Feature Article

Research Repositories (Part I) - Understanding Recipient Research Proposals
April 2013 Issue

By Mary A. Banks, BS, BSN,
Director, BUMC IRB
Authors has nothing to disclose with regards to commercial support.

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• Introduction
• What is a Repository?
• Recipient Research
• IRB review of RECIPIENT RESEARCH Protocols:
• Summary
• Quiz

Introduction

“Knowledge is of two kinds.  We know a subject ourselves, or we know where we can find information on it.” - Samuel Johnson

The question of how to best review and oversee repository research is a topic of much discussion throughout the country.  In years past, data and specimens were collected and analyzed on a study-by-study basis.  Now, most investigators, institutions, and sponsors better appreciate the long-term value of research data and specimens and, as such, want to make the most of all available data and specimens whenever possible.   

In order to best accommodate this growing desire to retain research data and samples for future use, BUMC has given considerable attention to this topic over recent months.  In September 2011, a new BUMC “full board” IRB Panel was constituted and named, “Panel Orange”.  While Panel Orange is duly constituted to review all types of human subjects research, the main mission of BUMC IRB Panel Orange has been to focus on the regulatory and institutional requirements specific to repository and genetic research.  In addition, when INSPIR II was instituted in May 2011, a specific section of the INSPIR application was created that addressed repository-specific questions.  Recently, the BUMC Clinical Research Seminar Series devoted two sessions to the topic of repository research. The PowerPoint slides and videos of those presentations are currently available via the CRRO website.  

What is a Repository?

For the purpose of this discussion, a “repository” is any collection of data, human tissue, or information derived from human data or human tissue, that you have saved or set aside for future use or research purposes. Repositories are also sometimes known as banks, biospecimen banks, data registries, etc. It is important to note that the federal regulations use the global term of “repositories” when describing both data and specimens.

Repositories can be formal or informal, large or small, not for profit or commercial. Data repositories contain information from or about individual human beings. The data can be identified or de-identified. It can include genetic information or not.

Specimen repositories can include blood or tissue samples (such as fat cells or skin cells, saliva, urine, breast milk, semen, isolates, DNA, cell lines, and other materials derived from humans). They can also include diagnostic materials (such as x-rays, CT scans, MRIs, laboratory results, etc.).

The following are a few examples of repositories:

• BMC Clinical Data Warehouse (CDW)
• BMC i2b2 and Boston Healthnet MDHR
• BMC Bio-specimen Archive Research Core (BARC)
• Framingham Heart Study
• NIH dbGaP

Recipient Research

The remainder of this article will be devoted to a discussion of RECIPIENT RESEARCH. For the purpose of this article, this term will be used to describe human subjects research which involves obtaining and analyzing data and/or specimens FROM A REPOSITORY rather than directly from research subjects.

The key determining factor as to the level of review required is the identifiability of the research data/specimens.  In accordance with the federal regulations and guidance, the greater the potential for identification of the subjects (i.e., the donors of the samples/data), the greater the potential risks; and, therefore, the more scrutiny necessary for the research protocol.

Following this process, RECIPIENT RESEARCH might require only Expedited or Exempt review by the IRB; but, in rare instances, may require review by the convened (full board) IRB. This determination is predominately based on whether there are identifiers associated with the data/samples.

Prior to this discussion, it is important to remind the reader about the definition of certain key terms used to describe the identifiability of data.  These terms are described in detail in the BUMC Privacy and Confidentiality Module.  A few of these terms are listed below, but investigators should consult the Privacy Module for a detailed discussion. By far, the most significant problem that occurs related to IRB review of repository research is the misuse of the following terms.

Terminology

Anonymous
This is an unofficial term usually meaning that NO ONE is able to associate the data/specimens with individual subjects--neither the holders of the data/specimens, nor the recipients. Anonymous data/specimens don’t contain direct identifiers.  Coded samples are NOT anonymous because, by having a code, someone can link the data/specimens back to the identifiers.

Coded
This term refers to data/samples identified by a unique study ID and can be linked to subjects via a master code or key.  Usually the keepers of the repository retain the master code and only release the data/samples to recipients with the “study IDs”.  In this way, without the master code, the recipients cannot ascertain the identities of the subjects.  

De-identified
This is a HIPAA term. De-identified data/specimens are stripped of ALL 18 “HIPAA identifiers”.  De-identified data may be anonymous or may be “coded”.  Coded data can be “de-identified” even if it has a study ID, as long as the study ID is not derived from a HIPAA identifier (e.g., subjects’ initials, dates of birth, etc.).  Data sets that contain dates (admission, discharge, surgery, birth, death, specimen collection, etc.) can’t be called de-identified because dates are identifiers.
 
 Data released to RECIPIENT investigators by repositories can be: 

• Coded and de-identified
• Coded and a Limited Data Set
• Coded and contain a HIPAA identifier (e.g., subjects’ initials)
• Anonymous (no one can link to identifiers) and de-identified
• Anonymous and a Limited Data Set

Retrospective versus Prospective
The IRB considers the term “retrospective” to mean that the data/samples exist at the time of the IRB submission (not at the time of proposed use by the investigators).

IRB review of RECIPIENT RESEARCH Protocols

The following is a discussion of the various potential pathways for IRB review of RECIPIENT RESEARCH Protocols:

Not Human Subjects Research (NHSR)

“NHSR” is a term used at BUMC based on regulatory guidance by OHRP (Office of Human Subjects Research) which describes a category of research that they have determined does not meet the regulatory definition of “human subjects” and/or “research”.  As such, NHSR protocols do not have to meet all of the commonly known regulatory requirements of “non-exempt” human subjects research. In accordance with an OHRP regulatory guidance, the BUMC IRB has been delegated the responsibility of determining whether RECIPIENT RESEARCH meets the definition of NHSR.   

A RECIPIENT RESEARCH protocol that qualifies for NHSR review is among the simplest and most straightforward type of protocol for investigators to write and for the IRB to review.  It requires completion of a simplified INSPIR application with only a limited number of questions to be answered.  The investigator creates an NHSR IRB protocol by selecting the FIRST OPTION under Question 10.3 (Review Path Determination) of the INSPIR application.

In order for a RECIPIENT RESEARCH protocol to qualify as NHSR, it must meet the following criteria:

• All the data/specimens that the recipient investigator will be analyzing for the research project must come from an established repository. Research involving the collection of data/samples directly from subjects does not qualify as NHSR.
• None of the investigators involved in the RECIPIENT RESEARCH project will ever be able to, now or at any point in the future, ascertain the identities of the subjects.  This means that the data/samples obtained from the repository may be anonymous (meaning that once released, the recipient investigators and the keepers of the repository will not be able to link the data/specimens back to individual subjects).
• RECIPIENT RESEARCH protocols involving coded data/specimens may qualify for NHSR review if there is an agreement in place that states that the recipients will never receive the master code; and the recipients agree that they will never make any attempt to ascertain the identities of the subjects. Here is a link to a sample agreement. By signing the agreement, the recipients verify that they will never be able to ascertain the identities of the subjects (donors); thus, this agreement is referred to as the BUMC “Not Engaged” in Human Subjects Research Agreement.
• None of the investigators on the recipient project can be investigators on the repository. This is because, by nature of their role, the investigators on the repository will have access to subject identifiers.  
• No results from the RECIPIENT RESEARCH can be put back into the repository.
• The research project does not involve collection of data directly from subjects’ medical/clinical/billing records by recipient investigators. Obtaining data from the Institution (for example, from the BMC Clinical Data Warehouse) would qualify for NHSR review.

Exempt review under Category 4

In some rare instances, RECIPIENT RESEARCH might not meet the criteria for NHSR review, but might qualify for Exempt review under federal Exempt category (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.” 
For these situations, the investigator should complete Question 10.3 (Review Path Determination) of the INSPIR application by selecting the FOURTH option (“This study fits into one or more of the Federal Exempt categories”), and then by selecting Category 4 in the subsequent questions. 

Expedited or Full Board Review

Sometimes recipient investigators need identifiers so that subjects’ identities can be ascertained.   This will not usually qualify for NHSR or Exempt review. The IRB will need to carefully review the RECIPIENT RESEARCH protocol to determine whether the proposed RECIPIENT RESEARCH is consistent with the repository rules, whether the research is consistent with the repository consent or consent waiver, and whether additional consent will be required.
In accordance with the regulations, human subjects research which doesn’t meet the criteria for NHSR review or Exempt review requires “Non-exempt” review.   “Non-exempt” research must be reviewed either by the full convened IRB Board (Full Board review) or by one designated IRB Board member (Expedited review).  The determination as to whether a RECIPIENT RESEARCH protocol requires Full Board or Expedited review is made by the IRB based on the risk level of the study.  As far as completing the IRB application, the requirements are the same.  Investigators need to select the LAST option in Section 10.3 (Review Path Determination) and then answer all the subsequent questions.  

Non-exempt research review is most frequently needed for RECIPIENT RESEARCH under the following circumstances:

• One or more of the recipient investigators are also the “keepers of the repository” and, therefore, have the ability to link the coded study data/specimens back to the individual participants
• There is an intent to put results from the analysis by the recipient investigators back into the repository
• The recipient investigators will receive genetic information or samples that might result in potential identification of subjects
• The IRB must make additional determinations because of the research population (e.g., prisoner research) 

HIPAA

As part of its review of RECIPIENT RESEARCH, the IRB will review the proposal to determine the HIPAA requirements.  In most instances, if the recipient investigators are obtaining clinical data and/or specimens from a repository, then this is NOT HIPAA exempt. The data/specimens in the repository were most likely collected under HIPAA (i.e., with a HIPAA authorization or HIPAA waiver).   Most likely, the recipient investigator will be obtaining data that are either de-identified (i.e., stripped of all 18 HIPAA identifiers including dates) or a Limited Data Set.  Therefore, when completing an NHSR, Exempt, or “Non-Exempt” RECIPIENT RESEARCH protocol, investigators will usually need to answer YES to Question 10.6 (HIPAA Compliance), and then complete the appropriate HIPAA form. More detailed information about this can be found in the BUMC Privacy and Confidentiality Module.

Summary

The two major types of repository research reviewed by the IRB are for RECIPIENT RESEARCH and for the establishment of a research repository.  This article provides an overview of repository research at BUMC, and then provides details about how RECIPIENT RESEARCH protocols are reviewed.

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