# Presentation: 522643

## Human Subjects Research 

- Valery M. Gordon,  Ph.D., M.P.H.
- NIH Extramural Human Subjects Research Policy Officer
- Office of Extramural Programs
- Office of Extramural Research, OD, NIH
- (301) 435-0945
- _[vg10w@nih.gov](http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm)_

**Notes:**

My expertise is in Human Subjects Protections and I serve as a resource to help NIH staff puzzle out some of the questions about research proposed in applications or contracts with respect to requirements for the protection of HS.
I like to think about these issues- why?- because these are often not easy questions and I enjoy a challenge. The applicants and reviewers are clever and creative and want to extend the boundaries of knowledge. This often means that they want to stretch definitions and re-define requirements. An easy question is nice once in a while, but if you talk to most anyone who has called me, they will tell you that the first answer I usually give is, “It depends.” It depends on the information in the application and the info that may be missing from the application. It depends on the focus of the research study and the role of individuals involved in the study. But mostly it depends upon risk.

## Outline

- Human Subjects Research
- Pre-award Issues
- Information supplied by applicants
- Administrative Review
- Non-exempt human subjects research
- Exempt human subjects research
- Just-in-Time Policy for IRB Review
- Post-award Issues
- Specific Issues
- Delayed-onset of human subjects research
- Change in scope of research after award
- Responsibilities of Investigators and Institutions

## NIH Policy: Human Subjects research and protections from risk

- NIH is committed to the highest ethical and scientific standards for Human Subjects research
- NIH follows all parts of DHHS regulations:
- 	45 CFR 46 _Protection of Human Subjects_
**Office for Human Research Protections** (OHRP) ensures compliance with  DHHS regulations
- NIH has additional policy requirements for research involving Human Subjects

## Definition of a Human Subject

***Human Subject *****:**
- ... a living individual
- about whom an investigator... conducting research obtains
- 		(1) data through _intervention_ or _interaction_ 	with the individual, or
- 		(2) identifiable private information
- _http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm#46.102_

**Notes:**
a living individual:  studies using only cadaver samples is NOT HSR
About whom an investigator... conducting research: “a systematic investigation, designed to develop or contribute to generalizable knowledge, obtains data through:
Intervention: behavioral or biomedical
Interaction: includes collection of data, derived from some activity that the investigator does with or about the human subjects.
OR
Identifiable, private: if data are recorded so that someone can identify the person, and that person has a reason to assume that no recording of this information is taking  place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record). Private information must be individually identifiable (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information) in order for obtaining the information to constitute research involving human subjects.

## Definition of Research

***Research *****:**
- ... a systematic investigation
- research development,
- testing, or
- evaluation
- designed to
- develop or to contribute to generalizable knowledge
- _http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm#46.102_

**Notes:**
To meet the definition of HS research, the study must be organized (systematic).
Investigations into research development, testing, or evaluation, if systematic, may qualify as research
There must be a deliberate intention to develop or to contribute to generalizable knowledge. 

## Definition of Risk

- 	...the **probability** of
- harm
- 		or
- discomfort
- Extracted from:
- _http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm#46.102_

**Notes:**
What is risk? 
It is the probability that something bad will happen, in this case, as a result of participation in research.
The regulations were written to describe how to protect human subjects from research risk.

## “Engagement” in HS Research

- An institution becomes "**engaged**" in human subjects research when its employees or agents
- (i) intervene or interact with living individuals for research purposes; or
- (ii) obtain individually identifiable private information for research purposes _[[45 CFR 46.102(d),(f)]](http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm#46.102)_
- An institution is automatically considered to be "**engaged**" in human subjects research whenever it receives a direct HHS award to support such research. In such cases, the awardee institution bears ultimate responsibility for protecting human subjects under the award
- _(__http://ohrp.osophs.dhhs.gov/humansubjects/assurance/engage.htm__)_

## Application facepage:               Item 4.  Human Subjects Research

- PI should enter YES in Item 4 on application facepage;
**Exemptions** designated in Item 4a often represent the opinion of the PI because
- OHRP Guidance states Exemptions should be independently determined;
- 		_[http://](http://ohrp.osophs.dhhs.gov/humansubjects/guidance/wirbproc.pdf)__[ohrp.osophs.dhhs.gov/humansubjects/guidance/wirbproc.pdf](http://ohrp.osophs.dhhs.gov/humansubjects/guidance/wirbproc.pdf)_
- Institutions often designate IRB to make determination; and
- NIH does not require IRB approval until prior to award
- Required information must appear in the _Research Plan_ in **Section e. Human Subjects**

## Administrative Review for Human Subjects Protections

- _Non-exempt_ Human Subjects Research
- Risks
- Adequacy of protections against risks
- Data and Safety Monitoring for Clinical Trials
- Monitoring entity
- Adverse Event Reporting
- Potential benefits
- Importance of knowledge to be gained
- _http://grants.nih.gov/grants/funding/phs398/phs398.html_

**Notes:**
Since Administrative review of aps has been a source of questions, I will address the issue in 2 separate ways: 
For non-exempt HS research, the Protections of Human Subjects section must address: Go over Bullets
The new 398 states the NIH policy and the new format requires applicants to address 4 issues that come directly from the regulations (rather than the 6 that were required before)

## Administrative Review (con’t)

- _Exempt_ Human Subjects Research
- Exemption Category
- Justification for exempt status
- Population sample
- Number
- Age range
- Health status
- Sources of research materials or data

**Notes:**
Protection of HS section must address: BULLETS

## Exemptions 1, 2*

- Research in educational settings on educational strategies
- Surveys, interviews, observations of public behavior, if participants
- cannot be identified, either directly or indirectly; OR
- may be identified, but would not be put at risk if information is disclosed
- 	*E2 only applies to research with children for observations of public behavior when the PI(s) do not participate in the activities being observed
- 	_http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm#46.101_

## Exemption 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."
- 	(_[http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm#46.101](http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm#46.101)__)_
- In order to be exempt from the requirement of IRB review and approval under exemption 4, researchers must propose the use of data or samples that are either:
- 		- _**existing**_** and publicly available**
- 		OR
- 		- _**existing**_** and unidentifiable**

## Human Subjects Concern

- Any actual or potential unacceptable risk, or inadequate protection against risk, to human subjects as described in any portion of the application.

**Notes:**
Concerns are questions that must be answered, information that must be supplied, or issues that must be resolved, prior to funding.

## “Just-in-Time” Information is requested for Applications that are likely to be awarded

- NIH staff ask that specific information be submitted, co-signed by the authorized institutional official.
- If the application is “Unacceptable” in terms of human subjects protection or inclusion,
- NIH Program Official requests the PI / Authorized Official to resolve these issues
- The response is assessed and approved by NIH staff

## Awards: Human Subjects Issues

- Before award: NIH staff require:
- _OHRP Assurance Number_ for grantee
- _Certification of IRB review and approval_ from IRB registered under grantee’s Assurance number
- _Acceptable/Resolved Human Subjects protections_; &
- Inclusion Tables

## Notice of Grant Award: terms and conditions

- Grantees may not draw funds from the payment system or make obligations against Federal funds for research involving human subjects _at any site_ engaged in non-exempt research for any period not covered by both an
**OHRP-approved assurance** and an
**IRB approval**
- consistent with 45 CFR Part 46.
- Only activities that do not directly involve human subjects (i.e., are clearly severable and independent from those activities that do involve human subjects) may be conducted under this award until the **concerns have been resolved** to the satisfaction of the NIH.

## Awards: Human Subjects Issues

- After award:
- Annual Progress reports to the NIH and certification of continuing IRB review for non-exempt research from the grantee
- Adverse Event Reports

## Specific Issues

- Delayed-onset  Human Subjects Research

## Applications lacking definite plans for involvement of human subjects 

- “Certain types of applications ... are submitted ... with the knowledge that [human] subjects may be involved within the period of support, but definite plans would not normally be set forth in the application ...”
- “These applications need not be reviewed by an IRB before an award may be made.”
- However, “no human subjects may be involved in any project supported by these awards until the project has been reviewed and approved by the IRB” **and**
- A revised award has been issued by NIH
- _http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm#46.118_

## Specific Issues

- Change in Scope: Addition of Human Subjects research after award

## Change in Scope

- In general, the PI may make changes in the methodology, approach, or other aspects of the project objectives.
- However, the grantee must obtain prior approval from NIH for changes in scope, direction, type of training, or other areas that constitute a significant change from the aims, objectives, or purposes of the approved project.
- _http://grants2.nih.gov/grants/policy/nihgps_2001/part_iia_5.htm_

## Actions likely to be considered a change in scope include: 

- Change in the specific aims approved at the time of award;
- Any change from the approved use of animals;
_**Any change from the approved use of human subjects**_;
- Shifting the research emphasis from one disease area to another;
- A clinical hold by FDA under a study involving an IND or an IDE;
- Applying a new technology, e.g., changing assays from those approved to a different type of assay;
- Transferring the performance of substantive programmatic work to a third party through a consortium agreement, by contract, or any other means;
- Change in key personnel...
- 		_http://grants2.nih.gov/grants/policy/nihgps_2001/part_iia_5.htm_

## Research undertaken without the intention of involving human subjects 

- If an award is made for research that does not involve human subjects, “but it is later proposed to involve human subjects in the research, the research shall first be reviewed and approved by an IRB, ... a certification submitted, by the institution” to the NIH, and final approval given to the proposed change by the NIH.
- 	_http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm#46.119_
- May require external review
- 	_http://grants2.nih.gov/grants/policy/nihgps_2001/part_iia_5.htm_

## Responsibilities of Institutions

- Certification of IRB Review and Approval

## Certification of IRB Review and Approval

- The institution must certify that the research has been reviewed and approved by an IRB (includes all participating sites)
- 		[45CFR46103(b)]
-  Just-In-Time submission to NIH
- IRB approval is not required prior to NIH peer review of an application
- 	_http://grants.nih.gov/grants/policy/policy.htm_

## Responsibilities of PI and Institution

- Make sure that DHHS Regulations and NIH Human Subject Policy requirements are addressed in _applications and Progress Reports_ to NIH
- Provide “Just In Time” documentation when requested
- Comply with DHHS Regulations and NIH policies during the award
- If Human Subjects research changes after NIH peer review, the IRB must approve changes

## NIH Extramural Policy Information

- NIH Guide for Grants and Contracts publishes new and updated HS policies (it’s a listserve, so sign up)
- 	_[http://](http://grants.nih.gov/grants/guide/index.html)__[grants.nih.gov/grants/guide/index.html](http://grants.nih.gov/grants/guide/index.html)_
- NIH Grants Policy Statement
- 	_http://grants1.nih.gov/grants/policy/nihgps_2001/_
- PHS398 Instructions and Forms
- 	_http://grants.nih.gov/grants/funding/phs398/phs398.html_

## 
Questions?

**Questions?**