Safety Monitoring for Phase I and Phase II studies, 6/5/2000: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html.

NIH Guidance on Reporting Adverse Events to Institutional Review Boards for NIH-Supported Multicenter Clinical Trials, 6/11/1999: http://grants1.nih.gov/grants/guide/notice-files/not99-107.html.

NHLBI Adverse Events and Unanticipated Problems Reporting and Management (Interim Policy), May 2007: http://public.nhlbi.nih.gov/ocr/home/GetPolicy.aspx?id=16

OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events, 1/15/2007: http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm.

Definitions:

Adverse Event: As defined by OHRP, an adverse event is any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in the research, whether or not considered related to the subject’s participation in the research. Adverse events encompass both physical and psychological harms.

Authorized Organizational Representative (AOR): The individual authorized by the applicant organization to act for the applicant and to assume the obligations imposed by the Federal laws, regulations, requirements, and conditions that apply to grant applications or grant awards. This official is equivalent to the Signing Official (SO) in NIH’s eRA Commons. Responsibilities include:
• Submitting the grant on behalf of the company, organization, institution, or Government.
• Signing grant applications and the required certifications and/or assurances necessary to fulfill the requirements of the application process.

Award: The provision of funds by NIH, based on an approved application and budget or progress report, to an organizational entity or an individual to carry out a project or activity.

Awardee: An institution receiving a grant, cooperative agreement, or contract.

Clinical Trial: A biomedical or behavioral research study of human subjects designed to answer specific questions about biomedical or behavioral interventions (drugs, treatments, devices, or new ways of using known drugs, treatments, or devices). Clinical trials are used to determine whether new biomedical or behavioral interventions are safe, efficacious, and effective. Clinical trials of an experimental drug, treatment, device, or intervention may proceed through four phases:
Phase I. 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).
Phase II. Study in a larger group of people (several hundred) to determine efficacy and further evaluate safety.
Phase III. Study to determine efficacy in large groups of people (from several hundred to several thousand) by comparing the intervention to other standard or experimental interventions, to monitor adverse effects, and to collect information to allow safe use.
Phase IV. Studies done after the intervention has been marketed. These studies are designed to monitor the effectiveness of the approved intervention in the general population and to collect information about any adverse effects associated with widespread use.

Clinical Research: Patient-oriented research, including epidemiologic and behavioral studies, outcomes research, and health services research. Patient-oriented research is research conducted with human subjects (or on material of human origin such as tissues, specimens, and cognitive phenomena) in which a researcher directly interacts with human subjects. It includes research on mechanisms of human disease, therapeutic interventions, clinical trials, and development of new technologies, but does not include in vitro studies using human tissues not linked to a living individual. Studies falling under 45 CFR 46.101(a) (4) are not considered clinical research for purposes of this definition.

Contract: An award instrument establishing a binding legal agreement between NIH and an award recipient (awardee) obligating the latter to furnish products or services defined in detail by NIH and binding the Institute to pay for them. Go to the Office of Acquisition Management and Policy (OAMP) web site for information on contracts and contract opportunities.

Contracting Officer: Government employee authorized to execute contractual agreements and to obligate funds on behalf of the Government.

Cooperative Agreement: Financial assistance mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, scientific or program staff will assist, guide, coordinate, or participate in project activities.

Exempt Research: As stated in 45 CFR 46.101(b): Unless otherwise required by department or agency heads, research activities in which the only involvement of human subjects will be in one or more of the following categories are exempt from this policy:

1. Research conducted in established or commonly accepted educational settings, involving normal educational practices, such as (i) research on regular and special education instructional strategies, or (ii) research on the effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods.
2. Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures or observation of public behavior, unless:

   (i) Information obtained is recorded in such a manner that human subjects can be identified, directly or through identifiers linked to the subjects; and (ii) any disclosure of the human subjects' responses outside the research could reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability, or reputation.

3. Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior that is not exempt under paragraph (b)(2) of this section, if:
   

   ((i) The human subjects are elected or appointed public officials or candidates for public office; or (ii) federal statute(s) require(s) without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter.

4. Research, involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects.
5. Research and demonstration projects which are conducted by or subject to the approval of department or agency heads, and which are designed to study, evaluate, or otherwise examine:
   

   ((i) Public benefit or service programs; (ii) procedures for obtaining benefits or services under those programs; (iii) possible changes in or alternatives to those programs or procedures; or (iv) possible changes in methods or levels of payment for benefits or services under those programs.

6. Taste and food quality evaluation and consumer acceptance studies, (i) if wholesome foods without additives are consumed or (ii) if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe, by the Food and Drug Administration or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture.
   

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.

Grantee: The organization or individual awarded a grant or cooperative agreement by NIH that is responsible and accountable for the use of the funds provided and for the performance of the grant-supported project or activities. The grantee is the entire legal entity even if a particular component is designated in the award document. The grantee is legally responsible and accountable to NIH for the performance and financial aspects of the grant-supported project or activity.

Grants Management Officer (GMO): An NIH official responsible for the business management aspects of grants and cooperative agreements, including review, negotiation, award, and administration, and for the interpretation of grants administration policies and provisions. Only GMOs are authorized to obligate NIH to the expenditure of funds and permit changes to approved projects on behalf of NIH. Each NIH Institute and Center awarding grants has one or more GMOs with responsibility for particular programs or awards.

Human Subject: A living individual about whom an investigator (whether professional or student) conducting research obtains data through intervention or interaction with the individual or obtains identifiable private information. Regulations governing the use of human subjects in research extend to use of human organs, tissues, and body fluids from identifiable individuals as human subjects and to graphic, written, or recorded information derived from such individuals.

Human Subjects Research: A systematic investigation that includes human subjects.

Minimal Risk: As defined in 45 CFR 46.102, minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered by the research population in daily life or during the performance of routine physical or psychological examinations or tests.

For example, minimal risk in a healthy population may include venipuncture (blood draws), physical examinations, routine psychological testing, nutritional studies, behavioral research, survey/questionnaire studies, and observational research. This category includes specimen-based studies that do not qualify for an exemption and are considered to be clinical research by the applicable IRB.

Notice of Award (NoA): The legally binding document
• notifying the grantee and others that an award has been made;
• containing or referencing all terms and conditions of the award;
• documenting the obligation of Federal funds (may be in letter format and may be issued electronically).
   Previously known as Notice of Grant Award (NGA).

Office for Human Research Protections (OHRP): HHS office overseeing human subject protection for HHS-supported research. Go to OHRP.

Phase III Clinical Trial: As defined by NIH, a broadly based prospective investigation (usually involving several hundred or more human subjects) to evaluate an experimental intervention in comparison with a standard or control intervention or to compare two or more existing treatments. The definition includes pharmacologic, non-pharmacologic, and behavioral interventions given for disease prevention, prophylaxis, diagnosis, or therapy. Community trials and other population-based intervention trials also are included.

Phases of Clinical Trials: See Clinical Trial

Program Official: The NIH staff member responsible for the programmatic, scientific, and/or technical aspects of a grant. Note that this title is most frequently used to refer to the scientific or technical representative for grants, but the generic “program official” term also may refer to a Project Officer if the funding mechanism is a contract.

Project Officer: The NIH staff member designated as a Contracting Officer’s technical representative to coordinate the substantive aspects of an acquisition from its development through to contract award and administration.

Unanticipated Problem: According to OHRP, unanticipated problems generally include any incident, experience, or outcome that meets all of the following criteria:
(1) unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the subject population being studied;
(2) related or possibly related to participation in the research (in this guidance document, possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and
(3) suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

FAQs :

1) Q. How does the NHLBI policy differ from the NIH policy?

A. The NHLBI policy is aligned with the NIH policy and extends the requirement of DSM plans to include clinical research with greater than minimal risk in addition to clinical trials. The NHLBI policy explicitly requires IRB approval of the DSM plan.

2) Q. Who determines whether my research protocol has greater than minimal risk?

A. Your IRB has primary responsibility for determination of the level of risk to study participants. When a decision is made to fund your grant or contract, the PO will issue instructions to release funds for your research protocol if the study is clearly minimal risk, as defined in 45 CFR 46.102 (i). ( http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.102 .) If the PO considers your protocol to be of greater than minimal risk, an IRB-approved DSM plan will be requested. If you disagree with the PO 's assessment, you may be asked for clarification or certification of your IRB's determination of risk.

3) Q. Does this policy apply to all award mechanisms used by NHLBI?

A. Yes, this policy applies to all NHLBI-sponsored research projects regardless of whether they are contracts , grants , or cooperative agreements .

4) Q. My data and safety monitoring plan is part of my grant application. Is this sufficient, or am I required to send something else?

A. NHLBI Policy requires an IRB-approved DSM plan. The DSM plan in your grant application is sufficient if (1) it contains the essential elements listed in the NHLBI policy and (2) you can document that your IRB has reviewed and approved the relevant section of your grant application.

5) Q. What happens if I don't provide a DSM plan in my grant application?

A. If your application is selected for funding and is either a clinical trial or clinical research entailing more than minimal risk, NHLBI will place a term and condition on the Notice of Award (NoA) restricting all human subjects research activities until the grantee can demonstrate that the IRB has reviewed and approved the DSM plan. A similar process is followed for contracts.

6)  Q What if the human subjects aspect of my research begins after the first year of funding?

A. This policy only applies to human subjects research . For example, if the human subjects research portion of your study begins in year 3, then this policy must be followed prior to the commencement of human subjects research activities starting in year 3. Other research activities that do not involve human subjects may proceed. See the terms and conditions of the award for further information.

7) Q. I am concerned about protecting participants' privacy, as well as sending sensitive study data to the NHLBI PO .

A. It is important that all personal identifiers be removed from any documents before sending them to the NHLBI. In addition, the reporting requirements specify that summary recommendations should be sent to the PO . Please d o not send the confidential or sensitive data upon which such recommendations are based u nless specifically requested by the PO .

8) Q. Where and when do I send the data and safety monitoring (DSM) plan or minimal risk certification?

A. If the project is a grant or cooperative agreement, all official documentation must be sent (preferably electronically) to the Grants Management Officer —with a copy to the Program Official —listed in eRA Commons ( https://commons.era.nih.gov/commons/ ). If the project is a contract, this documentation should be sent to the Contracting Officer —with a copy to the Project Officer —per the contract. Please send the documentation anytime after the IRB has approved the DSM plan or indicated that the research is minimal risk but BEFORE any human subjects research commences. NHLBI also should be notified if the human subjects research, DSM plan, or minimal risk designation changes during the project period. This documentation must be countersigned by the Authorized Organizational Representative .

9) Q. What if I cannot submit the documentation electronically?

A. The documentation can be mailed or faxed to the applicable Grants Management Officer or Contracting Officer (see question 7 above). The following Grants Management central fax number will convert faxed documents to PDF files: ( 301) 451-5462.