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1 Introduction and Background This chapter provides basic information about the motivation for and the conduct of the study summarized in this report, beginning with a brief history of the biorepository currently under the aegis of the Joint Pathology Center (JPC) and a description of the status of its collection. It then presents the statement of task for the Institute of Medicine (IOM) committee respon- sible for the report and discusses the committee's approach to its task. The methodologic considerations that informed the committee's evaluation of the literature are addressed, and summary information on related National Academy of Sciences reports is presented. The chapter concludes with a description of the present report's organization. ESTABLISHMENT AND HISTORY OF THE ARMED FORCES INSTITUTE OF PATHOLOGY AND THE JOINT PATHOLOGY CENTER The collection of biospecimens currently held by the JPC had its origins in the U.S. Civil War. The Army Medical Museum was founded in 1862 by Army Surgeon General Brigadier General William Hammond (AFIP, 2011). It was given the task of collecting and cataloging all specimens of morbid anatomy that would be of interest in military medicine. The museum served primarily as a reference collection, but it also accommodated the visiting public. One of its earliest products was The Medical and Surgical History of the War of the Rebellion, a six-volume publication that cataloged the types of diseases and injuries that a military physician might encounter during service (U.S. Army Surgeon General's Office, 18611865). 17

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18 FUTURE USES OF THE DOD JPC BIOREPOSITORY The Museum was divided into the Pathology Department and Instruc- tion Laboratory in 1910, beginning its transformation from a storehouse to a consultation, research, and education facility. An extensive effort to document the medical consequences of combat was conducted during World War I and prompted a decision to split the institution's collection into two groupings: Series A, consisting of all specimens received before the U.S. declaration of war against Germany on April 2, 1917, and Series B, all specimens accessioned from that date on (Stone, 2011). The 1920 U.S. surgeon general's report made a strong statement in favor of general access to the nascent repository's materials (U.S. Surgeon General, 1920, p. 247): The Army Medical Museum is a very valuable connecting link between the Medical Department of the United States Army and the general medical profession of the United States, from the standpoint of scientific medicine and surgery. It has been the policy of the museum during the past year to encourage the use of its collections by civilian physicians and it is believed that only in this way will the museum fulfill its larger function of being not only a place for the exhibition of pathological and other material, but a great instruction center in pathology and epidemiology. With that endorsement, the museum created the first of the registries in the repository in cooperation with the Academy of Ophthalmology and Otolaryngology. Registries provided a means by which medical societies representing various specialties could donate materials, thereby strength- ening and diversifying the museum's collection while preserving valuable specimens for the medical community and creating links between civilian researchers and museum staff (Stone, 2011). Several other registries were established in the following years, including those for lymphatic tumors (1925), bladder tumors (1927), dental and oral pathology (1933), and dermatology (1937). Diagnosis and consultation services also expanded, particularly after a 1929 circular from the U.S. Army surgeon general called attention to this work (Henry, 1964). The introduction of the registries and the continued accession of thou- sands of pathologic specimens per month led to the museum's being re- named the Army Institute of Pathology in 1946 (Stone, 2011). Series A accessions were assigned to the museum, and Series B became known as the Central Repository (Henry, 1964). World War II brought another influx of specimens to the repository and with them a new mandate to serve all the U.S. armed forces and the Veterans Administration (VA, now the Department of Veterans Affairs) as their central pathology laboratory (Stone, 2011). In recognition of that en- largement of mission, the institute was renamed the Armed Forces Institute

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INTRODUCTION AND BACKGROUND 19 of Pathology (AFIP) in 1949. The number of new accessions continued to increase through the 1950s, reaching about 75,000 per year (Asterand, 2008). Institutional growth during the period included the introduction of branches in laboratory animals and in aerospace, forensic, and geographic aerospace pathology and expansions in military and civilian consultations and in educational and research programs (Stone, 2011). Over 200 research studies using biorepository materials were conducted in 19551960 alone (Stone, 2011). Congress chartered the American Registry of Pathology (ARP) in 1976 (PL 94-361; 10 U.S.C. 177) to facilitate the Armed Forces Institute of Pathology's (AFIP's) interactions with the civilian medical community. A provision of the charter permitted ARP to receive fees for such services as education courses and consultations, with AFIP staff holding joint ap- pointments with the two institutions (Stone, 2011). That cost-offsetting mechanism, which is not available to government entities, allowed further expansions in AFIP's clinical care (in the form of consultations), education, and research activities and attracted a number of clinicians and investiga- tors to its staff. Scientific and technologic advances in such fields as DNA analysis, microscopy, and digital image processing spurred AFIP's work in the 1980s and 1990s. The AFIP Department of Forensic Sciences became the Armed Forces Medical Examiner System (AFMES) in 1988. The Armed Forces DNA Identification Laboratory was absorbed into the AFMES 3 years later. That centralized system allowed surveillance of active-duty deaths and led to research into improvements in protective gear and emergency medicine. The era also saw the establishment of the first of a series of war and cohort registries that were created at the direction of Congress or on the initiative of VA or the Department of Defense DoD (Baker personal com- munication, 2011a). They include registries addressing military personnel who participated in the Persian Gulf War, Operation Iraqi Freedom, and Operation Enduring Freedom; former prisoners of war; those who received a diagnosis of leishmaniasis; and those exposed to Agent Orange, depleted uranium, nerve agents, or embedded metal fragments (JPC, 2011). Unlike almost all the other material in the repository, data and specimens in the registries were collected according to research protocols that were reviewed by an institutional review board (Baker personal communication, 2011a). As it entered the 21st century, the AFIP repository continued to serve as a major resource for the medical community, with its staff supplying educa- tion and diagnostic services and improving knowledge through research. Residency training, fellowships, postgraduate short courses, continuing edu- cation, and lectures were provided to both domestic and international medi- cal professionals, while state-of-the-art technologies were utilized in making advances in pathology and other sciences (Stone, 2011). Notably, a team of

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20 FUTURE USES OF THE DOD JPC BIOREPOSITORY more than 50 repository personnel used DNA analysis and other means to identify remains recovered from the September 11, 2001, terror ist attacks on the Pentagon and at the Shanksville, Pennsylvania, crash site--one of the most comprehensive forensic investigations in U.S. history (Stone, 2011). The Base Realignment and Closure (BRAC) Act of 1990 (PL 101-510) formalized a mechanism for improving the efficiency of the military by closing and consolidating operations. Several DoD hospitals and other health facilities were shuttered as part of various rounds of evaluations by an independent entity known as the BRAC Commission that was formed to implement the law. Pathology specimens and other diagnostic materials and data in 27 of the closed facilities were transferred to the AFIP repository to satisfy accreditation requirements for specimen retention (Baker, 2011). The 2005 BRAC Commission recommendation called for the disestablishment of AFIP with the exception of the National Museum of Health and Medi- cine and the tissue repository and for the relocation of the AFMES and the DNA registry (Defense Base Closure and Realignment Commission, 2005). In response, the DoD undertook a re-evaluation of the administration and scope of its pathology services. AFIP's disestablishment raised concerns in the clinical diagnostic and research pathology communities that were centered on the loss of ready access to the staff's expertise (McCook, 2011). The National Defense Authori zation Act of 2008 (PL 110-181, 722) created the Joint Pathology Center to absorb the AFIP repository collections and continue consultation services, education, and research. The DoD later formed a working group that developed a concept of operations for the organization. It defined the JPC's vision and mission as follows (JPC, 2012): Vision: The Joint Pathology Center (JPC) is the federal government's premier pathology reference center supporting the Military Health System (MHS), DoD and other federal agencies. Mission: The JPC provides world class diagnostic subspecialty pathol- ogy consultation, education and research services to federal agencies and operates the National Pathology Tissue Repository in support of the mission of the Department of Defense and other federal agencies. AFIP's civilian consultation mission was discontinued in September 2010, and the JPC took over from AFIP formal responsibility for accept- ing cases from the Military Health System and other federal government entities on April 1, 2011 (JPC, 2011). The JPC became fully operational in September 2011. A more detailed history of the repository can be found in Legacy of Excellence. The Armed Forces Institute of Pathology, 18622011 (Stone,

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INTRODUCTION AND BACKGROUND 21 2011), on which this section is based. Box 1-1 cites some examples of how repository materials have been used to advance scientific knowledge. THE JOINT PATHOLOGY CENTER BIOREPOSITORY As of 2011, the JPC tissue repository comprised some 7.4 million acces- sions1 containing specimens or data from about 3.2 million people (Baker personal communication, 2011a), making it the largest collection of human pathologic specimens in the world. About 3.2 million of the accessions are part of the Central Repository (also referred to as the Central Collection), which is composed primarily of biologic materials submitted for consulta- tion by military, other government, and civilian medical providers. Over the years, some of the materials were organized into collections of rare or otherwise interesting specimens. Those and the war and cohort registries noted above were flagged in the inventory database rather than separated from the rest of the collection. The remaining 4.2 million accessions are from the facilities that were closed under the BRAC process. They differ from the Central Collection in that they include the complete array of data and specimens collected in the course of provision of routine medical care. About two-thirds of the so- called BRAC Collection cases have both specimens and data; the remaining one-third have only data (Baker personal communication, 2011a). All told, the repository includes 55 million glass slides. 31 million paraffin-embedded tissue blocks. 500,000700,000 wet tissue samples.2 29 tissue microarray assays, each of which may contain hundreds of specimens. over 23 million digitized images of specimens. an unknown quantity of digitized radiologic images. other pathology and diagnosis-related holdings, including medico- legal materials and veterinary specimens (Baker, 2011). There are also 18 freezers with frozen samples that were still be- ing cataloged in early 2012. The samples include tissue, urine, and other bodily fluids submitted for testing environmental exposures in the depleted- 1The terms accession and case are used interchangeably in the literature and in this report to refer to a submission of material to a repository that is cataloged into its inventory. A particu- lar patient may have multiple accessions in a repository. In addition, an accession may include multiple types of material, such as a macroscropic specimen, paraffin blocks, and glass slides. 2 Wet tissue samples are fixed in formalin or some other preserving agent but not otherwise processed. They typically are stored in sealed, airtight containers.

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22 FUTURE USES OF THE DOD JPC BIOREPOSITORY BOX 1-1 Past Uses of the Joint Pathology Center Biorepository One of the primary reasons offered for preserving the Joint Pathology Center (JPC) biorepository is that specimens from this collection are instrumental in addressing public health issues (Auburn Health Strategies, 2005). The most prominent instance of this entails the use of tissue specimens in the repository to sequence the 1918 influenza virus, which killed more than 40 million people worldwide. That research was of great importance in that it may provide clues for avoiding future influenza outbreaks. In 1995, a research team led by Jeffery Taubenberger, chief of the Division of Molecular Pathology of the Armed Forces Institute of Pathology (AFIP), used technology that could extract RNA fragments from formalin-fixed, paraffin-embedded tissue to sequence the 1918 influenza virus. The researchers examined more than 100 autopsy cases from the pan- demic that were stored in the AFIP biorepository and found one case that tested positive for the presence of influenza RNA. From that sample, they sequenced four gene segments, which revealed that the pathogen was an H1N1 influenza A virus. It was feared that there would not be enough material to sequence the entire genome. Fortunately, another scientist, Johan Hultin, provided AFIP with an infected lung sample from a 1918 influenza victim in Brevig Mission, Alaska, whom he exhumed (Taubenberger et al., 2007). The investigators compared the sequences of one gene segment from both samples with the sequence of a third 1918 influenza sample--which was found in the AFIP biorepository after a second round of screening in 1997--and discovered that the three were almost identical. The researchers decided to sequence the rest of the genome by using the sample that contained the most material, the Alaska case. In the end, tissue samples from the AFIP repository were instrumental in sequencing 4 of 11 gene segments from the 1918 influenza virus. In 2008, Taubenberger's team followed up their study by examining 58 cases from 1918 influenza pandemic from the AFIP repository and 8,335 other cases to determine that the primary cause of death from the pandemic was secondary bacterial pneumonia (Morens et al., 2008). The data also correlate with findings from the 1957 and 1968 influenza pandemics and will aid in planning for future outbreaks. uranium registry program and other circumstances and frozen tissue left over from neuromuscular biopsies submitted for clinical diagnosis (Baker personal communication, 2011b). Slides are held in an automated storage and retrieval mechanism. Paraf- fin blocks, wet tissue samples, veterinary specimens, and other pathologic materials--including all the BRAC Collection--are stored in cardboard boxes in high-density storage units. The materials are housed in climate- controlled storage facilities in an annex of the Walter Reed Army Medical Center in Forest Glen, Maryland. Data associated with accessions vary according to when they were

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INTRODUCTION AND BACKGROUND 23 Specimens from the AFIP biorepository have also been important for other less notable discoveries. U.S. Army Lt. Col. Joseph Woodward was the first pathologist at AFIP, which was then called the Army Medical Museum. In 1862, he generated tissue sections from autopsies of Civil War victims who suffered from chronic diarrhea. Woodward used those sections to revolutionize the field of histology in the United States by establishing the use of synthetic aniline dyes to stain par- ticular parts of tissue (Woodward, 1865)--a practice that had been independently developed 2 years earlier in Germany but had not yet reached the United States (Saunders and Barron, 1970). Another important AFIP study occurred in 1983, when researchers examined biorepository cases of children who had Reye's syndrome, which causes dam- age to the brain and liver. They found that the syndrome was linked to the use of salicylate (aspirin) to treat chickenpox and upper respiratory infections (Starko and Mullick, 1983). After that discovery, the Food and Drug Administration issued a warning about the use of aspirin in children and infants who had influenza or chickenpox, and the warning has correlated with a decline in the occurrence of Reye's syndrome. AFIP researchers reviewed and performed autopsies from 2003 to 2005 on U.S. marines who died in Iraq and Afghanistan. The data obtained have been influ- ential in protecting and treating our troops. For example, researchers determined that having armor that protected the shoulder, back, chest, and side can prevent most fatal injuries (Global Security, 2006; Gutierrez, 2009); this resulted in the development of more efficient body armor for military personnel by the Depart- ment of Defense (DoD) (GAO, 2007). Body scans of those subjects revealed that the needles and tubes inserted into soldiers suffering from collapsed lungs were too small for about half of military personnel. That finding led the DoD to switch to thicker tubing to penetrate collapsed lungs for treatment (GAO, 2007; New York Times, 2009). Finally, specimens that have been archived at AFIP have been used to describe rare diseases, such as papillomatosis (Antila et al., 2008) and hibernoma (Murphey et al., 2004), so that they can be diagnosed more readily. sent to the repository. In recent decades, information accompanying most accessions in the Central Collection includes patient name, Social Security number,3 date of birth, repository accession number, surgical number, type of specimen, contributor's4 health care facility, and specialty branch num- 3Social Security numbers were first assigned in late 1936 (Social Security Administration, 2012). 4Contributor, in the repository's parlance, is the medical professional (often, a pathologist) who submits the specimen for consultation or storage, not the person from whom the speci- men was obtained.

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24 FUTURE USES OF THE DOD JPC BIOREPOSITORY bers associated with the consultation. The specimens themselves typically are labeled with at least two identifiers: the surgical number and the acces- sion number (Baker personal communication, 2011a). Other information that may also be associated with the sample includes age, sex, race, ethnic- ity, the contributor's working diagnosis, and details of the patient's clinical history--location and size of tumor, symptoms, duration of illness, physical and laboratory findings, type and date of surgeries, and other treatments (Baker personal communication, 2011a). Data related to specimens in the BRAC Collection vary because the submitting military treatment facility, rather than the repository, deter- mined which information was collected. It usually includes patient name, facility where the specimen originated, surgical number, and diagnosis (Baker personal communication, 2011a). Some of that information has been entered into the repository's database; other parts are available only in paper records, almost all of which had been captured in portable document format (PDF) by late 2011 (Baker personal communication, 2011a). Those data were received in paper form and then, in more recent years, either coded electronically or stored in image form. The database that contains them allows records to be searched for information on a particular person and for research, statistical, and inventory-management purposes. For the last several years, material submission has been routinized through the use of a Contributor's Consultation Request Form (JPC, 2011). The most recent version of the form, a PDF with a March 31, 2011, date stamp, is reproduced in Appendix C. It includes two items pertinent to the future use of specimens. The first is the biorepository's specimen-retention policy: 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. 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. 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. [emphasis added]

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INTRODUCTION AND BACKGROUND 25 The second is a Privacy Act Statement, which includes notification that submitted material may be used for research: 1. AUTHORITY: 5 U.S.C. 301 and 10 U.S.C. 176, 5 U.S.C. 552a, 10 U.S.C. 1079b. 2. PRINCIPAL PURPOSES: Medical information received is consid- ered during the consultative process and is used to form a database for education and research in pathology. Other patient information is used for filing and retrieval of consultation records. Information concerning the contributor is used to maintain contributor mailing lists. 3. ROUTINE USES: a. In addition to those disclosures generally permitted under 5 U.S.C. 552a(b) of the Privacy Act, these records or informa- tion contained therein may specifically be disclosed outside the DoD as a routine use as follows. b. Pathology consultation records are tracked in the Pathology Informa tion Management System database for filing and re- trieval of records, medical research, and statistical purposes. Individual consultation records may be released to the con- tributing medical care provider (physician, veterinarian), when required by law or as otherwise permitted by 45 C.F.R. 164. c. The DoD `Blanket Routine Uses' set forth at the beginning of the Army's compilation of systems of records notices also apply to this system. d. Pathology consultation records contain individually identifiable health information. The DoD Health Information Privacy Regu- lation (DoD 6025.18-R) issued pursuant to the Health Insurance Portability and Accountability Act of 1996, applies to most such health information. DoD 6025.18-R may place additional procedural requirements on the uses and disclosures of such information beyond those found in the Privacy Act of 1974 or mentioned in this Privacy Act Notice. 4. PROVISION OF INFORMATION: The provision of patient in- formation requested on this form is voluntary. However, if the information is not furnished, a consultation may not be possible. If so, the material submitted may be returned at the discretion of the JPC without a consultation. [capitalization in original] The committee was able to locate versions of the Contributor's Consulta- tion Request Form dated as far back as July 1995 that contain similar lan- guage; the JPC was unable to say how long before then such notifications to contributors had been in place.

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26 FUTURE USES OF THE DOD JPC BIOREPOSITORY The JPC does not have documentation regarding any consent forms signed by patients or research participants whose data or specimens were submitted to the repository (Baker personal communication, 2011a). Such consents may have been obtained for clinical procedures used to excise specimens at facilities where people received medical care, but it is highly unlikely that they included notification that the specimens could be sent to a remote repository or used later for education or research purposes. Con- sents for research use may have been obtained for some materials gathered for the war or cohort registries, but the JPC has no documentation on these (Baker personal communication, 2011a). The repository has a long history of conducting and collaborating on research, examples of which are highlighted in Box 1-1. In 2009, AFIP had 145 active research protocols (Baker personal communication, 2011b). Seventy-three (73) of these were internal to the institute, with no external collaborators. The remaining 72 protocols were collaborations with inves- tigators in a wide variety of settings: 3 U.S. Air Force 21 U.S. Army 17 Uniformed Services University of the Health Sciences (USUHS) 13 multi-agency collaboration (all federal agencies) 11 civilian academic universities 4 private-sector pharmaceutical or medical device companies 3 civilian hospitals ORIGIN OF THE STUDY AND STATEMENT OF TASK The DoD in 2010 asked IOM to conduct a study of the appropriate use of the biospecimens to be maintained by the JPC. It noted that the mission of the center includes support of two primary collections--the pathology material accumulated by AFIP in the course of its clinical, education, and research activities (the Central Collection) and pathology material from DoD military treatment facilities closed under the BRAC program (the BRAC Collection)--and other materials, such as the war and cohort regis- tries (Baker, 2011). The DoD tasked the committee with addressing several questions: 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 ad- vantages and disadvantages should be considered in defining the potential users of the repository in research?

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INTRODUCTION AND BACKGROUND 27 What are the ethical and legal considerations regarding utilization of the tissue repository in support of clinical care and education? 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 dis- posal of said specimens? Should the BRAC Collection of materials be maintained indefinitely? Can tissue collected for clinical use be used for research (i.e., from patients not specifically consented for use of tissue in research)? What are the ethical considerations regarding use of tissues origi- nally submitted for clinical use for research and can this be accom- plished within current accepted guidelines for clinical research? The tissue repository currently contains consult material from both federal facilities as well as that submitted for consultation by civil- ian providers. Can tissue within the repository from civilian pro- viders be utilized in the same manner as that from federal facilities? What considerations should be given to utilization for research of unique, one-of-a-kind, material within the Central Collection of the tissue repository? What existing or emerging technologies (either as an intrinsic func- tion or through partnership) should be considered in developing a plan for utilization of the tissue repository in research and how would they potentially affect the mission of the JPC? The DoD indicated that it would use the committee's input to inform future policy. THE COMMITTEE'S APPROACH TO ITS TASK The committee conducted an extensive examination of research on the scientific, legal, and ethical issues surrounding the management and use of biorepository resources in the course of its work. It did not review all such literature but attempted to cover the work that it believed to have been influential in shaping policy and practice at the time when it completed its task in mid-2012. Papers and reports reviewed were identified through extensive searches of relevant databases. Committee staff also inspected the reference lists of major papers, books, and reports for relevant citations, and committee members independently identified potential citations on the basis of their expertise. Three public meetings were held in AprilSeptember

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28 FUTURE USES OF THE DOD JPC BIOREPOSITORY 2011 at which JPC staff, invited experts, and other participants presented information for the committee's consideration. The committee visited the biorepository in conjunction with the first of those meetings. Appendix A lists the agendas for the public meetings, the speakers, and their topics. The committee also commissioned an analysis of property and other legal issues as they pertain to human biospecimens (Ossorio, 2012). The resulting paper was a helpful source of references and perspectives for the committee to consider. EARLIER REPORTS ADDRESSING ARMED FORCES INSTITUTE OF PATHOLOGY AND JOINT PATHOLOGY CENTER OPERATIONS Four outside reviews of the tissue repository's operation have been conducted since the BRAC Commission recommendation for disestablish- ment was promulgated. Salient results of the reviews are summarized below. 2005 Consensus Conference Shortly after the AFIP disestablishment announcement was released to the public in May 2005, a consensus conference was convened to evaluate the status and prospects of the repository (Auburn Health Strategies, 2005). Conference panelists at the 2-day August 2005 meeting included representa- tives of government, the private sector, and academic clinical and research pathology communities. The panelists offered a series of observations on the future of the repository. They agreed that it "should be maintained as a vibrant, living entity that permits appropriate access" and stated that a scientific review process should be instituted for obtaining materials from the Repository. The process should assure the quality of the proposed scientific study and the need for the Repository tissue. The review process should be cognizant of present and future needs of military medicine. It is critical to the public health that the Repository should be widely accessible and responsive to the needs of the research community. 2007 U.S. Government Accountability Office Report In response to a request by the Senate Committee on Health, Educa- tion, Labor, and Pensions, the Government Accountability Office (GAO) conducted an analysis of the possible effects of implementation of the BRAC recommendation to disestablish AFIP (GAO, 2007). Although AFIP was tasked to be a central resource for key pathology services, GAO con- cluded that its disestablishment would have a minimal effect on the DoD, VA, and civilian medical communities because the pathology consultation

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INTRODUCTION AND BACKGROUND 29 services that AFIP provided could be obtained from other institutions. It as- serted that the DoD--although recognizing that there would be challenges in finding new ways for government entities to obtain pathology consulta- tions and in managing the repository assets to ensure their continued use in military and civilian research--had yet to formulate strategies to address these issues. GAO noted that the DoD had contracted for an assessment of the repository's assets and their potential for research; the contract resulted in the Asterand (2008) report discussed below. 2008 Asterand Report Asterand, a commercial supplier of human tissue and biofluids, was contracted by the DoD's Uniformed Services University of the Health Sci- ences in September 2007 to assess the accuracy and completeness of the AFIP databases and to analyze the state of the repository's specimens. As part of the effort, the firm offered an estimate of the research and commer- cial value of the specimens and recommendations to improve the collec- tions. Its report was delivered in December 2008 (Asterand, 2008). Asterand's survey found that about 75 percent of requested retrievals of Central Collection cases yielded the correct records and matched the diagnoses that were requested. The information associated with the cases varied (Asterand, 2008, p. 52): All have summary diagnostic sheets with basic clinical information. All include an AFIP diagnostic report, and most include the standard pathol- ogy report from the submitting institution. Autopsy cases almost invari- ably include complete clinical history, pertinent laboratory studies, gross and microscopic descriptions, and diagnostic summaries. Some cases have X-ray images as well. In general, older samples had fewer data associated with them. Asterand also found that some of the documentation associated with some older samples--which exist as microfiches derived from paper records5--was illegible because of the poor quality of the media. Limitations in the read- ability of materials that have been scanned into digital form and changes in pathology nomenclature over the decades also affected the ability to access older specimens with particular characteristics. Asterand's examination of the utility of Central Collection specimens for research purposes yielded mixed results. Over 50 percent of sampled cases had tumor (primary, metastatic, or both) and normal tissue from the same patient--a characteristic beneficial for research on the role of genetics 5Many of these fiche have been converted to digital (PDF) format.

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30 FUTURE USES OF THE DOD JPC BIOREPOSITORY in disease. About 97 percent of 2,773 sampled cases had at least one read- able slide; the most common readability problems in the remainder were dried or cracked mounting media and faded stains. Accompanying records identified the correct lesion in 94 percent of the roughly 2,700 slides that were spot-checked by pathologists. The state of formalin-fixed, paraffin- embedded (FFPE) tissue blocks depended on the age of the samples. Three- fourths of specimens from 19171969 (541 examined), about half of those from 19701999 (505 examined), and one-fourth of those from 19992002 (83 examined) had at least one aberration that impaired analysis; desicca- tion was identified as a problem in most of the aberrant samples. That may have been a result of storage conditions. Until the mid-1980s, the collection was housed in facilities without climate controls, and this led Asterand to comment that "considering the typical Washington DC summer weather, there were detrimental effects of heat and humidity on some samples stored under these conditions" (p. 9). Immunohistochemical analysis--performed on 377 samples represent- ing the period 19172002--found that a high level of simple antigenicity had been preserved with "no evidence of time-dependent decrease in spe- cific staining" (p. 91). The vast majority of wet tissue specimens examined were in poor condition. More than 99 percent of the 338 specimens from 19171969 were completely desiccated, as were over 72 percent of the 218 from 19702002. Asterand observed that "it is unclear whether desiccated tissue samples can be rehydrated to restore cellular architecture and ready the tissues for future studies" (p. 92). It noted that the volume of tissue stored with a case decreased over time and that although "many samples have sufficient volume to provide tissues for various research projects" (p. 89), "limits in sample size or retention [in materials collected after 1980] may preclude further study" (p. 116). The BRAC Collection of materials, consisting of medical records and tissue specimens transferred to the repository for storage and maintenance from closed military health facilities, were evaluated separately. Documen- tation related to these materials consists primarily of digitized copies of paper case reports, and there may be multiple discrete reports for a given person. The type and amount of information available varies from between records and between facilities. Importantly, there is no diagnosis field coded in the collection database. Those characteristics make it relatively difficult and time-consuming to retrieve specific information from the collection and limit its potential for research use. Asterand's analysis of BRAC Collection specimens was limited to 13 of the 24 closed facilities stored in the repository at the time of the survey. It found that 99 percent of the roughly 9,000 slides examined were readable and that 98 percent of diagnoses associated with the slides were correctly linked with their pathology record. Of the 617 FFPE blocks that were

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INTRODUCTION AND BACKGROUND 31 evaluated, 64 percent had at least one aberration that would limit research utility; air bubbles in the paraffin were the most prevalent aberrations. By and large, Asterand found "sufficient tissue for a variety of experimental procedures" (p. 110). Asterand estimated the commercial value of the collections by extrapolat- ing survey results regarding the accessibility of relevant data and viability of tissues to the entire repository and applying its knowledge of the market for specimens. Its most conservative estimate--based on the current state of the collection, accessibility of the materials to requesting parties without restric- tion, and the provision of complete tissue blocks (that is, without preser vation of any portion for future use)--was about $1.4 billion.6 The report concluded that "the greatest strengths of the Central Re- pository for research and educational purposes lie in the breadth and depth of its materials and in the potential for developing cohorts for rare and unusual diseases" but that both it and the BRAC Collection "are in need of better data organization and enrichment of patient clinical information (particularly follow-up) [and that] each would benefit from selection and development of disease-based cohorts of cases with adequate amounts of representative stored tissues" (pp. 117118). Asterand offered several recommendations for maximizing the value of the repositories, indicating that these were predicated on "the understand- ing that the value of the collections can only be realized through permitting widespread access" (p. 133). They included assessing "the retrievability and quality of the RNA of tissues in both the Central and BRAC repositories to further refine the precise value and potential utility of the repositories for research" and discarding samples that have no usable tissue or have dete- riorated to the point where they can no longer be used. 2008 Defense Health Board Review In June 2008, the DoD asked the Defense Health Board (DHB)--an independent federal advisory committee tasked with providing the military with advice and recommendations on health-related issues--to review its strategic plan for the establishment of the JPC and offer its opinion on the plan's appropriateness and feasibility (Parisi, 2008). The board delivered its conclusions in December of that year (DHB, 2008). The DHB offered a series of observations and recommendations regard- ing the JPC's scope of service, governance, and organizational structure. It expressed the strong belief that "the Tissue Repository is a national treasure 6This estimate should be viewed skeptically because the anecdotal experience of other bio- repositories indicates that their presumed value as research materials sources was not borne out in practice (Silberman, 2010).

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32 FUTURE USES OF THE DOD JPC BIOREPOSITORY and resource from which significant potential for research and advances in medical care will result" (p. 8). However, the report counseled the DoD "to consider the legal issues that may arise in situations where non-DoD entities may have access to and utilize some of these assets," stating (DHB, 2008, p. 5) that it is essential that the plan clearly delineate the access and usage limits of the resources available through the Tissue Repository. The Board advises DoD to thoroughly define the route of access to specimens for civilian sec- tor research and include a direct communication mechanism to ensure a facilitated process for interagency and civilian avenues of approach. NATIONAL ACADEMY OF SCIENCES REPORTS ADDRESSING RELATED TOPICS A number of National Academy of Sciences reports have addressed topics relevant to the issues under consideration here. Salient publications are summarized below. Monitoring Human Tissues for Toxic Substances (NRC, 1991) de- scribed the benefits of using tissue specimens to evaluate the health effects of exposures to chemicals in the environment. The report described the need for quality control in maintaining biospecimens in the short term and the long term. It noted that "access to specimens in an archive must be carefully controlled" and that "in each case, it must be determined whether a pro- jected use will provide useful data and its value must be balanced against the need to maintain specimens for future studies" (p. 106). Effect of the HIPAA Privacy Rule on Health Research (IOM, 2006), the proceedings of a workshop, evaluated the rule's impact on research, including considerations regarding the bureaucracy, informed consent, and clinical trials. A participant observed that the Common Rule has been inter- preted to permit broad research consents whereas the Privacy Rule requires study-specific consents and that this often led to confusion in the research community. A resulting suggestion was to allow both broad and specific consent of biospecimen preservation, maintenance, and use under HIPAA. Beyond the HIPAA Privacy Rule: Enhancing Privacy, Improving Health Through Research (IOM, 2009) assessed whether the HIPAA Privacy Rule was having an effect on health research and offered recommendations to promote efficient health research while maintaining the privacy of person- ally identifiable health information. The report stated that the Privacy Rule did not protect privacy as well as it should and that it was hindering effec-

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INTRODUCTION AND BACKGROUND 33 tive and efficient health research. Its recommendations included improving data and privacy security and the proper application of privacy protections. Conducting Biosocial Surveys: Collecting, Storing, Accessing, and Protecting Biospecimens and Biodata (NRC, 2010) evaluated the best approaches to the collection, storage, use, and sharing of biospecimens gathered in social-science surveys and studies. The committee recommended that potentially sensitive data or data that could be used to identify a particular research subject should be shared only under very restricted circumstances and only if the data have been encrypted. The report also recommended that the National Institutes of Health develop procedural standards that would maintain the privacy of data held in repositories, including the use of informed consents. Establishing Precompetitive Collaborations to Stimulate Genomics- Driven Drug Development (IOM, 2011) summarized the results of a July 2010 workshop convened to elucidate a conceptual framework for the sharing of stored biospecimens and associated data by academe, industry, government, and other stakeholders. Speakers emphasized that high-quality data can be derived only from high-quality biospecimens. Workshop partic- ipant Carolyn Compton, a member of the present committee, noted that the salient question was not "Can I get access to existing samples?" but "Do I want them?" Highly variable specimen quality and lack of consent for research use were among the other identified barriers to effective research. ORGANIZATION OF THIS REPORT The remainder of this report is divided into three chapters and sup- porting appendixes. Chapter 2 addresses the determinants of the research value of biospecimens held in repositories, concentrating on scientific and technical considerations. It begins with a summary of the means by which specimens are preserved and an explication of the education, clinical care, and research uses to which they are put. The text then describes the tech- nologies used to manage specimen and data acquisition and to maintain and analyze specimens and data. It concludes with a discussion of the scientific and technical limitations on using in research samples that were originally obtained for pathology purposes. Legal, ethical, and regulatory considerations regarding the use of re- pository specimens in clinical care, education, and research activities are taken up in Chapter 3. It begins with a general discussion of these consid- erations and previous scholarly work concerning them. The text then ad- dresses considerations regarding the source of specimens, before finishing with an examination of the federal laws and regulations, DoD rules, and

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34 FUTURE USES OF THE DOD JPC BIOREPOSITORY AFIP and JPC regulations regarding research on biospecimens and their associated data. Chapter 4, the final chapter, builds on the foundation of the foregoing to draw out the overarching themes of the report and presents the com mittee's findings, conclusions, and recommendations related to its statement of task. Agendas of the public meetings held by the committee are provided in Appendix A. Appendix B contains a reproduction of the latest (as of the time this report was completed) version of JPC's Contributor's Consultation Request Form. DoD Instruction 3216.02, which delineates the military's rules regarding the protection of human subjects and adherence to ethical standards in DoD-supported research, is reproduced in Appendix C. Bio- graphic information on the committee members and staff responsible for this study are provided in Appendix D. REFERENCES AFIP (Armed Forces Institute of Pathology). 2011. The AFIP Letter 169(1). Antila KM, Mkisalo H, Arola J, Numminen K. 2008. Best cases from the AFIP: Biliary papillomatosis. Radiographics 28(7):2059-2063. 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. Auburn Health Strategies. 2005. AFIP tissue repository consensus conference. Consensus confer ence statement. August 30-31, 2005. http://www.auburnstrat.com/news/tissueconsensus905/ (accessed January 5, 2012). Baker personal communication. 2011a. 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 personal communication. 2011b. 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. November 28, 2011. A copy of this document is available from The National Academies Public Access Records Office. Baker TP. 2011. The Joint Pathology Center. April 21, 2011 presentation to the Committee on the Appropriate Use of the Armed Forces Institute of Pathology's Tissue Reposi- tory Follow ing Its Transfer to the Joint Pathology Center. Washington, DC: Institute of Medicine. Defense Base Closure and Realignment Commission. 2005. The 2005 Defense Base Closure and Realignment Commission report. Arlington, VA: Defense Base Closure and Realign- ment Commission. DHB (Defense Health Board). 2008. Defense Health Board Review of the Joint Pathol ogy Center work group concept of operations for the establishment of the Joint Pathology Center. Memorandum dated December 19, 2008. http://www.health.mil/ dhb/recommendations/2008/DHB%20Review%20of%20ConOps%20for%20the%20 Establishment%20of%20the%20JPC.pdf (accessed January 17, 2012).

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