Findings, Conclusions, and Recommendations
This chapter builds on the foundation laid in Chapters 1–3 to draw out the overarching themes of the report and present the committee’s findings, conclusions, and recommendations related to its statement of task.
OPENING OBSERVATIONS AND GENERAL RECOMMENDATIONS
The Joint Pathology Center (JPC) faces major challenges as it transforms into a modern biorepository that provides clinical consultation, education, and research services. Many of these arise from the way in which much of the existing collection of biospecimens and associated clinical data were obtained. The challenges include determining the utility of the collection—which consists of materials collected, handled, and stored under a variety of conditions—and establishing appropriate ethical and legal standards for using the materials, especially in research, inasmuch as they were generally collected without sources’ consent for use in research.
The threshold issue that the JPC must confront in facilitating use of the repository is the uncertainty regarding the utility of its collection of biospecimens. Experience with other biorepositories that, like the JPC, are composed of samples collected in the absence of a purposefully designed protocol indicates that their value may be severely limited by the state of specimens and their associated documentation (Compton et al., 2009). Variations in the preanalytic handling of specimens, in specimen preparation and fixation, in postfixation handling and storage, and in accompanying documentation greatly affect their suitability for some forms of analysis. That is not to say that such specimens lack value—almost all have utility
in at least some applications—but it indicates that the operators of such a repository must be circumspect in their expectations and representations. Advances in technology will undoubtedly change the criteria for determining whether particular specimens are fit for purpose in ways that may make fewer or more of them useful.
The committee recommends that the JPC, as part of its plan for improving the use of repository materials in research, evaluate the strengths and limitations of the collection to the extent permitted by its resources and current science and technology, consider how to enhance the repository’s value given the JPC’s organizational and budgetary constraints, and formulate its retention policy and dissemination management and marketing strategies accordingly. In this regard, the committee believes that it is crucial for the JPC to find ways to engage the relevant professional community in discussion concerning future use of the repository so that it can understand better the potential demand for collection materials and how to facilitate their use.
The committee believes that the JPC will increase its appeal to researchers as an important source of biological materials if the repository undertakes a more thorough documentation of its holdings and makes this information more easily accessible to medical professionals and scientists so they can better determine whether the JPC has specimens that meet their needs. Harvard’s Pathology Specimen Locator (PSL) Core, for example, provides a searchable database of pathology samples left over from diagnostic procedures performed in five university-associated facilities (NCI, 2009). These samples are made available for research study with their accompanying clinical data. The PSL Core uses a number of privacy safeguards for its database: it may be accessed only via a password provided to qualified investigators, data transmissions are encrypted, all data are deidentified and coded with link-backs to repository specimens and data held on a separate fire-wall-protected system, users are limited in how much information they can access on specific specimen sources, and data access is further limited if a query returns only a small number of source individuals who meet the search criteria (Drake et al., 2007).
The JPC may wish to consider whether the utility of a subset of biorepository samples could be enhanced via limited, focused audits of existing materials (both specimens and data) in response to requests for access to those materials. For example, following a request for samples of a particular disease, repository staff or an honest broker might abstract annotations from the database for archived cases or perform a specific screen on archived samples as an add-on service to assess the accuracy of the recorded diagnosis, viability of the tumor, or quality of the specimen.1 Thus, the
1Such information would be appended to existing records to enhance their future value.
biorepository might offer two tiers of samples: unscreened—where the recipient would take on the burden of reviewing sample quality—and prequalified samples that pass a JPC lab screen. Presumably the cost of such an audit would be borne by the requesting party. The ability to provide such services would of course be dependent on the availability of the requisite expertise and any organizational and budgetary constraints.
The JPC may also wish to consider means such as the “honest broker” model for providing specimens and data to researchers while protecting the interests of specimen sources in privacy and confidentiality. An honest broker is an individual, organization, or system that serves as neutral intermediary between a provider of materials (a source individual or biorepository, for example) and researchers, collating pertinent specimens and data, replacing identifying information with a code, and releasing only coded information to the researchers (Eiseman et al., 2003; NCI, 2011). The code may be maintained consistently for a specific specimen and study or generated anew for each study (or investigator) to lessen the chance of unsanctioned linkage of records between investigations. Information on subjects may be from one source or several.2
The notion of an honest broker has not only been adopted by some biorepositories (Amin et al., 2008; Boyd et al., 2009; Dhir et al., 2008; Drake et al., 2007) but also has been applied more generally in facilitating the dissemination of materials to life-science researchers (Boyd et al., 2006). It is critical that the organization managing the brokering process define appropriate policies for exchange of information between the repository and the researcher as well as train and certify its personnel on how to execute those policies.3 Honest brokers may either be entities that are outside and independent of a biorepository or be situated within the organization, provided that they are disassociated both from the research projects in which the data and specimens are being employed and from the management of the specimens and data within the repository.
The JPC indicated to the committee that it would like to make repository materials available for research on a cost-neutral basis (Baker, 2011). Because the federal government is in general prohibited from charging nongovernment entities for such services,4the committee recommends that the JPC immediately determine whether it has the statutory ability to recover
2For example, depending on the study, the Department of Defense, the Department of Veterans Affairs, the Centers for Medicare and Medicaid Services, private insurers, and the Centers for Disease Control and Prevention (through the National Death Index) might have relevant data on a particular subject.
3An example of such practices is described by the University of Pittsburgh Medical Center (UPMC, 2008).
4Federal organizations can recover such costs from other parts of the federal government through interagency transfers (31 U.S.C. § 1535).
the costs of providing specimens and data for approved research projects. If it does not, the JPC should work with Department of Defense (DoD) leadership to determine the best way to establish such an ability. The committee notes that other government agencies have used such mechanisms as partnering with nonprofit organizations (which may accept nongovernment funds) to provide services that they cannot charge for or to receive funds from outside parties.5
Another major set of challenges arises from the application of current legal and ethical standards to the repository. The nature of these challenges depends on whether the focus is on previously collected biologic materials and medical information already held by the biorepository or on biologic materials and medical information to be collected and accessioned in the future. There is no documentation of the nature and extent of the consents by source individuals for future use associated with the JPC’s existing biospecimens, associated data, and medical records. The challenge is to determine under what conditions previously archived materials may now be used for research and to devise policies and practices that reflect that determination and to govern future collection of biospecimens and medical information in a way that complies with relevant and evolving legal and ethical standards.
In the sections below, the committee elaborates on its recommendations regarding those and other issues raised by the DoD in the committee’s statement of task. The DoD’s questions6 are organized in two major categories: those related to the retention and maintenance of biospecimens and those related to the future use of biospecimens and associated data and medical records in clinical care, education, and research. Issues of future use are further divided into ethical and legal considerations and scientific considerations.
RETENTION AND MAINTENANCE OF BIOSPECIMENS
General Retention and Maintenance Issues
The Tissue Repository currently contains paraffin-embedded tissue, glass slides, wet (formalin-fixed tissue) and frozen tissue; some of it is not usable for consultation, education, and research given current technology. Should material not deemed currently usable for consultation, education, and research be stored indefinitely or should the JPC develop a plan for disposal of unusable or non-viable specimens and are there any legal considerations with disposal of said specimens?
5For example, the CDC Foundation (CDC Foundation, 2012).
6The questions posed by DoD appear in italics at the start of each subsection below.
The JPC’s current retention policy is set forth in two documents that spell out how the repository obtains material by retaining specimens and other material submitted to it for consultative and research purposes. Section 4-1 of the Contributor’s7Manual (2012) provides this general information:
a. Slides submitted with each case are retained at the JPC. If blocks are also submitted, representative slides prepared at the JPC may be sent to the contributor as enclosures to the consultation report. Exceptions to this slide retention policy are normally approved by the senior pathologist of the service that would review the case. If the return of original slides is approved, digital images of the slides will be made for retention in the case folder.
b. Paraffin blocks and wet tissue specimens may be returned to the original contributor upon request. The return of blocks should be requested at the time of submission on the JPC Contributor’s Consultation Request Form or later by separate correspondence.
c. Clinical and gross photographs will be copied for retention at the JPC and the originals returned if their return is requested at the time of submission. X-ray films will also be copied for retention and returned.
The JPC’s Contributor’s Consultation Request Form (JPC, 2011) supplies further detail:
- MICROSCOPIC SLIDES SUBMITTED WITH EACH CASE ARE RETAINED PERMANENTLY. Under certain circumstances original slides may be returned to the Contributor if requested by the Contributor and approved by the JPC. If slides are returned, then each slide will be digitized at the expense of the Contributor.
- [Tissue] blocks are retained for a minimum of ten (10) years, unless return is requested by the Contributor at the time the case is submitted. Contributors may request return or loan of blocks at some later time. If blocks are returned, then JPC will retain representative diagnostic material.
- Other pathologic material, X-rays, CT scans, MRI scans, echograms, angiograms, photographs, and similar diagnostic studies may be retained for education and research or discarded.
The committee did not identify any ethical considerations that would call for routine retention of specimens beyond the limits specified in the
7In JPC’s nomenclature, the “contributor” is the pathologist, other medical professional, or institution that sends a specimen to the repository. It does not refer to the specimen source.
CAP guidelines, DoD regulations, or other legal requirements. Once the JPC makes a decision to retain rather than return materials, a policy is needed regarding how long the repository should hold onto them. Any retention policy adopted should continue, at a minimum, to follow the guidelines and requirements set forth in the College of American Pathologists (CAP) Laboratory Accreditation Program8 in addition to the DoD’s Clinical Laboratory Improvement Program (CLIP) standards. CLIP standards conform to the Centers for Medicare and Medicaid Services Clinical Laboratory Improvement Amendments (CLIA) certification requirements except where they “may be required to meet unique aspects of DoD missions, training, and preparations during peace, contingency, and war time operations which preclude compliance” (DoD, 1994; § 4.3). Table 4-1 summarizes the guidelines and requirements.
As the committee noted above, some of the biological materials being held by the JPC cannot be reliably or productively interrogated using current methods. Since advances in tissue-analysis technology continue to be made, no one can confidently predict the potential future scientific value of particular repository specimens. That prospect depends not only on the refinement or development of technologies but on whether the materials held by the JPC turn out to be worth examining in comparison with those held by other sources, such as more modern biorepositories and hospital or university pathology departments. Several existing and emerging technologies in morphology, RNA, DNA, and bioinformatics—detailed in Chapter 2—hold the potential for making JPC repository materials more useful than they are now by permitting specimens previously considered unusable to be analyzed or by allowing more information to be extracted from specimens. However, technologic advances could clarify that the collection, processing, and storage conditions of some JPC specimens have rendered them undesirable or unsuitable for future use. A good policy will thus include a process for periodically assessing how new analytic technologies relate to the material held in the JPC collection and be updated regularly to reflect technological advances.
The possibility that some currently unusable material might become useful does not mean that all of the material that the JPC holds must be stored indefinitely to safeguard against losing something of possible prospective value. The committee recommends that the JPC develop protocols for determining when to retain potentially useful materials and when to dispose of specimens that have no special research or educational value and are past the point of required retention for clinical use.
8The JPC held full CAP accreditation at the time that this committee completed its work in the middle of 2012.
TABLE 4-1 Specimen Retention Policy, Guidelines, and Requirements for the Joint Pathology Center (JPC), Clinical Laboratory Improvement Program–Clinical Laboratory Improvements Amendments (CLIP–CLIA), and College of American Pathologist (CAP) Laboratory Accreditation Program as of 2012
|Medium||JPC (JPC, 2011)||CLIP–CLIA (42 CFR § 493.1105; AFIP, 2007)||CAP (CAP, 2010)|
|Slides||Permanently||Cytology: 5 years
Histology: 10 years
|Permanently stained slides—microbiology: 7 days
Cytogenetics—permanently stained: 3 years
Cytology: 5 years
Surgical pathology: 10 years
Fine-needle aspiration: 10 years
Nonforensic autopsy: 10 years
Forensic autopsy: permanently
Cytogenetics fluorochrome-stained: discretion of laboratory director
|Paraffin blocks||10 years; representative samples of returned specimens are retained||2 years||Surgical pathology: 10 years
Nonforensic autopsy: 10 years
Forensic autopsy: permanently
|Wet tissue||10 years||Until diagnosis is obtained||Surgical pathology: 2 weeks after final report
Nonforensic autopsy: 3 months after final report
Forensic autopsy: 1 year
Cytogenetics: until adequate metaphase cells are obtained
|Other pathology materials||Discarded or retained at the JPC’s discretion||Clinical and gross radiographic diagnostic materials: 2 years||Urine: 24 hours
Serum–heparinized or EDTA plasma–cerebrospinal fluid–body fluids: 48 hours
Peripheral blood smears–body-fluid smears: 7 days
Cytogenetics fixed-cell pellet: 2 weeks after final report
Body fluids–tissues for toxicology: 1 year
Patient test records: 2 years
Cytogenetics diagnostic images: 20 years
Accession log: permanently
Gross photographs/negatives: permanently
Representative tissue suitable for DNA analysis: permanently
|Pathology reports||Permanently||No specific requirements||Surgical pathology: 10 years
Cytology: 10 years
Nonforensic autopsy: 10 years
Cytogenetics: 20 years
Forensic autopsy: permanently
Among the considerations in such protocols is the condition of a specimen and its accompanying data. The committee recommends that the criteria for determining when specimens should be disposed of include whether the specimens fall into any of these categories:
- Wet tissue specimens and slides that have been obviously contaminated, desiccated, or otherwise damaged.
- Tissue blocks that have been contaminated, exhausted, dried out, or have otherwise deteriorated.
- Frozen specimens that show evidence of freezer burn or of having been melted and refrozen.
- Specimens of any type that cannot be associated with a data record in the system.
Specimens in those categories should be disposed of unless they meet the standards for retention discussed in “Use of Rare and Unique Materials” below. It should be noted that although visual inspection yields some information on sample quality, specimens that have no apparent damage may still have degraded biomolecular integrity and may thus be unsuitable for some research applications.9
Auditing the vast holdings of the JPC repository to determine the condition of specimens would be a long and expensive undertaking. The committee recommends that as long as it is less expensive to retain specimens than it is to assess their condition comprehensively, specimens be evaluated only when they are retrieved for clinical, education, or research purposes. If a specimen is found to satisfy the disposal criteria, it should be removed from the collection. If and when the cost of retaining specimens exceeds the estimated cost of auditing the collection, a procedure for setting priorities for review and systematically removing specimens that are not usable for clinical, education, or research purposes from the collection should be implemented.
Two types of specimens merit particular attention in any review of materials for possible removal from the collection and disposal.
- Information developed for the Asterand report (2008) suggests that almost all wet tissue specimens are in poor condition: a survey of materials found that more than 99 percent of such specimens accessioned in 1917–1969 and more than 72 percent of those in 1970–2002 were completely desiccated. The committee suggests that the JPC prioritize the review of wet tissue specimens in any audit of the holdings that it conducts and that it consider conduct-
9Such specimens may still be useful for light microscopy.
ing a focused audit of wet tissue materials to remove contaminated and desiccated specimens.
- Frozen tissue is especially vulnerable to melting and deterioration, and freezers are expensive to maintain and monitor properly. The committee suggests that the JPC prioritize the review of frozen tissue specimens in any audit of the holdings that it conducts and that it consider conducting a focused audit of frozen materials to remove specimens that show evidence of past melting or freezer burn. If the audit of specimen quality suggests that the frozen tissue resources are potentially useful, the JPC should ensure that the freezers are being maintained according to current laboratory practice guidelines (ISBER, 2012; NCI, 2011), including the use of continuous temperature monitoring and recording, alarms, emergency power supply, and the like.
The materials contained in the Base Realignment and Closure (BRAC) Collection come from a variety of sources and are likely to vary greatly in their quality and in the documentation associated with them. The committee believes that other biorepositories are likely to have readily available alternatives for such materials that are more suitable for future research because they have been collected under more modern, more uniform, or better documented circumstances. An exception might be specimens that could be used as reference materials,10 although it is unclear whether auditing the BRAC Collection would be the most cost-effective way of obtaining suitable samples. The committee offers further comments on the BRAC Collection materials below.
Material contained in some of the war and cohort registries may be subject to additional retention requirements that were part of the agreement made by the repository to serve as custodian. Any retention requirements agreed to in setting up such a registry will need to be honored. If specimens are no longer fit for registry or other purposes, the JPC will need to consult with the government entity that provided them when making decisions about their future disposition. Advice from the DoD Office of the General Counsel may be needed.
Statutory requirements for retention change, and the committee recommends that the JPC seek the advice of the DoD Office of the General Counsel regarding the procedures it should have in place to conform to the laws in force when implementing disposal policies.
10A reference material is, in this context, a specimen that is an exemplar of a particular medical condition or tissue characteristic. Reference materials are typically used for educational purposes or as an aid in diagnosis.
The BRAC Collection
Should the BRAC Collection of materials be maintained indefinitely?
BRAC Collection materials were moved to the JPC repository when the medical facilities that held them were closed. They are subject to CLIP and other requirements for retention for possible further clinical reference. The information available to the committee suggests that the BRAC Collection of materials has no greater value for education or research purposes than the collections of pathology materials found in hospitals comparable with the facilities that transferred them. The several reasons for this determination include the relationship of the BRAC Collection to other collections, the provenance associated with it, and the methodologic challenges associated with its use in a research setting.
First, the specimens and data in the BRAC Collection appear no different from ones that can be obtained from other sources, such as hospital and university pathology departments and currently open military healthcare facilities. To the extent that rare disorders were identified by pathologists in the facilities that contained the materials that became the BRAC Collection, it is expected that the specimens would have been sent to the Armed Forces Institute of Pathology (AFIP) for consultation and hence become part of the Central Collection or one of the special registries. Furthermore, the material in the BRAC Collection is not classified in such a manner as to make it easy to identify any particular rare specimen that does not already reside in the Central Collection. On the basis of that observation, the committee believes that the materials in the BRAC Collection as a whole are not rare or unique and offer no special opportunities for education or research.
Second, the documentation associated with the BRAC Collection and the storage protocols for the specimens are varied and some specimens do not have any accompanying documentation. Having information on how specimens were prepared and managed before transfer to the repository and data on the persons from whom the specimens were derived greatly enhances their utility for research purposes. Although data are associated with specimens in the BRAC Collection, the collection’s heterogeneous nature makes use of samples problematic for research and perhaps for education. In contrast, specimens and data can be obtained from other sources that provide better and more consistent documentation. Furthermore, for research that requires data beyond what is contained in pathology department records, it will typically be easier to use material obtained from medical facilities—which will possess accompanying medical records linked to the specimens—than materials from the BRAC Collection, for which the medical records may not be held by the JPC.
Finally, the one characteristic that is sometimes mentioned as a reason
why the BRAC Collection would be attractive to researchers—its considerable size—actually provides little advantage, because it is not expected that the collection will be analyzed as a single source. Indeed, for many types of research, it would be a mistake to do so given the unknown (and unknowable) variations in clinical and pathologic practices among the contributing sources. In hypothesis-driven research, treating specimens or data from disparate sources as though they came from a single source would introduce potential errors into analyses and, for most types of studies, would confound analysis. It is possible to deal with such potential biases by treating each source as a variable in the analysis or by analyzing specimens from each source and composing the results with statistical techniques, such as meta-analysis. However, if the components of the BRAC Collection are treated separately, they are no more attractive than other collections of specimens and data and, for the reasons already mentioned, are actually less useful for research than materials with better documentation.
Therefore, the committee recommends that the JPC retain materials in the BRAC Collection for potential clinical consultation only for as long as required by CAP or CLIP–CLIA guidelines and requirements, whichever specifies the longer period. For the sake of simplicity, the date of each BRAC facility collection’s accession into the JPC repository could be treated as the starting date for calculating how long the material should be retained. Thereafter, no scientific reason exists for the JPC to retain the BRAC Collection, other than any of its component parts that—notwithstanding the committee’s doubts on this score—have proven attractive to researchers or educators.
USE OF BIOSPECIMENS IN CLINICAL CARE, EDUCATION, AND RESEARCH
Ethical and Legal Considerations
Use in Clinical Care and Education
What are the ethical and legal considerations regarding utilization of the Tissue Repository in support of clinical care and education?
The ethical and legal considerations regarding use of the repository in the support of clinical care and education depend on the circumstances of the proposed use.
The use of the stored biospecimens and other clinical data in the JPC repository for clinical care of the person from whom they were obtained is subject to the same considerations as arise in the management of any clini-
cal pathology collection. First, as previously described, the materials must be retained in compliance with legal and professional requirements and accreditation guidelines. Second, sufficient information must exist about the specimens to allow them to be used in a clinically useful and responsible fashion (that is, they are “fit for purpose”).
As discussed in Chapter 3, use of repository materials for the medical care of other persons—notably, genetically related persons and persons who have a life experience (such as an exposure or service in a military unit) in common with the source—constitutes a special case that requires careful consideration of the relevant ethical and legal issues as well as the circumstances of the request. The committee recommends that the JPC develop a policy for evaluating such requests and, when it is appropriate, fulfill them in a manner that protects the privacy of persons from whom the specimens were obtained. The policy should include consideration of whether the material can be provided in a deidentified manner, whether access is necessary to address a medical need that cannot be equally well met by another available means, and applicable legal constraints.
JPC’s predecessor, AFIP, had a distinguished history of educational use of specimens and data; the best known example is its AFIP Fascicles series of reference texts. Generally speaking, educational use of repository materials that have been stripped of all information that would allow sources to be identified poses no ethical or legal issues and should continue to be facilitated by the JPC. But it should be noted that the DNA identifiability concerns that apply to research applications are also relevant to educational uses: DNA in otherwise anonymized biologic material is uniquely identifying if sequenced and matched to a separate source (or reference sample) that includes personal information. The committee recommends that dissemination of biospecimens by the JPC for educational purposes should be subject to strict compliance with rules and procedures to protect source identity. Those requirements should be developed and updated to ensure that reidentification of source individuals cannot readily be accomplished. In addition, material-transfer agreements11 and other documents offered to individuals and institutions seeking access to JPC repository materials (whether for education or other purposes) should explicitly forbid reidentification efforts.
Use in Research
Can tissue collected for clinical use be used for research (i.e. from patients not specifically consented for use of tissue in research)?
11Material-transfer agreements are also addressed below in the section “Access to Repository Materials.”
What are the ethical considerations regarding use of tissues originally submitted for clinical use for research and can this be accomplished within current accepted guidelines for clinical research?
As Chapter 3 notes, the policy landscape governing research on clinically collected specimens that are assembled in a biorepository and then made available for research use is in transition. The Department of Health and Human Services (HHS) Office for Human Research Protections has determined that deidentified specimens and data collected for clinical care can be used for research without patient consent because such work is not considered research on human subjects (HHS, 2008). Furthermore, the Common Rule has exempted studies using “existing data, documents, records, pathological specimens, or diagnostic specimens … 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.”12 When research is undertaken on clinically derived materials after the death of the source individual, it is not research on a “human subject” (who under the Common Rule must be a living person) and so does not require consent although Health Insurance Portability and Accountability Act (HIPAA) privacy rules, Federal Privacy Act (5 U.S.C. § 552a), and some state-specific restrictions still apply in such circumstances.13 Should a study using stored specimens be subject to the Common Rule, the institutional review board (IRB) reviewing the proposal may waive the requirement of informed consent if it finds that the research poses minimal risk to the source individuals and that it would be impracticable to recontact them for permission to use their stored specimens or data in research (Miller and Emanuel, 2008; Rhodes et al., 2011).
This approach to research on stored specimens and data, however, is being reconsidered by policy makers. Increasing capabilities for reidentification of genetic material (Homer et al., 2008; McGuire and Gibbs, 2006) have raised concerns about the adequacy of deidentification measures. Emerging public opinion also suggests that research to which a source did not consent can be a source of concern even when material is deidentified (Hull et al., 2008; Kaufman et al., 2009; Lemke et al., 2010; Trinidad et al., 2011). Legal challenges to research use of clinically derived material
12The usual citation for the Common Rule is to the version published by the Department of Health and Human Services (HHS) because the Office for Human Research Protections (OHRP) in HHS is the lead agency for the Common Rule. The quoted exemption appears at 45 CFR § 46.101(b)(4) in the HHS regulations; the same provision appears in the Department of Defense (DoD) regulations at 32 CFR § 219.101(b)(4).
13Washington State, for example, defines deceased persons as human subjects (RCW 70.02.140; 1991).
(such as newborn blood spots, as in Bearder v. State of Minnesota14) further indicate growing concern over research use without consent. A 2011 Advance Notice of Proposed Rulemaking from HHS invited comment on possible changes in the regulations governing human-subjects research, including a proposed change that would seek at least general consent from individuals at the time that they receive clinical care, asking permission for future research use of specimens and data (HHS, 2011).
Against that backdrop, the committee believes that it is important to consider which approaches for using archived clinical data and specimens in research and which approaches for accessioning new data and specimens accomplish the goals of protecting and respecting source individuals, meeting public expectations, and supporting the efficient functioning of the repository. It offers guidance based on both current (middle of 2012) and emerging legal, regulatory, and ethical standards.
The committee recommends that the JPC adopt a policy regarding research use of tissues originally submitted for clinical consultation that places transparency and respect for source individuals and populations at its core. The procedures adopted should remain flexible enough to adapt to the changing legal, regulatory, and ethics landscape. The policy should include the elements listed below:
• Establishment of a Data Access Committee (DAC) that would examine requests to use repository materials (both specimens and data) and that would operate in addition to the Research Review Committee and IRB that the JPC already uses.15 It would be composed of persons in and outside the JPC who have expertise in research ethics, military research, and research on biospecimens. The DAC’s responsibilities should comprise
— evaluating whether proposed research meets the JPC’s goals for the use of its materials.
— determining whether the researcher’s credentials and specimen- and data-handling protocols satisfy the JPC, DoD, and current legal and regulatory requirements.
— reviewing and providing guidance on the proper management of any ethical issues raised by the proposed research.
— ensuring that data use and material transfer agreements made with researchers protect the privacy of source individuals and
14A10-101 (Minnesota Supreme Court, November 16, 2011).
15The most current repository protocol regarding review of research proposals available at the time of this report was contained in AFIP Regulation 70-1, AFIP Research Program, dated June 7, 2005. The protocol called for review of proposals by a research committee and an IRB and specified the composition and function of these bodies. The committee understands that this regulation is being followed by the JPC.
obligate the researchers to keep information secure, to avoid efforts to identify data or specimen sources, and to otherwise protect the interests of specimen sources and the DoD.
• Solicitation of input from the community of people—in particular, active-duty military, veterans, and their family members—whose specimens are held by the repository through, for example, representation on the DAC or creation of a community advisory board. DACs are in use by other repositories to address such issues, which lie beyond considerations related to the scientific merit of a proposed research initiative (Broad Institute, undated; NCBI, undated; NCI, 2012a).
• Notification through public means—for example, posting on its website, in newsletters, and in other media that reach the military community and the general public—of the JPC’s intention to allow repository materials to be used for research purposes, including — examples of the kinds of research that have been done with repository specimens in the past.
— a description of the oversight and review mechanisms governing access to the materials that can be easily understood by the general public.
— a clear statement that no access will be allowed without the review and approval of an IRB.
— user-friendly means by which people may ask questions or request that a good-faith effort be made to determine whether the repository holds specimens from them, with the option to request that any specimens be withheld from research use (through, for example, a Web form, e-mail address, or telephone number for inquiries).16 The committee notes that given the state of the records and the manner in which subject information is coded, it may not be feasible to make such a determination in all cases; this limitation should be made clear to persons who make inquiries, and they should be assured that personally identifiable information will be protected in all circumstances.
• Posting, in a forum such as the JPC website, of the active research projects that are using repository materials. This will promote accountability to specimen sources and citizens regarding how repository materials are being used; it will also help to inform the
16Procedures for withdrawing data and materials from research use are in place in other repositories of military biospecimens, including the collection maintained as part of the Department of Veterans Affairs Million Veteran Program (http://www.research.va.gov/resdev/mvp/veterans.cfm).
research community about the repository’s collection and potential research uses.
• Regular review of JPC forms, protocols, and procedures to ensure that they meet evolving legal and regulatory requirements and reflect best practices for biorepository operations and management, as defined by, for example, the National Cancer Institute (NCI, 2011) and the International Society for Biological and Environmental Repositories (ISBER, 2012).
Protocols and procedures regarding research use of materials should be public documents and should be regularly updated on the JPC website.
One way that many modern biorepositories manage the difficult issues involved in the ethical use of their materials is to educate specimen sources on the possible use of their materials in research and to seek their consent for such uses. The JPC has no direct control over the mechanisms used to obtain consent from sources whose specimens are sent to its repository. However, it can—in consultation with legal and ethics experts in and outside the military—develop recommended language to be added to existing consent forms and devise accompanying educational materials (such as brochures) that allow substantive choice regarding the research use of specimens obtained for clinical consultation. The JPC can also suggest that physicians who seek consultations with the JPC use consent forms that include this language and can ask the contributing physician for information about research consent from the source individual as part of the Contributor’s Consultation Request Form and code that information in the JPC database for future use. Several model educational materials (NCI, 2012b) and consent forms (Beskow et al., 2011; Hansson et al., 2006; Hofmann, 2009) could serve as a starting point for developing recommended materials for source individuals to consider.
More broadly, the committee believes that the DoD should consider changing patient education materials and consent requests and forms in the manner outlined above to facilitate future use of pathologic materials in research.
The JPC’s IRB may be able to consider many research-use requests under the provisions for exemption or waivers of consent under the Common Rule and waivers or alterations of the authorization to use protected health information (PHI) under HIPAA regulations. Current exemptions17 from human-subjects regulations include studies that use deidentified data
17Changes to the Common Rule that would require that clinical materials used in research be obtained from individuals who had been informed of their potential use in research and afforded the opportunity to give (or withhold) permission for such use of their specimens and data were under debate in mid-2012 (Emanuel and Menikoff, 2011; HHS, 2011).
and specimens not originally collected for the research (HHS, 2008). Regulatory requirements for waiver of consent under the Common Rule are set forth in 45 CFR 46.116(d) and are as follows18:
(1) the research involves no more than minimal risk to the subjects;
(2) the waiver or alteration of consent will not adversely affect the rights and welfare of the subjects;
(3) the research could not practicably be carried out without the waiver or alteration; and
(4) whenever appropriate, the subjects will be provided with additional pertinent information after participation.
HIPAA (HHS, 2007) allows waiver or alteration of the requirement of authorization for the use of PHI in research when an IRB or privacy board determines that
1. The use or disclosure of the PHI involves no more than minimal risk to the privacy of individuals based on, at least, the presence of the following elements:
a. An adequate plan to protect health information identifiers from improper use and disclosure.
b. An adequate plan to destroy identifiers at the earliest opportunity consistent with conduct of the research (absent a health or research justification for retaining them or a legal requirement to do so).
c. Adequate written assurances that the PHI will not be reused or disclosed to (shared with) any other person or entity, except as required by law, for authorized oversight of the research study, or for other research for which the use or disclosure of the PHI would be permitted under the Privacy Rule.
2. The research could not practicably be conducted without the waiver or alteration.
3. The research could not practicably be conducted without access to and use of the PHI.
Some study protocols may require recontact and reconsent of sources. The determination of whether and under what conditions this is necessary should be made by the JPC’s IRB based on factors including the level of identifiers requested and the sensitivity of the research question being asked.
Acceptable uses of materials for research may be broader when consent is documented. The terms of the consent, if available, must be carefully
18As of early 2012.
considered. Some specimens in the war and cohort registries may have been provided under consents that included research use, but the JPC has no documentation of such consents (Baker personal communication, 2011).
Given the changing legal, regulatory, and ethics landscape, this guidance should be reviewed in light of further developments before implementation.19
Use of Consultation Materials from Federal Facilities and Civilian Providers
The Tissue Repository currently contains consult material from both federal facilities as well as that submitted for consultation by civilian providers. Can tissue within the repository from civilian providers be utilized in the same manner as that from federal facilities?
Access by researchers to human materials that entered the JPC repository from federal facilities and from civilian providers20 is generally governed by the same legal requirements and ethical standards. The JPC has an ethical obligation to ensure all materials (as well as data) in its repository are utilized in a manner that respects the privacy of the specimen sources, prevents misuse by researchers who obtain access to them, and protects the security and other interests of the government. Additional protections regarding research on human subjects, especially requirements regarding informed consent, do apply to U.S. military service members,21 and these impose additional review and procedural responsibilities on the JPC.
As noted above, materials contained in some of the war and cohort registries may be subject to additional or different handling requirements that were part of the agreement made by the repository to serve as custodian. The JPC will need to conform to such requirements when making policies for the materials.
Current and Emerging Technologies
What existing or emerging technologies (either as an intrinsic function or through partnership) should be considered in developing a plan for utiliza-
19The Advance Notice of Proposed Rulemaking issued by HHS in 2011, for example, may lead to changes in the Common Rule that could affect the recommendations offered here.
20The providers are the physicians who and medical facilities that submitted materials for consultation or educational purposes, not the persons from whom the samples were derived. When the provider is a medical professional, this person is also a contributor as defined above.
21These are spelled out in DoD Instruction 3216.02 (November 8, 2011), Protection of Human Subjects and Adherence to Ethical Standards in DoDSupported Research.
tion of the Tissue Repository in research and how would they potentially affect the mission of the JPC?
Several existing and emerging technologies in protein and gene-expression profiling and advances in DNA, elemental, and chemical studies—detailed in Chapter 2—hold the potential for making the JPC repository materials more useful by permitting specimens previously considered unusable to be analyzed or by allowing more information to be extracted from specimens.
For example, advances in proteomics allow the identification of proteolyzed protein fragments and their association with the protein from which they are derived. That allows one to circumvent, in part, any protein degradation that has occurred during specimen transport, handling, and fixation. In theory, posttranslational modifications of proteins can also be detected in the proteolyzed fragments, and this allows insight into cell signaling events. DNA analysis has become quicker, and the ability to detect pathogens responsible for past epidemics and disease clusters can be of value in understanding virulence in future outbreaks. Although mRNA is quite unstable unless specimens are handled very carefully, mRNA analyses can still be useful under some conditions. Small non-coding RNAs, such as micro RNA (miRNA), are very stable and are of increasing importance in certain scientific studies.
However, although the technical ability to extract and analyze biomolecules from archived specimens has improved and is likely to increase, the many unknown types and degrees of preanalytic variation to which the specimens have been subjected before stabilization will affect the validity of analytic results and may limit many types of research studies. This shortcoming is not limited to JPC materials but is endemic in older collections of biomaterials and collections that were assembled for purposes other than research (Carlson, 2010; Khleif et al., 2010). The committee is thus uncertain whether these research methods can successfully be applied broadly to the JPC repository collection and whether the collection will be the best source for investigators seeking to exploit the new technologies.
If the JPC is to fulfill its stated mission to provide “world class” research services, it will need to establish procedures that minimize the adverse consequences of inconsistent preanalytic handling of new specimens it acquires. The committee therefore recommends that the JPC adopt a set of best practices for the collection, processing, and storage of all incoming specimens, either by developing its own standards or by using one developed by another entity—for example, NCI’s Best Practices for Biospecimen Resources (NCI, 2011). The best practices should be posted on line, contributors should be encouraged to follow them, a means should be established for identifying specimens that have been handled in accordance with the best practices (check-off boxes on the Contributor’s Consultation
Form, for example), and compliance should be recorded on a specimen’s record. Even if those handling procedures are not optimal for a particular type of analysis, having specimens that are subject to well-defined, uniform handling rules will allow investigators to factor the specimens’ condition in their studies. The best practices should be revisited regularly and updated as necessary.
Technologies that present solutions to biobanking challenges of quality control, quality management, specimen tracking, retrieval or aliquoting, inventory control, or other issues could also be of great benefit to the repository (Frey, 2010). Devices that allow high-throughput generation of molecular quality-control data, for example, may be of use in selecting cases when certain quality thresholds are required (Patel et al., 2006). The extent to which such technologies should be adopted, however, depends on the extent to which the JPC envisions streamlining repository management, making the repository available to external researchers, and conducting research in its own right.
As the JPC takes steps to enhance its laboratory information management system by improving basic search and analytic functionality, its system should, at a minimum, include fields that detail how specimens were collected and handled before accessioning in the repository, quality-control data, and what record there is of consent to future research use.
If the JPC contemplates moving beyond basic management of the repository to support clinical, educational, and research use toward more active involvement in research or enhancement of its collection by adding new data generated by researchers, the committee suggests that it consider investing in high-performance computing technologies to assist in processing the volumes of data that will be produced. This class of technologies is not necessary to maintain the repository, but it may enable greater use by merging biologic and computational proficiencies.
The committee notes that implementation of such systems requires outlays for equipment and training that may not be feasible in the current funding environment. The JPC will need to consider whether its current budget allows such investments and, if so, which have highest priority.
Digitization of slides, which has already been performed on some of the collection, preserves visual information in a form that may be more easily deidentified and disseminated for research and educational purposes. However, it is a time-consuming process: digitizing a slide at 400× magnification with three Z-axis planes, for example, takes a minimum of 5 minutes per slide with current (2012) technology. Unless the slide illustrates a rare condition or is to be used as part of a teaching or reference collection, it is questionable whether that is worth the effort. Moreover, digitizing slides that lack associated clinical data is likely to be of little value in research. Association of specimens with clinical data is highly desirable
from a research perspective,22 but raises issues of consent and privacy that are discussed elsewhere in this report. Nonetheless, the committee believes that there may be merit in digitizing all new cases coming to the repository and suggests that the JPC consider whether it is feasible given economic and logistical circumstances.
Finally, the committee believes that the JPC would derive value from pursuing research partnerships with the Department of Veterans Affairs (VA). Specimens held by the repository and data on long-term health outcomes possessed by VA can be productively combined to examine questions regarding the health consequences of military service and the determinants of disease and wellness. The JPC may wish to consider using the unique resources of the DoD to advance the state of the art in pathology through, for example, partnering with the DoD’s cutting-edge research entities to explore how technologies developed for other purposes might be used in pathology applications. It should also consider partnering with DoD medical or information-technology investigators to examine how JPC materials and data may be combined with other DoD or federal databases to facilitate medical research.
Use of Rare and Unique Materials
What considerations should be given to utilization for research of unique, one-of-a-kind, material within the central collection of the Tissue Repository?
Rare and unique materials in the Central Collection of the repository are a resource for the JPC, the country, and the global scientific community. As the experience with genetic analysis of the 1918 influenza virus illustrates, such materials may play a vital role in today’s health research. The question of what constitutes rare and unique material is complex, however, and depends on several factors: even relatively common diseases have rare subtypes, for example. Moreover, particular collections of specimens may be “unique” in the aggregate, although until a particular set of desired material characteristics is defined it may not be possible to determine whether or not other similar collections are available elsewhere or whether the number of representative samples in the collection is small or unusual enough to merit special handling. It is also difficult to predict what may prove to be valuable at some future time or under particular circumstances.
22Moreover, in circumstances in which research using personally identifiable information is permissible, data-matching techniques may allow content from diverse military and civilian databases to be merged and married to specimens, thus expanding the array of studies that can performed on them and enhancing their value.
Eiseman et al. (2003) note that “[i]n most cases, the procedure for prioritizing requests for rare or precious tissue is the same as that used for easily available tissue” but that some repositories have “specific policies for regulating the distribution of the last sample of a particular specimen” and that such policies are considered best practice (pp. 102–103). However, there are no generally-recognized protocols for evaluating whether and when to exhaust a specimen.
The committee recommends that the following considerations be taken in account in evaluating whether any given specimen should be made available for research:
- The age of the specimen.
- The disease state that it represents.
- The specimen’s medical, scientific, and historical23 significance.
- The condition of the specimen and its fitness for the proposed use.
- Whether a proposed use would exhaust the research potential of the specimen.
- Whether the same research need might be met by another, less rare specimen or another source of specimens.
- The importance of the public-health or military need the proposed use aims to meet.
The JPC should also develop criteria for determining when a collection of specimens—rather than an individual sample—is unique or has special medical, scientific, or historic value, and for managing access to such collections.
The JPC does not have any specific policy regarding how the depletion of a repository specimen should be factored into decisions regarding access to it, beyond ensuring that all applicable CAP and CLIA–CLIP retention requirement are met (Baker personal communication, 2011). The committee believes that the JPC needs such a policy to ensure that the repository remains a resource for otherwise unobtainable material. The committee recommends that the JPC establish criteria for deciding whether to deplete a specimen to exhaustion. The criteria should be determined in close consultation with pathology subspecialty experts in and outside the JPC. Detailed recommendations are beyond the scope of the present committee’s task but the criteria may include such considerations as the following:
- Retaining a set percentage of the tissue-containing portion of a tissue block unless a designated repository officer authorizes its use.
23The National Museum of Health and Medicine (http://www.medicalmuseum.mil) houses military pathology specimens with historical value and would be the authority on this question.
- Retaining a set number of stained or unstained tissue sections from a specimen.
- Not permitting any specimens collected before a given date to be used for research without specific review of whether the need justifies depletion of the resource and without explicit authorization by a designated repository officer.
- Not disposing of any specimen collected before a given date, no matter its condition.
More broadly, the JPC should consider whether the goal of sustaining and enhancing the research potential of its collection could be advanced by requiring researchers who receive specimens to return analysis results to the repository for integration into the specimens’ documentation. Such a requirement would need to be predicated on the JPC’s developing the infrastructure to manage such returns.
Access to Repository Materials
Given the defined mission and vision of the Joint Pathology Center, should access to repository materials be limited to the federal government or open to a larger pool of potential users? What advantages and disadvantages should be considered in defining the potential users of the repository in research?
Permitting wide access to the JPC repository materials promotes the public good through the advancement of medical and scientific knowledge. It also benefits the DoD by fostering the development of information on the determinants of disease and good health in service members and veterans.
The JPC’s mission and vision are focused on service to the DoD and the rest of the federal government but do not preclude working with other entities. The committee does not believe that there are any intrinsic advantages or disadvantages to any particular set of potential users of the repository’s resources. The committee recommends that there be no a priori restrictions on which applicants may apply for access to the repository’s specimens and data.
When data or specimens are disseminated to outside investigators, the JPC must be especially attentive to employing mechanisms to manage privacy and security issues properly. The committee recommends that the JPC condition its provision of repository materials to researchers outside of the federal government on
- Approval of a Data Access Committee that develops and applies criteria for determining whether the interests of specimen and data sources,24 the repository, and the federal government are being met.
- Participation of a DoD-affiliated monitor trained in and assigned the responsibility of ensuring the appropriate use of repository specimens and data and safeguarding the interests of its sources, the repository, and the federal government. The monitor would also facilitate research by helping outside investigators to identify and gain access to the most appropriate JPC resources for a particular project.
- Implementation of data-use agreements and material-transfer agreements, as appropriate, to help to protect the identified interests. A data-use agreement (DUA) is, in brief, a contract between a data provider (here, the JPC) and a user (such as a researcher) that explicates how the data may be used, who may have access to them, how they must be stored and secured, and how they must be handled after the authorized research is completed. A material-transfer agreement (MTA) serves the same purpose for such items as biospecimens. DUAs and MTAs were used by AFIP and are widely used by other research biorepositories and by the federal government to inform investigators of their responsibilities and to gain their agreement to abide by a set of requirements.
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