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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, Mäkisalo 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).
OCR for page 35
INTRODUCTION AND BACKGROUND 35
GAO (U.S. Government Accountability Office). 2007. Military base realignments and closures:
Impact of terminating, relocating, or outsourcing the services of the Armed Forces Insti
tute of Pathology. GAO-08-20, Dec 10, 2007. Washington, DC: GAO.
Global Security. 2006. Statement of Major General William D. Catto, Commanding General,
Marine Corps Systems Command, before the House Armed Services Committee Tacti
cal Air and Land Forces Subcommittee and Readiness Subcommittee on Marine Corps
Body and Vehicle Armor. http://www.globalsecurity.org/military/library/congress/2006_
hr/060201-catto.pdf (accessed March 27, 2012).
Gutierrez JT. 2009. The modular tactical vest: A case study in success and failure. Quantico,
Virginia: United States Marine Corps.
Henry RS. 1964. The Armed Forces Institute of Pathology. Its first century. 1862-1962. Wash-
ington, DC: Office of the Surgeon General, U.S. Army.
IOM (Institute of Medicine). 2006. Effect of the HIPAA privacy rule on health research: Pro
ceedings of a workshop presented to the National Cancer Policy Forum. Washington,
DC: The National Academies Press.
IOM. 2009. Beyond the HIPAA privacy rule: Enhancing privacy, improving health through
research. Washington, DC: The National Academies Press.
IOM. 2011. Establishing precompetitive collaborations to stimulate genomics-driven drug
development. Washington, DC: The National Academies Press.
JPC (Joint Pathology Center). 2011. Contributor's Consultation Request Form. Form coded
with a creation date of 03/31/2011. http://www.jpc.capmed.mil/docs/consultation_
request_form.pdf (accessed January 23, 2012).
JPC. 2012. The Joint Pathology Center (JPC). http://www.jpc.capmed.mil (accessed January 15,
2012).
McCook A. 2011. Death of a pathology centre: Shelved. Nature 476:270-272.
Morens DM, Taubenberger JK, Fauci AS. 2008. Predominant role of bacterial pneumonia as a
cause of death in pandemic influenza: Implications for pandemic influenza preparedness.
Journal of Infectious Diseases 198(7):962-970.
Murphey MD, Carroll JF, Flemming DJ, Pope TL, Gannon FH, Kransdorf MJ. 2004. From
the archives of the AFIP: Benign musculoskeletal lipomatous lesions. Radiographics.
24(5):1433-1466.
New York Times. May 25, 2009. Autopsies of war dead reveal ways to save others. http://
www.nytimes.com/2009/05/26/health/26autopsy.html (accessed March 27, 2012).
NRC (National Research Council). 1991. Monitoring human tissues for toxic substances.
Washington, DC: National Academy Press.
NRC. 2010. Conducting biosocial surveys: Collecting, storing, accessing, and protecting bio
specimens and biodata. Washington, DC: The National Academies Press.
Ossorio PN. 2012. Property and intellectual property considerations affecting the Armed
Forces Institute of Pathology's Tissue repository following its transfer to the Joint Pathol
ogy Center. Paper commissioned by the Committee on the Review of the Appropriate
Use of AFIP's Tissue Repository Following Its Transfer to the Joint Pathology Center.
Parisi JE. 2008. Defense Health Board (DHB) Review of the Department of Defense (DoD)
concept of operations (ConOps) for the establishment of the Joint Pathology Center (JPC).
PowerPoint presentation. http://www.health.mil/dhb/downloads/2008_DEC_1/08_Parisi_
Report%20for%20DHB%20Dec%2008%20FINAL.pdf (accessed January 17, 2012).
Saunders LZ, Barron CN. 1970. A century of veterinary pathology at the A.F.I.P., 1870-1970;
Dr. Woodward on Bovine Pleuropneumonia. Pathologia Veterinaria 7:193.
Silberman S. 2010. Libraries of flesh: The sorry state of human tissue storage. Wired. May 24,
2010. http://www.wired.com/magazine/2010/05/ff_biobanks/all/1 (accessed January 18,
2012).
OCR for page 36
36 FUTURE USES OF THE DOD JPC BIOREPOSITORY
Social Security Administration. 2012. Social Security history. Frequently asked questions.
http://www.ssa.gov/history/hfaq.html (accessed January 23, 2012).
Starko KM, Mullick FG. 1983. Hepatic and cerebral pathology findings in children with fatal
salicylate intoxication: Further evidence for a relation between salicylate and Reye's
syndrome. Lancet 321(8320):326-329.
Stone P. 2011. Legacy of excellence. The Armed Forces Institute of Pathology, 18622011.
http://www.bordeninstitute.army.mil/other_pub/loe.html (accessed December 28, 2011).
Taubenberger J, Hutlin J, Morens D. 2007. Discovery and characterization of the 1918 pan-
demic influenza virus in historical context. Antiviral Therapy 12(4 Pt B):581-591.
U.S. Army Surgeon General's Office. 1861-1865. The medical and surgical history of the war
of the rebellion. 6 Volumes. Washington, DC: U.S. Government Printing Office.
U.S. Surgeon General. 1920. Annual report of the Surgeon General of the Public Health Ser
vice of the United States for the fiscal year 1920. Washington, DC: GPO.
Woodward J. 1865. On the use of aniline in histological researches, with a method of investi-
gating the histology of the human intestine and remarks on some points to be observed
in the study of the diseased intestine in camp fevers and diarrheas. American Journal of
Medical Sciences 49:106-113.
