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4 Findings, Conclusions, and Recommendations This chapter builds on the foundation laid in Chapters 13 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 trans- forms 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 clini- cal 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 bio- specimens. 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 prepara- tion and fixation, in postfixation handling and storage, and in accompany- ing documentation greatly affect their suitability for some forms of analysis. That is not to say that such specimens lack value--almost all have utility 109

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110 FUTURE USES OF THE DOD JPC BIOREPOSITORY 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 determin- ing 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 im- proving 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 reposi- tory's value given the JPC's organizational and budgetary constraints, and formulate its retention policy and dissemination management and market- ing strategies accordingly. In this regard, the committee believes that it is crucial for the JPC to find ways to engage the relevant professional com- munity 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 re- searchers 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 sci- entists 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 facili- ties (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 de identified 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 bio repository 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 particu- lar disease, repository staff or an honest broker might abstract anno tations from the database for archived cases or perform a specific screen on ar- chived 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.

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FINDINGS, CONCLUSIONS, AND RECOMMENDATIONS 111 biorepository might offer two tiers of samples: unscreened--where the recipient would take on the burden of reviewing sample quality--and pre- qualified 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 hon- est broker is an individual, organization, or system that serves as neutral intermediary between a provider of materials (a source individual or bio- repository, 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 ap- propriate 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, pro- vided 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 reposi- tory materials available for research on a cost-neutral basis (Baker, 2011). Because the federal government is in general prohibited from charging non- government entities for such services,4 the 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).

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112 FUTURE USES OF THE DOD JPC BIOREPOSITORY 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 com- mittee 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 recommenda- tions regarding those and other issues raised by the DoD in the com mittee's statement of task. The DoD's questions6 are organized in two major cat- egories: 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 con- siderations 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.

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FINDINGS, CONCLUSIONS, AND RECOMMENDATIONS 113 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's7 Manual (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) sup- plies further detail: 1. MICROSCOPIC SLIDES SUBMITTED WITH EACH CASE ARE RETAINED PERMANENTLY. Under certain circumstances origi- nal 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. 2. [Tissue] blocks are retained for a minimum of ten (10) years, un- less 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 repre- sentative diagnostic material. 3. Other pathologic material, X-rays, CT scans, MRI scans, echo- grams, 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.

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114 FUTURE USES OF THE DOD JPC BIOREPOSITORY 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 Patholo- gists (CAP) Laboratory Accreditation Program8 in addition to the DoD's Clinical Laboratory Improvement Program (CLIP) standards. CLIP stan- dards 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 mis- sions, 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 be- ing 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 col- lection, processing, and storage conditions of some JPC specimens have ren- dered 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 pro- spective 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.

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FINDINGS, CONCLUSIONS, AND RECOMMENDATIONS 115 TABLE 4-1 Specimen Retention Policy, Guidelines, and Requirements for the Joint Pathology Center (JPC), Clinical Laboratory Improvement ProgramClinical Laboratory Improvements Amendments (CLIPCLIA), and College of American Pathologist (CAP) Laboratory Accreditation Program as of 2012 CLIPCLIA (42 JPC CFR 493.1105; CAP Medium (JPC, 2011) AFIP, 2007) (CAP, 2010) Slides Permanently Cytology: Permanently stained slides--microbiology: 5 years 7 days Histology: Cytogenetics--permanently stained: 3 years 10 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 10 years; 2 years Surgical pathology: 10 years blocks representative Nonforensic autopsy: 10 years samples of Forensic autopsy: permanently returned specimens are retained Wet 10 years Until diagnosis is Surgical pathology: 2 weeks after final tissue obtained report Nonforensic autopsy: 3 months after final report Forensic autopsy: 1 year Cytogenetics: until adequate metaphase cells are obtained Other Discarded Clinical Urine: 24 hours pathology or retained and gross Serumheparinized or EDTA plasma materials at the JPC's radiographic cerebrospinal fluidbody fluids: 48 hours discretion diagnostic Peripheral blood smearsbody-fluid materials: smears: 7 days 2 years Cytogenetics fixed-cell pellet: 2 weeks after final report Body fluidstissues 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 Permanently No specific Surgical pathology: 10 years reports requirements Cytology: 10 years Nonforensic autopsy: 10 years Cytogenetics: 20 years Forensic autopsy: permanently

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116 FUTURE USES OF THE DOD JPC BIOREPOSITORY Among the considerations in such protocols is the condition of a speci- men 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 contami- nated, 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 Mate rials" 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 con- dition of specimens would be a long and expensive undertaking. The committee recommends that as long as it is less expensive to retain speci- mens 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 set- ting 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. 1. 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 19171969 and more than 72 percent of those in 19702002 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.

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FINDINGS, CONCLUSIONS, AND RECOMMENDATIONS 117 ing a focused audit of wet tissue materials to remove contaminated and desiccated specimens. 2. 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, emer- gency 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 commit- tee 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 audit- ing 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 rec- ommends 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 medi- cal condition or tissue characteristic. Reference materials are typically used for educational purposes or as an aid in diagnosis.

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118 FUTURE USES OF THE DOD JPC BIOREPOSITORY 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 Col- lection 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 deter- mination include the relationship of the BRAC Collection to other collec- tions, 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 differ- ent 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 edu- cation. 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 depart- ment records, it will typically be easier to use material obtained from medi- cal 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

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FINDINGS, CONCLUSIONS, AND RECOMMENDATIONS 119 why the BRAC Collection would be attractive to researchers--its consider- able 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 unknow- able) 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 con- found 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 mate rials in the BRAC Collection for potential clinical consultation only for as long as required by CAP or CLIPCLIA 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 re- tained. 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-

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126 FUTURE USES OF THE DOD JPC BIOREPOSITORY 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 fed- eral facilities as well as that submitted for consultation by civilian pro viders. 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 reposi- tory from federal facilities and from civilian providers20 is generally gov- erned 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 reg- istries 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. Scientific Considerations 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 DoD-Supported Research.

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FINDINGS, CONCLUSIONS, AND RECOMMENDATIONS 127 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 sig- naling 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 bio molecules 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 v alidity of analytic results and may limit many types of research studies. This short- coming 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 uncer- tain 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 incom- ing specimens, either by developing its own standards or by using one developed by another entity--for example, NCI's Best Practices for Bio specimen 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

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128 FUTURE USES OF THE DOD JPC BIOREPOSITORY 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 q uality 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 manage- ment system by improving basic search and analytic functionality, its sys- tem 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 process- ing 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 out- lays for equipment and training that may not be feasible in the current fund- ing 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 pur- poses. 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 illus- trates 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. Asso ciation of specimens with clinical data is highly desirable

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FINDINGS, CONCLUSIONS, AND RECOMMENDATIONS 129 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 out- comes 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 medi- cal 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 illus- trates, 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 mate rial 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.

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130 FUTURE USES OF THE DOD JPC BIOREPOSITORY Eiseman et al. (2003) note that "[i]n most cases, the procedure for pri- oritizing requests for rare or precious tissue is the same as that used for easily available tissue" but that some repositories have "specific policies for regu- lating the distribution of the last sample of a particular specimen" and that such policies are considered best practice (pp. 102103). 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 avail- able 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 CLIACLIP retention requirement are met (Baker personal communication, 2011). The commit- tee 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 consul- tation 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.

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FINDINGS, CONCLUSIONS, AND RECOMMENDATIONS 131 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 justi- fies 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 knowl- edge. 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 enti- ties. 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

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132 FUTURE USES OF THE DOD JPC BIOREPOSITORY 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 par- ticular project. Implementation of data-use agreements and material-transfer agreements, as appropriate, to help to protect the identified inter- ests. 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. REFERENCES AFIP (Armed Forces Institute of Pathology). 2007. Pamphlet 40-24. Technical instructions for the DoD Clinical Laboratory Improvement Program. Washington, DC. Amin W, Parwani AV, Schmandt L, Mohanty SK, Farhat G, Pople AK, Winters SB, Whelan NB, Schneider AM, Milnes JT, Valdivieso FA, Feldman M, Pass HI, Dhir R, Melamed J, Becich MJ. 2008. National Mesothelioma Virtual Bank: a standard based biospecimen and clinical data resource to enhance translational research. BMC Cancer 8:236. Asterand. 2008. Assessment of the Department of Defense's tissue repository located at the Armed Forces of Pathology in Washington DC. Detroit, MI: Asterand, Inc. Baker personal communication. 2011. Responses to questions posed by the Institute of Medicine Committee on the Review of the Appropriate Use of AFIP's Tissue Repository Following Its Transfer to the Joint Pathology Center by COL Thomas P. Baker, MD, Interim Director, Joint Pathology Center. September 6, 2011. A copy of this document is available from The National Academies Public Access Records Office. Baker TP. 2011. The Joint Pathology Center. Presentation before the Committee on the Review of the Appropriate Use of AFIP's Tissue Repository Following Its Transfer to the Joint Pathology Center, April 21, 2011. Beskow LM, Namey EE, Cadigan RJ, Brazg T, Crouch J, Henderson GE, Michie M, Nelson DK, Tabor HK, Wilfond BS. 2011. Research participants' perspectives on genotype-driven research recruitment. Journal of Empirical Research on Human Research Ethics 6(4):3-20. 24Including privacy interests.

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FINDINGS, CONCLUSIONS, AND RECOMMENDATIONS 135 Rhodes R, Azzouni J, Baumrin SB, Benkov K, Blaser MJ, Brenner B, Dauben JW, Earle WJ, Frank L, Gligorov N, Goldfarb J, Hirschhorn K, Hirschhorn R, Holzman I, Indyk D, Jabs EW, Lackey DP, Moros DA, Philpott S, Rhodes ME, Richardson LD, Sacks HS, Schwab A, Sperling R, Trusko B, Zweig A. 2011. De minimis risk: a proposal for a new category of research risk. American Journal of Bioethics 11(11):1-7. Trinidad SB, Fullerton SM, Ludman EJ, Jarvik GP, Larson EB, Burke W. 2011. Research prac- tice and participant preferences: The growing gulf. Science 331(6015):287-288. UPMC (University of Pittsburgh Medical Center). 2008. Honest broker certification process related to the de-identification of health information for research and other duties/ requirements of an honest broker. Policy: HS-EC1807; dated December 22, 2008. http:// cancerregistrynetwork.upmc.com/research/HB/policies/HSEC1807%20Honest%20 Broker%20Certification%20Process.pdf (accessed June 9, 2012).

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