VA San Diego Health Care System
Institutional Review Board
INQUIRY of CONCERNS
HUMAN SUBJECT RESEARCH PROTOCOL H120108
October 19, 2018

 CONTENTS
page
I.

Introduction and Review Method

1

II. Protocol Overview

1

III. Concerns, Findings, and Conclusions

2

A.
B.
C.
D.

Concern #1:
Concern #2:
Concern #3:
Concern #4:

Acquisition of Samples Prior to Clinical Use
PI Altered Clinical Sample Compromising Diagnosis
Research Staff Altered the Clinical Sample Compromising Standard of Care
Research Study Compromised Clinical Care

IV. Remedial Actions and Recommendations
APPENDIX A: Investigative Charge Letter Relevant excerpts from protocol H120108
APPENDIX B: InTeam Sample Preparation Instructions

2
4
5
7
8

A-1
B-1

 VASDHS INSTITUTIONAL REVIEW BOARD
INQUIRY of CONCERNS
HUMAN SUBJECT RESEARCH
PROTOCOL H120108
I. Introduction and Review Method
The VASDHS Institutional Review Board (IRB) serves as the primary IRB of record for human
subject research conducted under VASDHS Federalwide Assurance (FWA00001893).
The VASDHS IRB was charged with investigating concerns related to research conducted
under VASDHS IRB approved protocol H120108 titled, “Integrated Approaches for Identifying
Molecular Targets in Alcoholic Hepatitis” (InTEAM). The apparent concerns were submitted
to the VASDHS Chief of Staff, who forwarded the allegations to the IRB with a request for
review.
The purpose of this review was to evaluate each concern and if a concern was substantiated,
in part or in full, to determine whether protocol or policy violations occurred, whether there
was any risk posed to subjects or others, and to provide recommendations to VASDHS
Leadership regarding each of the concerns.
To facilitate the fact-finding portion of this inquiry, the IRB established a review team
consisting of an IRB voting member, an Human Research Protection Program Analyst, and the
Director of the Research Projects Section. The findings were presented to the convened IRB
on October 11, 2018, for review and determination.
The IRB’s review included individual interviews with the Principal Investigator (PI), primary
Study Coordinator, Chief, Pathology and Laboratory Medicine Service (PALMS), Interventional
Radiology, and review of the referenced protocol, research records, and medical records
pertaining to research activities of subjects enrolled in this study.

II. Protocol Overview
InTEAM is a 10-site multicenter National Institutes of Health funded research program to
study alcoholic hepatitis.
VASDHS patients who have suspected alcoholic hepatitis and who meet study related
inclusion/exclusion criteria are eligible to participate in the study. The purpose of this study is
to collect and preserve samples of blood, urine, stool, and liver tissue from patients with
alcoholic hepatitis to be used in future research studies. The purpose of future studies using
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 these samples will be to develop new methods for diagnosing alcoholic hepatitis and its
complications, to develop new markers for disease severity, and to identify new targets for
improved therapy. The Liver Center of the Division of Digestive Diseases at the University of
North Carolina is the program lead for this project and is responsible for management of the
biorepository.
The local study, identified as Protocol H120108 titled, “Integrated Approaches for Identifying
Molecular Targets in Alcoholic Hepatitis” (InTEAM) was initially approved by the VASDHS IRB
on March 6, 2013.
At the time of this review, 41 VASDHS patients had been enrolled in the study including 19
control subjects and 22 subjects with diagnosis or suspected diagnosis, of alcoholic hepatitis.
Research Records documented that the PI had obtained liver biopsy specimens from 9 of the
22 subjects with alcoholic hepatitis between September 2014 and December 2016. It is noted
that the PI of record during this period retired from the VA in June 2018, and the former CoInvestigator has assumed the role of PI.

III. Concerns, Findings, and Conclusions
The VASDHS IRB was requested to review and evaluate four specific concerns.
A. Concern #1: Acquisition of Samples Prior to Clinical Use
Concern that research (liver) samples were being acquired under the guise of excess samples
from clinical standard of care before they were provided to and used by Pathology for
standard of care diagnostic purposes.
Findings
1. VHA Handbook 1106.01 §3.a(2)j stipulates that the Chief, PALMS “provides oversight for
all laboratory testing performed under the medical center/health care system.” The
Chief, PALMS confirmed that PALMS is responsible for management, oversight, and
distribution of archival samples remaining after clinical testing is completed.
2. The IRB’s understanding of the definition of an archival sample is tissues remaining after
clinical use and diagnosis has been completed, i.e., excess sample. Archival samples
would not include additional tissue collected specifically for research purpose. PALMS
concurred with the IRB’s understanding of archival samples and further informed that if a
portion of a clinical sample is needed for research that sample may only be provided by
PALMS after clinical processing is complete.
3. The IRB confirmed with PALMS that archival samples were not requested by or provided
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 to the PI for use in this study.
4. Versions 1.16 and 1.17 of Protocol H120108 1 document in §5, 9, 9.1, 9.6, 9.7b, and 10 that
if a liver biopsy was done as part of standard of care, the PI would request access to the
archival samples for research purposes. [See Appendix A.]
5. VASDHS Medical Center Memorandum (MCM) 113-03 further establishes local policy and
procedures for collecting and processing laboratory specimens for diagnostic purposes.
MCM 113-03 defines research specimens as any “specimen collected for the purpose of
internal or external research approved through the appropriate committees and IRB.”
6. The IRB established the following regarding local collection and processing of liver
biopsies for clinical diagnosis of alcoholic hepatitis: (a) liver biopsies are generally
performed by Interventional Radiology (IR); (b) IR places the clinical sample in a prepared
and labeled vessel containing formalin fixative; (c) the specimen is transported to PALMS
by a designated escort, who is responsible to sign upon delivery; and (d) PALMS takes
custody and is responsible for clinical testing, any requests for archival tissue for research
purposes are processed after clinical testing is complete.
7. Medical records documented that IR performed the liver biopsies for the nine subjects
associated with this study and that all procedures were ordered as clinically indicated
procedures.
8. The PI and study coordinator confirmed that for the nine specimens obtained for this
study, all were obtained directly from IR. Therefore, these were not archival samples as
indicated in the IRB approved protocol since clinical testing had not been completed.
9. IR reported that the study coordinator notified when patients enrolled in this study were
scheduled for a liver biopsy. Prior to the patient’s procedure, the study coordinator
provided a prelabeled specimen tube to IR for the sample. IR further reported that if in
the judgement of the surgeon, sufficient tissue was obtained for clinical purposes and it
was deemed safe for the patient, an additional sample was obtained for research. The
clinical specimen was processed in accord with standard clinical procedures and the
research specimen was placed in the vial provided by the study coordinator and retrieved
by the PI.
Conclusion
This review substantiated that the IRB approved protocol described acquisition of excess
clinical samples for this research study. Specifically, the protocol consistently documented
that archival samples would be obtained.
1

Versions 1.16 and 1.17 were the IRB approved protocol versions between September 2014 and December 2016 when
liver biopsy samples were obtained for this study.

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 The review did not substantiate the concern that a portion of the clinical specimen was
provided for research purposes prior to use by Pathology for standard of care diagnostic
purposes. Instead, the IRB found that a research specimen was obtained independent of the
clinical sample after the IR surgeon determined that a sufficient specimen was obtained for
clinical purpose.
Nevertheless, the IRB found that the neither protocol nor ICD adequately described the
collection of the research specimen independent of the clinical specimen. Potential risks
associated with this finding are discussed in Concern #3.
B. Concern #2: PI Altered Clinical Sample Compromising Diagnosis
Concern that the PI changed the size of the liver biopsy available to Pathology. Included in
this concern was implication that this was a violation of the IRB, and may have limited
Pathology’s ability to make a diagnosis thus compromising patient care.
Findings
1. As established in Concern #1, IR performed the liver biopsies for the nine subjects
associated with this study. IR reported that the PI was not present during any of the
associated procedures and did not have access to the clinical sample. IR and Pathology
records documented the collection and transfer of custody of the specimens between
these Services.
2. Regarding the size of a clinical specimen, PALMS and IR reported that there is not an
established minimum/maximum volume of liver tissue required for clinical testing. IR
informed that the sample size and number of cores obtained is variable and depends on
the professional judgement of the surgeon to assess a “good sample.” The IRB confirmed
through review of IR and Pathology reports for the nine subjects, up to five cores were
collected and specimen samples sent to pathology were comprised of one to four cores
per patient.
3. IR reported recalling at least one occurrence when a research sample was requested, but
was not provided because the surgeon did not obtain what was considered more than
sufficient for clinical purposes. The IRB confirmed through review of CPRS and research
records that subjects P002 and P003 were enrolled in the study at the time of a clinically
indicated biopsy but a sample was not provided to the PI for research purpose. The
records did not document why a research sample was not obtained.
4. MCM 113-03 requires and the Chief, PALMS confirmed that if an insufficient or otherwise
inadequate sample was received that would impair or limit the unit’s ability to make a
diagnosis, this must be documented and would be included in the pathology report. The
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 IRB reviewed pathology records for the nine subjects. Records for all nine subjects
contained a clear testing outcome and none documented any concern regarding the
specimen quality or difficulty in establishing a diagnosis.
Conclusion
This review did not substantiate that the PI changed the size of the liver biopsy available to
Pathology. Instead, the review confirmed that the PI did not have access to the clinical
sample after it was obtained by IR and transported to PALMS for processing. The review
found that the IR surgeon was responsible for ensuring that a sufficient clinical specimen was
obtained prior to provision of tissue for research purpose. The IRB did not substantiate that
PALM’s ability to make a diagnosis was compromised.
It is noted that if the PI had altered the clinical sample, this would have represented a
violation of clinical practices, not a violation of the IRB. The IRB does not have review or
oversight responsibility for clinical practices or procedures.
C. Concern #3: Research Staff Altered the Clinical Sample Compromising Standard of Care
Concern that the PI had his clinical coordinators go to Radiology and cut a piece from the liver
biopsy during the procurement procedure BEFORE the biopsy was fixed and sent to
Pathology. This was done because a frozen biopsy is optimal for the research, and is alleged
to be a serious IRB violation. As a result, the realistic turn-around time for the diagnosis using
these samples could not be standard of care.
Findings
1. As previously established, IR performed the liver biopsies for the nine subjects associated
with this study. IR reported that neither the PI nor the study coordinator was present
during any of the associated procedures and these individuals did not have access to the
clinical sample. IR and Pathology records documented the collection and transfer of
custody of the specimens between these Services.
2. IR and PALMS confirmed that liver specimens for clinical diagnosis of alcoholic hepatitis
are deposited into prelabeled specimen containers containing a fixative solution.
3. IR and the study coordinator informed that when patients enrolled in this study were
scheduled for a clinically indicated liver biopsy, the study coordinator was responsible to
bring a prelabeled specimen tube to IR. The PI and study coordinator confirmed that the
collection container for research did not contain fixative solution and this was in accord
with the master protocol’s collection guidelines.
4. A review of the IRB protocol file found the following:
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 a. H120108 Versions 1.16 and 1.17 were silent regarding whether the research sample
would be obtained as fixed or unfixed tissue. Nevertheless, as previously established,
both versions of the protocol described receipt of archival samples for research
purposes. It is understood through this review that clinical (liver) biopsy specimens
are fixed and, therefore, the archival samples would consist of fixed tissue. However,
it is not apparent whether this was known by the IRB at the time of review/approval.
b. A February 24, 2014, dated version of the “Master Protocol,” 2 which was submitted as
a component of an April 10, 2014, IRB approved study amendment adding a control
group, documented that the biopsies would be placed in formalin containers and
unfixed tissue would not be obtained. Specifically, the document noted that the “local
protocol does not call for freezing a portion [of the specimen]. If this were done it
would be immediately frozen in liquid nitrogen and stored at -80C and later sent to
the Human Biorepository Core…”
c. The June 2, 2014 approved Informed Consent Document (ICD), which was signed by
the nine subjects from whom liver biopsy tissue was obtained, informed that a portion
of the patient’s clinical biopsy may be collected for research purposes. [See Appendix
A.] The ICD did not inform that additional tissue may be taken or address whether
there were any additional risks related to the biopsy procedure (i.e., in addition to
risks identified within the clinical consent for this procedure).
d. A July 21, 2014, dated version of the Master Protocol, which was submitted as a
component of a September 30, 2014, IRB approved study amendment altering
eligibility requirements, documented that the biopsies would be unfixed and placed in
either sterile saline or RNALater® solution.3 [See Appendix B]
Conclusion
This review did not substantiate that the PI’s research staff altered the clinical biopsy.
Instead, the review confirmed that research staff did not have access to the clinical sample.
The review found that the IR surgeon was responsible for ensuring that a sufficient clinical
specimen was obtained prior to provision of tissue for research purpose and that the clinical
sample was appropriately transported to PALMS for processing.
The review substantiated that the research specimens were obtained as unfixed samples.
Since the master protocol describes preparation of unfixed frozen samples, the IRB concluded
that frozen biopsy specimens were likely optimal for the research project. However, since the
2

Multisite studies frequently utilize a Master Protocol that describes study expectations at all performance sites and
serves as a basis for the local site investigator to request local approval. The VASDHS IRB does not approve “Master
Protocols”, rather the PI is responsible to disclose in the local IRB application all work that will be conducted at this site.

3

The amendment request did not mention a change in handling or processing of the research sample.

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 local IRB approved protocol described use of “archival samples” without specifying that these
were unfixed samples, the IRB concluded that a protocol omission had occurred. The IRB
further concluded that the consent form omitted information related to potential risks
associated with taking more tissue than would have been taken for clinical diagnosis.
In consultation with IR, the IRB understands that the procedural risks delineated in the clinical
consent would have been slightly higher for patients from whom additional tissue was
removed for research. However, IR explained to the IRB reviewers that a transjugular biopsy,
which was the method used for the nine subjects, uses a smaller core to obtain the specimen
than a percutaneous liver biopsy. The smaller core requires more cores be obtained to secure
a sufficient sample for pathology, but also carries less risk of bleeding and other
complications. The method of collection was not determined based on the patient’s
participation in the study, but rather what was clinically indicated for the patient’s care.
Nevertheless, the research consent form should have informed patients of the elevated risk
of procedural complications associated with the tissue obtained for research purpose. IR
records did not document that any procedural complications had occurred in association with
the procedures for the nine subjects.
The review did not substantiate that the ability to make a diagnosis was compromised.
Instead, the review found that the clinical sample was obtained and handled in accord with
standard of care practice. Therefore, the turn-around time for diagnosis was not affected by
the subjects’ participation in the research study.
D. Concern #4: Research Study Compromised Clinical Care
Concern that this protocol compromises the care of the patient by obtaining the research
sample.
Findings
1. As established throughout this review, this inquiry found that the clinical specimen was
obtained, managed, and processed in accord with standard of care procedures and
patient records document these practices. Patient records and Interviews with IR further
confirmed that all biopsies were clinically indicated.
Conclusion
This review did not find evidence to support the concern that patient care was compromised
by obtaining the research sample.

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 IV. Remedial Actions and Recommendations
Based on the above findings, the IRB made the following recommendations:
1. On October 11, 2018, the VASDHS IRB determined that serious noncompliance occurred
by the collection of an independent research specimen instead of use of archival tissue as
described in IRB approved protocol H120108. This finding will be reported in accord with
VHA Handbook 1058.01.
2. The current PI must amend the local protocol and informed consent document to
accurately describe collection of a research specimen in addition to the clinical specimen.
This includes correcting all references to collection of archival samples; ensuring that §9,
9.6, and 25 accurately describe involvement of IR; and ensuring the risks associated with
collection of the research specimen are described in the protocol and in the informed
consent document.
3. The current PI must respond to the IRB acknowledging the serious protocol violation and
describing how protocol compliance will be ensured going forward.
4. The former PI should be notified of the outcome of this review.
5. The Human Research Protection Program (HRPP) will review with the VASHDS Office of
Research Agreements Management (ORAM) to determine whether development of
protocol based inter-service agreements could help assign responsibility and provide
transparency related to research vs. clinical procedures.

Certification on behalf of the VASDHS IRB:

______________________________
William Penny, MD
Chair, VASHDS IRB

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 APPENDIX A
EXCERPTS FROM IRB APPROVED
PROTOCOL H120108 AND CONSENT FORM
Protocol H120108 Versions 1.16 and 1.17:
•

§5 Lay Summary – “If the patients have a liver biopsy in the course of their routine
care, we request that we have access to archival tissue samples for further studies
only.” trouble

•

§9 Design and Methods – “If the patients have a liver biopsy in the course of their
routine care, we request that we have access to archival tissue samples for further
studies only.”

•

§9.1 Clinical Procedures – “If a liver biopsy is done as part of standard of care, we will
request access to the archival samples.”

•

§9.6 Specimens – “If the patients have a liver biopsy in the course of their routine care,
we request that we have access to archival tissue samples for further studies only.”

•

§9.7b Biorepository detail – “If the patients have a liver biopsy in the course of their
routine care, we request that we have access to archival tissue samples for further
studies only.”

•

§10 Human Subjects – “Liver biopsy is not required for this protocol. (The protocol
assures that archival liver biopsy tissue from patients is only used if published guidelines
are followed as specified in AASLD Practice Guideline Hepatology 2010;51:307 and EASL
Practice guideline. J Hepatology 2012;57:399. Specifically, these guidelines state that
the liver biopsy is done to help in clinical decision making for severe alcoholic hepatitis,
that liver biopsies are not done for investigational purposes only, and liver biopsies are
not considered clinically indicated if no treatment for ALD or AH is contemplated.)

Informed Consent Document (ICD) v.2014-06-02:
•

§3 What will happen to you – “If a liver biopsy is done this will be part of your routine
care to make sure of the diagnosis and not part of the research process. However, if
available, a portion of this sample may be collected for research purposes.”

•

§4 Research Procedures – “If liver biopsy specimens are obtained as part of routine
clinical care, a portion of this biopsy may be collected for research.”

A-1

 APPENDIX 

lnTeam Master Protocol 7/21/2014]
Liver Biopsy Processing Procedures

LI HE BICI PST.

 

 

Components: ?ne 5 mL white tope tube. Two prelabeled 2 mL blue top
[Liver Bf Ill-lift} tubes
Also needed: sterile gloves. saline. sterile tweezersfneedle. Fll'lliillaterlt?iI antlir or dry ice.

General Instructions:

El 1. The transjugtdar liver biopsy [we advise the use of tru-cut instead of aspirative
biopsies] is for both clinical and research purposes. A fragment of the liver tissue
[approrc 50% of the cylinder] should be processed for diagnostic purposes using
the local protocol.

El 2. The remaining liver tissue [0.1-0.2 cm is the minimum] shordd be processed for
the lnTeam Human Eiorepository. The liver tissue can be processed in two ways:

Method 1: Frozen

El 1. Liver tissue should be rinsed in saline solution and kept as sterile as possible
throughout the entire process.

El 2. Using sterile tweezers fneedle. transfer the liver tissue to one ofthe prelabled 2
mL blue toped cryovials.

El 3. Liver tissue should be immediately frozen in dry ice.

El 4. Match the 4: di 't code on the blue cap vials and check the
appropriate Co Iected box on each v1al labe on the Specimen Collection Log
Record patient ID.

El 5. Immediately after dispensing liver tissue into vials. blue cap vials should be stored
at or in liquid nitrogen until shi ing.

El 6. Write comments in the space labeled otes g. problems with blood draw.
insuf?cient volume. spills. and identify the speci?c aliquot by the three character
code].

The frozen liver biopsy vials are to be placed into a plastic bag with ai sheet
of absorbent DriMop and shipped on dry ice.

El

Method 2: 

El 1. Liver tissue should be rinsed in saline solution and kept as sterile as possible

throughout the entire process.

El 2. Fill blue cap liver biopsy vial with 1 mL of RNAlaterE?J.

El 3. Using sterile tweezers fneedle. transfer the liver tissue to one ofthe prelabled 2
mL blue toped cgrovials. The cryovial can be kept overnight at room temperature
or a few days at if necessary.

. Match the four digit code on the blue cap vials and check the
appropriate Collected box on each vial label on the Specimen Collection Log.
record atient ID.

5. Store ue cap vials at -2[l?C or until shipping.

6. Write comments in the space labeled Notes g. problems with blood draw.

insuf?cient volume. spills. and identify the speci?c aliquot by the three character
code.

El The 31-2] frozen liver biopsy vials are to be placed into a plastic bag with a sheet

of absorbent DriMop and shipped on dry ice.

El
.42.

El
El

Which method to use:

El 1. If there is ordy enough liver tissue for 1 cryovial. preferably utilize method 1. If
this is not possible. method 2 is permissiblenot available for immediate freezing of the cryovial. utilize Method 2.
We recommend that the FIR personnel have some vials and Rl??laterf?i ready for
use.

El 3. If there is enough liver tissue for more than 1 cryovial. preferably utilize both
Method 1 and 2 if possible. This will allow the most use from our specimens.