# Presentation: 664052

## ETHICAL AND REGULATORY ASPECTS OF USE OF TISSUE SAMPLES FOR RESEARCH

**VA RESEARCH DAY**
**SAN DIEGO, CALIFORNIA**
**OCTOBER 28, 2004**
**Rina Hakimian**
**DHHS Office for Human Research Protections**
**Phone:301-402-2136 **
**Fax:  301-402-0527**
**Email:  rhakimian@osophs.dhhs.gov**

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## Federal regulations 
Human subject protections (Common Rule and FDA)
Health Information privacy (HIPAA)
State laws
International guidelines
Guidance: OHRP, NBAC 

**Federal regulations **
**Human subject protections (Common Rule and FDA)**
**Health Information privacy (HIPAA)**
**State laws**
**International guidelines**
**Guidance: OHRP, NBAC **

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**Notes:**
consent, risks, privacy, ownership/intellectual property

## 
Basic DHHS Policy for Protection of Human Research Subjects (First adopted 1974, revised 1991)

Federal Policy for the Protection of Human Subjects 

Subpart A:  “The Common Rule” (1991) 
Additional protections for vulnerable populations in Subparts B-D

Applies to human subjects research funded by any of 17 federal agencies

**Basic DHHS Policy for Protection of Human Research Subjects (First adopted 1974, revised 1991)**
**Federal Policy for the Protection of Human Subjects **
**Subpart A:  “The Common Rule” (1991) **
**Additional protections for vulnerable populations in Subparts B-D**
**Applies to human subjects research funded by any of 17 federal agencies**

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## APPLICABILITY OF REGULATIONS

_**Research**_** involving **_**human subjects **_**conducted or supported by HHS that is not otherwise **_**exempt**_
**Non-exempt human subjects research conducted at an institution holding an applicable Assurance of Compliance**

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## APPLICABILITY OF THE HHS REGULATIONS

**Research [45 CFR 46.102(d)]?**
**Human subjects [45 CFR 46.102(f)]?**
**Exempt [45 CFR 46.101(b)]?**

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## FEDERAL REGULATIONS: COMMON RULEWHAT’S COVERED BY 45 CFR 46?

**DEFINITION OF RESEARCH****:  **
**A systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.  [45 CFR 46.102(d)]**

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## FEDERAL REGULATIONS: COMMON RULEWHAT’S COVERED BY 45 CFR 46?

**DEFINITION OF HUMAN SUBJECT****:**
**A “living individual” about whom an investigator obtains either  data through intervention or interaction with the individual; or **
_**Identifiable**_** private information**
**45 CFR 46.102(f)]**

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## FEDERAL REGULATIONS: COMMON RULEWHAT’S EXEMPT 45 CFR 46?

**WHAT’S EXEMPT?**
**Exemption 45 CFR 46.101 (b) #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.**_

## WHAT’S MEANT BY “EXISTING”?

**Specimens and data are existing at the time the research is proposed ****to an institutional official for a determination of whether the research is exempt**** **
**Since research repositories and databases often continually accrue new specimens/data, Exemption 4 may not apply **

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## WHAT’S MEANT BY “PUBLICLY AVAILABLE”?

**Available without restrictions or conditions**
**Since research repositories and databases often impose restrictions or conditions on access, Exemption 4 may not apply **

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## WHAT’S MEANT BY “RECORDED BY THE INVESTIGATOR IN SUCH A MANNER THAT SUBJECTS CANNOT BE IDENTIFIED DIRECTLY OR THROUGH IDENTIFIERS”

**Information recorded is not directly or indirectly identifiable**
**Information cannot be coded**
**Even if all specimens and data to be obtained are existing at the time the research is proposed, researchers often need individually identifiable or coded information; thus Exemption 4 may not apply **

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## HOWEVER...MOST RESEARCH THAT INVOLVES OBTAINING SPECIMENS OR INFORMATION FROM REPOSITORIES CAN PROBABLY BE CONDUCTED WITHOUT OBTAINING IDENTIFIABLE INFORMATION, AND THUS... WOULD NOT BE HUMAN SUBJECTS RESEARCH UNDER 45 CFR PART 46

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## RESEARCH REPOSITORIES & DATABASES:  3 PATHS TO HUMAN SUBJECTS RESEARCH

**RESEARCH REPOSITORIES & DATABASES:  3 PATHS TO HUMAN SUBJECTS RESEARCH**

**Creating a research repository/database ****through intervention or interaction with individual**
**Creating a research repository/database by ****obtaining identifiable private information**
**Obtaining identifiable private information ****from a research repository/database****.  **

**Notes:**
The Privacy Rule imposes conditions on uses and disclosures of protected health information (individually identifiable information held by covered entities or their business associates). 

Creation of a research database or repository, and the use or disclosure of PHI from a database or repository for research, may each be considered a research activity under the Privacy Rule.

## OHRP GUIDANCE: COMPONENTS OF REPOSITORIES

**Repository activities involve three components:**
** **
**the collectors of tissue samples; **
**the repository storage and data management center; and **
**the recipient investigators.**
**Each component must satisfy certain requirements**

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## OHRP REPOSITORY GUIDANCE (1997) 

**Tissue collector**

**Tissue collector**

**Tissue collector**

**Repository Storage**
**And **
**Data Management Center**

**Recipient Investigator**

**Recipient Investigator**

**Recipient Investigator**

**OHRP REPOSITORY GUIDANCE (1997)**** **

**IRB Review**
**Informed Consent **
**Submittal Agreement**
**Assurance of Compliance**

**IRB Review**
**Sample Informed Consent **
**Certificate of Confidentiality**
**Assurance of Compliance**

**Recipient Agreement**
**Local Policies**

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## FEDERAL REGULATIONS: COMMON RULE WHEN IS RESEARCH USING CODED DATA IS NOT HUMAN SUBJECTS RESEARCH? 

**OHRP GUIDANCE ON RESEARCH INVOLVING CODED PRIVATE INFORMATION OR BIOLOGICAL SPECIMENS (2004)**
**	**

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## 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**_**. **
**	****[45 CFR 46.102(f)]**

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## IDENTIFIABLE PRIVATE INFORMATION 

**	****Private information must be **_**individually identifiable**_** in order for obtaining the information to constitute research involving human subjects.  [45 CFR 46.102(f)]**

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## IDENTIFIABLE PRIVATE INFORMATION

**	**_**Individually identifiable**_**:  The identity of the subject is or may readily be ascertained by the investigator or associated with the information. **
**	****[45 CFR 46.102(f)]**

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## RESEARCH USING CODED DATA/BIOLOGIC SAMPLES

**Private information or samples that retain a link to individually identifying information is ordinarily considered by OHRP to be individually identifiable to the investigator.**
**But, there are exceptions...**

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## EXAMPLES OF WHEN CODED DATA/BIOLOGIC SAMPLES ARE NOT INDIVIDUALLY IDENTIFIABLE TO INVESTIGATORS

**The key to the code is destroyed;**
**The investigator and the holder of the individually identifying information sign an agreement prohibiting the release of individually identifying information to the investigator under any circumstances, until the individuals are deceased;**

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## 
There are IRB-approved written policies and operating procedures for a repository or data management center that prohibit the release of individual identifiers to the investigator under any circumstances, until the individuals are deceased; or

There are other legal requirements prohibiting the release of the link to the investigator, until the individuals are deceased. 

**There are IRB-approved written policies and operating procedures for a repository or data management center that prohibit the release of individual identifiers to the investigator under any circumstances, until the individuals are deceased; or**
**There are other legal requirements prohibiting the release of the link to the investigator, until the individuals are deceased. **

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**EXAMPLES OF WHEN CODED ****DATA/BIOLOGIC SAMPLES ARE **_**NOT**_** INDIVIDUALLY IDENTIFIABLE TO INVESTIGATORS**

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**IN THESE EXAMPLES, THE RESEARCH DOES NOT INVOLVE HUMAN SUBJECTS BECAUSE INVESTIGATORS CANNOT READILY ASCERTAIN THE IDENTITY OF THE INDIVIDUALS.**

## OHRP GUIDANCE:USAGE AGREEMENTS

**Recipient-investigators should not be provided access to the identities of donors or to information through which the identities of donors may readily be ascertained; thus not conducting human subjects research (HSR).**
**If recipient-investigators receive identifiable, private information they are engaged in HSR and need to obtain an Assurance of Compliance and IRB review of the proposed research.**

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## TWO CAVEATS ABOUT THE EXAMPLES: 

**Person(s) doing coding of data/samples and person(s) holding codes are not part of research team.**
**Samples/data not being obtained for the specific research in question by an interaction or intervention with living individuals.**

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## INFORMED CONSENT

**IF:**
**Samples collected for research purposes OR**
**Samples are associated with information that allows investigators to readily identify the donor,**** **

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**THEN**** i****nformed consent must be obtained **
**unless appropriately waived by the IRB.**

## INFORMED CONSENT

**A clear description of:**
**Operation of the specimen repository.**
**Specific types of research to be conducted.**
**Procedures for protecting the privacy of subjects and maintaining the confidentiality of data.**

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## 
Possible consequences of genetic testing (e.g., insurance risks, misattributed paternity), when appropriate.

Future withdrawal of the samples from the study (i.e., state whether subjects may, in the future, request that their samples be destroyed or that all personal identifiers be removed from samples).

**Possible consequences of genetic testing (e.g., insurance risks, misattributed paternity), when appropriate.**
**Future withdrawal of the samples from the study (i.e., state whether subjects may, in the future, request that their samples be destroyed or that all personal identifiers be removed from samples).**

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**INFORMED CONSENT**

## Length of time that samples will be stored.  If storage time is indefinite, so state.

Subjects' access to information learned from the research, if they so choose.     

**Subjects' access to information learned from the research, if they so choose.     **

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**INFORMED CONSENT**

## Conditions under which data/specimens will be released to recipient-investigators; e.g.:

No secondary use.
Subjects have option to allow secondary use.
Only release samples stripped of all identifiers.
Only release of coded samples.
Subjects to be contacted for additional consent for secondary use.

**No secondary use.**
**Subjects have option to allow secondary use.**
**Only release samples stripped of all identifiers.**
**Only release of coded samples.**
**Subjects to be contacted for additional consent for secondary use.**

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**INFORMED CONSENT**

## FEDERAL REGULATIONSHUMAN SUBJECTS RESEARCH

**WAIVER OR ALTERATION OF INFORMED CONSENT****:**
**Minimal risk to subjects**
**No adverse effect on subjects’ rights and welfare**
**Research could not practicably be carried out otherwise**
**Whenever appropriate, subjects provided additional pertinent information following participation**

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## OHRP PLANS TO ISSUE FURTHER GUIDANCE ON:

**Research repositories and databases**
** **
**Exemptions under 45 CFR 46.101(b)**

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