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Appendix B
Gene Expression–Based Tests
Developed at Duke University
and Used in Clinical Trials
The emergence of high-throughput omics technologies beginning
around the mid-1990s led to development of new approaches for studying
the dynamics of biological systems. Multidisciplinary collaborations were
formed among molecular biologists, bioinformatics experts, and statisti-
cians at many institutions to devise experimental strategies and statistical
methods for the analysis and interpretation of these rich new sources of
data. At Duke University, researchers were pursuing these new avenues
of research. In 2000, Joseph Nevins and Mike West founded the Com-
putational and Applied Genomics Program (CAGP), a multidisciplinary
research program (Kornbluth and Dzau, 2010). The CAGP formed the
basis for what later became the Center for Applied Genomics and Tech-
nology (CAGT). As one of the initial centers of the Duke Institute for
Genome Science and Policy (IGSP), which was formed in 2003 (Kornbluth
and Dzau, 2010), CAGT researchers used various types of genomic analy-
ses to elucidate potential mechanisms of oncogenesis and to understand
the complexity of cancer phenotypes. DNA microarray analysis became a
powerful tool in the CAGP/CAGT for the study of regulatory pathways
essential for cancer initiation and tumor growth, and researchers devel-
oped several gene expression–based tests to predict patient responses to
chemotherapeutic agents and published the results. At a very early stage
in the discovery research, such tests were taken into clinical trials. The
primary publications were criticized for major problems in data presenta-
tion and statistical analysis. Eventually, concerns were raised by statisti-
cians about the validity of the tests and about potential harm to patients
enrolled in the trials.
239
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240 EVOLUTION OF TRANSLATIONAL OMICS
The Institute of Medicine (IOM) committee’s statement of task refers
to three trials that were conducted at Duke University. Table B-1 outlines
some information related to those trials.
This appendix provides a concise summary of the research objectives
and the approaches taken in developing several of the gene expression–
based chemosensitivity tests implemented in the three clinical trials in
Table B-1, and presents findings that provide important insights about pro-
cesses that were in place at Duke University, to enlighten the development
of and to provide motivation for many of the IOM committee’s recom-
mendations that are intended to enhance the integrity of future omics-
related research. Many of these findings are in key areas that include the
responsibilities of investigators and institutions, conflict of interest issues,
and the roles of funders, regulatory authorities, journals, and biostatistical
collaborators.
DEVELOPMENT AND EVALUATION PROCESS
Investigators are responsible for systematic and rigorous development
of omics-based tests. Chapters 2, 3, and 4 explain the IOM committee’s
recommendations on omics-based test discovery, development, and evalu-
ation for clinical use. These recommendations are meant to help establish
a process, agreed on by all collaborating disciplines, for the discovery and
development of omics-based tests with the goal of improving patient care
and outcomes.
Discovery and Test Validation Phases
Chapter 2 explains the technologies, statistical methods, computational
methods, and bioinformatics methods that should be used in the discovery
and confirmation of omics-based tests. Recommendation 1 defines critical
steps in the discovery and confirmation of new candidate omics-based tests.
Recommendation 2 (Chapter 3) focuses on omics-based test development
and validation within a clinical laboratory certified under the Clinical
Laboratory Improvement Amendments of 1988 (CLIA) , in preparation for
use in patient management decisions in clinical trials or for eventual use
in patient management decisions in medical care. These steps include the
design, optimization, validation, and implementation of the locked-down
test in single or multiple CLIA-certified laboratories. Recommendation 2
also emphasizes discussion of a candidate test with the Food and Drug
Administration (FDA) prior to validation.
The sections below present facts from the discovery and validation
phases of the gene expression–based tests developed at Duke University
and used in the three clinical trials the committee was tasked to evaluate:
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241
APPENDIX B
TABLE B-1 Clinical Trials Related to Duke University Gene Expression–
Based Tests Listed in the Institute of Medicine Committee’s Statement of
Task
ClinicalTrials.gov
Number NCT00636441 NCT00509366 NCT00545948
ID BOP0801 TOP0602 TOP0703
Official title A Randomized Phase II Prospective Phase II Prospective Study
Phase II Trial Study Evaluating the Evaluating the Role of
Evaluating the Role of Personalized Directed Cisplatin-Based
Performance of Chemotherapy Chemo With Either
Genomic Regimens for Vinorelbine or Pemetrexed
Expression Chemo-Naive Select for the Adj[uvant]
Profiles to Direct Stage IIIB and IV T[herapy] of Early Stage
the Use of Non-Small Cell Lung NSCLC in Patients Using
Preoperative Cancer (NSCLC) in Genomic Expression
Chemotherapy Patients Using a Profiles of Chemo
for Early Stage Genomic Predictor of Sensitivity to Guide
Breast Cancer Platinum Resistance Therapy
to Guide Therapy
Disease Breast cancer Lung cancer Lung cancer
Start date April 2008 February 2007 October 2007
Trial listed in March 2008 July 2007 October 2007
ClinicalTrials.gov
Patient accrual
Intended 270 80 117
Actuala 56 47 24
Sponsor DOD Eli Lilly/Duke/NCI Eli Lilly/Duke
Principal Paul K. Marcom, Gordana Vlahovic, Neal Ready, Ph.D., M.D.,
investigator(s) M.D., Duke M.D., M.H.S., Duke Duke University Medical
University University Center, Hematology/
Oncology, Duke
Comprehensive Cancer
Center
Chemosensitivity Doxorubicin Cisplatin Pemetrexed and
test (Adriamycin) (prospective) vinorelbine (prospective)
and docetaxel
(prospective)
Termination date 11/4/2010 11/4/2010 2/3/2011
Citations in Potti et al. Bild et al. (2006); Potti et al. (2006a,b,
ClinicalTrials.gov (2006a) Potti et al. (2006a) 2007b)
NOTE: DOD = Department of Defense, NCI = National Cancer Institute, NSCLC = non-small
cell lung cancer.
aPersonal communication from Michael Cuffe, Duke University School of Medicine, July 23,
2010.
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242 EVOLUTION OF TRANSLATIONAL OMICS
(1) tests for docetaxel and doxorubicin (Adriamycin) sensitivity were used
in the trial NCT00636441; (2) a test for cisplatin sensitivity was used in
the trial NCT00509366; and (3) tests for pemetrexed and vinorelbine
sensitivity were used in the trial NCT00545948. For each, a brief explana-
tion of test discovery and validation is provided, including information on
the confirmation of the gene expression–based computational models; the
availability of the data, metadata, computer code, and fully specified com-
putational procedures used in the discovery and confirmation of the test;
and whether the tests were locked down prior to progression to subsequent
phases of test development.
Information regarding the CLIA laboratory and FDA aspects of test
validation is general rather than specific for each of the tests discussed
below. Communication with FDA is discussed later in this appendix. The
committee had little information relating to the design, optimization,
validation, and implementation of the tests in the CLIA-certified labora-
tory. At the March 2011 meeting, Nevins informed the committee that,
at the time of performance testing, the laboratory was CLIA registered.
(A certificate of registration does not indicate CLIA compliance but only
that a CLIA application was submitted to the Centers for Medicare &
Medicaid Services [CMS]; however, it does allow a laboratory to perform
moderate and high complexity testing until an onsite survey is performed
leading to CLIA certification if compliance to the regulatory standards is
demonstrated.) The laboratory became CLIA certified during the course
of the trials. Nevins stated that the investigators had implemented data
quality control and security systems as well as an automated system for
running the computational procedures that would ensure high-quality,
reliable data (Nevins, 2011). The clinical trial protocols indicate that
patient sample processing and microarray analyses were conducted in a
CLIA-certified laboratory setting (Marcom, 2008; Ready, 2010; Vlahovic,
2010). It is not clear from the trial protocols where the computational
procedures were performed on the data, but the Duke Clinical Genom-
ics Studies Unit defined operational standards for “array data analysis
through an automated system designed and controlled by a Duke Faculty
biostatistician” (Kornbluth and Dzau, 2010, p. 5). Two of the protocols
note that the data were available for quality assessment and analysis
by a computational biologist (Ready, 2010; Vlahovic, 2010). As noted
by Baggerly and by Lisa McShane, the computational models were not
locked down when their performance was evaluated prior to use in the
clinical trials (Baggerly, 2011; McShane, 2010a). As described in Chapter
3 and reflected in the committee’s recommendations, this constitutes a
serious flaw in the test development process.
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APPENDIX B
Docetaxel and Doxorubicin Chemosensitivity Tests (Potti et al., 2006a)
Used in Breast Cancer Trial NCT00636441
The Duke researchers first published gene expression–based chemo-
sensitivity tests for docetaxel and doxorubicin in the 2006 Nature Medicine
paper (Potti et al., 2006a). This paper also presented chemosensitivity tests
for five other chemotherapeutic drugs: paclitaxel, topotecan, 5-FU, cyclo-
phosphamide, and etoposide. The drugs were chosen based on availability
of gene expression microarray data and in vitro drug response (sensitivity)
measures from the NCI-60 cell line panel from the National Cancer Insti-
tute (NCI) (Potti et al., 2006a).
A subsequent study conducted to evaluate the ability of the docetaxel
and doxorubicin tests to predict patient response to a combination taxane
chemotherapy regimen (docetaxel and epirubicin; abbreviated TET) or a
non-taxane chemotherapy regimen (fluorouracil, epirubicin, and cyclo-
phosphamide; abbreviated FEC), respectively, was published in 2007
(Bonnefoi et al., 2007). Both papers have now been retracted (Bonnefoi et
al., 2011; Potti et al., 2011a).
The Duke researchers’ general approach for identifying signatures for
each of the drugs was to first identify cell lines from the NCI-60 panel that
were the most sensitive and resistant to the drugs. Then, they used statistical
methods to develop the gene expression–based signatures that would form
the basis of the computational models in the tests. However, conflicting and
confusing information in the papers and the cited references regarding the
data and the statistical methods contributed to the inability of colleagues
in the scientific community to understand and replicate the generation
of the computational models (Baggerly, 2011; McShane, 2010a; Review
of Genomic Predictors for Clinical Trials from Nevins, Potti, and Barry,
2009). For example, the authors describe using Bayesian binary regression
analysis, but the paper cited for this analysis (Pittman et al., 2004) pres-
ents a different statistical methodology for Bayesian binary prediction tree
models. In addition, there were simple linear regression analyses reported
in which p-values were stated to have been obtained by use of a log-rank
test. The log-rank test is a statistical testing method applied for analysis of
survival (time-to-event) data; its citation in the simple linear regression set-
ting should have signaled a need for statistical review. The committee does
not know if the paper was reviewed by a statistician either internally at
Duke or during the Nature Medicine review process, but whatever statisti-
cal review occurred for this paper was inadequate. These instances point to
the risks of relying on journal publication as the sole basis for judging the
soundness of science, particularly when the results are poised for transla-
tion into the clinic.
Several datasets were used to confirm the gene expression–based com-
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244 EVOLUTION OF TRANSLATIONAL OMICS
putational models generated. Potti et al. (2006a) reported using leave-
one-out cross-validation to confirm the docetaxel computational model
developed from drug sensitivity data derived from the NCI-60 breast cancer
cell lines. The docetaxel test was reported to have been validated on several
independent sets of data from ovarian and lung cancer cell lines and from
clinical samples of breast and ovarian tumors; some of these data had been
previously published and others were generated at Duke. The doxorubicin
test also was reported to have been confirmed using leave-one-out cross-
validation and then validated on independent gene expression datasets
from breast, ovarian, and leukemia studies (Bonnefoi et al., 2007; Potti et
al., 2006a).
Both the docetaxel and doxorubicin tests were used as part of compu-
tational models developed to predict response to multidrug chemotherapy
regimens. Potti et al. (2006a) reported that when a compuational model
for predicting sensitivity to combined TFAC (paclitaxel, 5-FU, Adriamy-
cin, and cyclophosphamide) was applied to gene expression data from 51
patients in a breast neoadjuvant treatment trial, there was a statistically
significant association between the predicted multiregimen response prob-
ability and response outcome. Similar statistically significant results were
reported from a second collection of breast cancer specimens from patients
who had received FAC (5-FU, Adriamycin, cyclophosphamide). Bonnefoi
et al. (2007) reported good performance of multidrug sensitivity tests when
applied to samples from the intergroup neoadjuvant therapy trial EORTC-
10994/BIG-00-01, which randomized patients with estrogen-receptor-neg-
ative breast tumors between treatment arms for TET (docetaxel for three
cycles followed by epirubicin plus docetaxel) and FEC (fluorouracil, epi-
rubicin, and cyclophosphamide). The doxorubicin computational model
described in Potti et al. (2006a) was used in lieu of an epirubicin computa-
tional model. The reported successful extension of the computational model
methodology to multidrug regimens was seen as important because many
cancer patients receive multidrug chemotherapy regimens.
Several aspects of the validations reported in Bonnefoi et al. (2011)
and Potti et al. (2006a) raise questions about the rigor with which those
validations were conducted. There was a lack of information about how the
thresholds applied to the response probabilities generated by the computa-
tional models were selected for the validations involving clinical samples in
these studies (Bonnefoi et al., 2011; Potti et al., 2006a), and the reported
use of different thresholds for the two tumor types (breast and ovarian)
indicates that these two validation studies on clinical samples could not
have been based on an appropriately locked-down computational model
(which must include locking down any threshold). In addition, neither
paper states that the investigators were blinded to the response outcome
data when they calculated the predicted response probabilities (Bonnefoi et
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245
APPENDIX B
al., 2011; Potti et al., 2006a). The Bonnefoi et al. (2007) paper states that
several authors had full access to all of the raw data, but it is not known
when in the course of the study they may have used that access.
The drug sensitivity measures and gene expression microarray data used
to develop the docetaxel and doxorubicin tests were publicly available in
the database from the NCI-60 website.1 Computer code used to generate
the gene expression-based computational models in Potti et al. (2006a) was
available on a Duke website (Baggerly and Coombes, 2009). However, when
statisticians Keith Baggerly and Kevin Coombes attempted to assess the
validity of the tests at the request of colleagues at MD Anderson Cancer Cen-
ter who were interested in using the tests or the same approach to develop
new tests, they found insufficient information to reproduce the published
results, using the available data and the methods published in the Nature
Medicine paper (Baggerly, 2011). Therefore, Baggerly and Coombes began
corresponding with the principal authors at Duke to better understand the
data and methodology. At first there was an exchange of questions and
answers regarding the data, cell line labels, and gene lists. However, after
multiple exchanges between November 2006 and June 2007, Baggerly and
Coombes were still unable to reproduce the results and communications
between the groups broke off (Baggerly, 2011). The statisticians submitted
correspondence to Nature Medicine outlining their unresolved concerns and
questions. Their correspondence was published along with a reply (Coombes
et al., 2007; Potti and Nevins, 2007). The concerns included an inability to
reproduce the selection of cell lines from sensitivity measures, errors in gene
lists, incorrect figures, combining of training and test sets in developing the
computational models, and an inability to produce the reported test per-
formance results. Further communication between Baggerly and Coombes
and the authors and journals is described in the section on journals later in
this appendix. When the Nature Medicine paper was eventually retracted
on January 7, 2011, corruption of additional validation datasets was noted,
with an explicit statement that the authors had been “unable to reproduce
certain crucial experiments showing validation of signatures for predicting
response to chemotherapies, including docetaxel and topotecan” (Potti et
al., 2011a, p. 135).
The clinical trial using these tests, NCT00636441, titled A Randomized
Phase II Trial Evaluating the Performance of Genomic Expression Profiles
to Direct the Use of Preoperative Chemotherapy for Early Stage Breast
Cancer, was listed in ClinicalTrials.gov on March 9, 2008. This trial was
temporarily suspended from October 19, 2009, to February 12, 2010. The
trial was suspended again on July 23, 2010, and terminated on November
4, 2010. This trial and the following two clinical trials named in the IOM
1 See http://dtp.nci.nih.gov/docs/cancer/cancer_data.html (Potti et al., 2006a).
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246 EVOLUTION OF TRANSLATIONAL OMICS
statement of task are discussed in more detail later in this appendix (see
section on evaluation for clinical use).
Cisplatin Chemosensitivity Test (Hsu et al., 2007) Used in Lung Cancer
Patients in NCT00509366
The gene expression–based chemosensitivity test for cisplatin was pub-
lished in the Journal of Clinical Oncology (Hsu et al., 2007), along with
a chemosensitivity test for pemetrexed; this paper has now been retracted
because of the “inability to reproduce the experiments demonstrating a
capacity of a cisplatin response signature to validate in either a collection
of ovarian cancer cell lines or ovarian tumor samples” (Hsu et al., 2010,
p. 5229). The general statistical approach used to develop the compu-
tational models was similar to the one reported in Potti et al. in Nature
Medicine (2006a); the authors had made computer code available on a
Duke website. The cisplatin test was developed using publicly available
gene expression microarray data and drug sensitivity data from a study
published in the International Journal of Cancer (Gyorffy et al., 2006).
Hsu et al. (2007) reported that the cisplatin test had been validated in two
experiments. The first experiment used data from ovarian cancer cell lines
on which the Duke investigators had performed drug sensitivity experi-
ments and gene expression microarray profiling. A second experiment
used clinical specimens from patients with ovarian cancer. There were no
reported validation attempts using clinical tumor samples from patients
with lung cancer, but the first trial in which the cisplatin test was used to
guide therapy was the NCT00509366 trial for advanced lung cancer. As
described in Chapter 3 and indicated in Figure S-1, the omission of such a
validation step constitutes a critical flaw in the test development process.
Problems with posted data and figures were identified by Baggerly
and Coombes for both the cisplatin and pemetrexed tests (Baggerly and
Coombes, 2009). For example, they identified off-by-one errors in gene
lists for both tests, “outlier” genes reported for the cisplatin test that could
not be reproduced from the data (even after accounting for the off-by-one
error), and a reversal of sensitive/resistant labels in a data figure for the
pemetrexed test. Baggerly and Coombes (2009) noted in their analysis:
“one theme that emerges is that the most common errors are simple (e.g.,
row or column offsets); conversely, it is our experience that the most simple
errors are common.” The statisticians were particularly concerned that the
four outlier genes (probesets) mistakenly reported for the cisplatin test were
exactly those cited in Hsu et al. (2007) as providing biological plausibility
for the model. Even with access to the publicly available primary data and
code posted by the authors on a Duke website, Baggerly and Coombes were
unable to reproduce the published results. Further information on Baggerly
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APPENDIX B
and Coombes’s examination of the cisplatin and several other tests is pro-
vided later in this appendix.
The clinical trial, NCT00509366, titled Phase II Prospective Study
Evaluating the Role of Personalized Chemotherapy Regimens for Chemo-
Naive Select Stage IIIB and IV Non-Small Cell Lung Cancer (NSCLC)
in Patients Using a Genomic Predictor of Platinum Resistance to Guide
Therapy, began accruing patients in June 2007 (McShane, 2010b) and was
listed in ClinicalTrials.gov on July 30, 2007, temporarily suspended from
October 6, 2009, to February 12, 2010, resuspended on July 23, 2010, and
terminated on November 4, 2010.
Pemetrexed (Hsu et al., 2007) and Vinorelbine Chemosensitivity Tests
Used in Clinical Trial of Lung Cancer Patients NCT00545948
The gene expression–based chemosensitivity test for pemetrexed was
published in the Journal of Clinical Oncology (Hsu et al., 2007); as men-
tioned in the previous section, this paper has now been retracted (Hsu et
al., 2010). The gene expression–based chemosensitivity test for vinorelbine
does not appear to have been published; the protocol for NCT00545948
cites Potti et al., Nature Medicine (2006a) as the relevant reference (Ready,
2010). The general statistical approach used to develop the computational
model for pemetrexed was similar to that in Potti et al. (2006a). The peme-
trexed test was developed using methods similar to those used to develop
the cisplatin test, but the data source was different. This test was developed
using the publicly available gene expression data and drug sensitivity data
derived from the NCI-60 cell lines. Hsu et al. (2007) reported that the
pemetrexed test had been validated using in vitro drug sensitivity data
from an independent set of 17 NSCLC cell lines. This appears to have been
the only validation study conducted before the pemetrexed test was used
to direct patient therapy in the NCT00545948 clinical trial. In this trial,
the pemetrexed test was used along with a similar gene expression–based
test for vinorelbine sensitivity to determine which of those drugs should be
coupled with cisplatin for adjuvant therapy.
As mentioned in the previous section, problems with posted data and
figures were identified by Baggerly and Coombes for both the cisplatin
and pemetrexed tests. They were able to detect these problems using the
data that were available from the NCI-60 website and the same computer
code mentioned in the previous two sections that was also used for this test
(Baggerly and Coombes, 2009). Further information on their examination
of the pemetrexed and several other tests is provided later in this appendix.
No information is available relating to the vinorelbine test.
The clinical trial NCT00545948, titled Phase II Prospective Study Eval-
uating the Role of Directed Cisplatin Based Chemo With Either Vinorelbine
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248 EVOLUTION OF TRANSLATIONAL OMICS
or Pemetrexed for the Adj[uvant] T[herapy] of Early Stage NSCLC in
Patients Using Genomic Expression Profiles of Chemo Sensitivity to Guide
Therapy, was listed in ClinicalTrials.gov on October 17, 2007, temporarily
suspended from October 6, 2009, to February 11, 2010, suspended again
on July 23, 2010, and terminated on February 3, 2011.
Evaluation for Clinical Utility and Use Stage
Chapter 4 presented the committee’s third recommendation, regarding
steps important for taking a validated omics-based test into clinical trials.
The decisions to move the tests into clinical trials and subsequent decisions
about use of the tests to guide therapy in the clinical trials are described in
greater detail in the next section on Roles and Responsibilities. The series
of events following publication of the Baggerly and Coombes paper in
the Annals of Applied Statistics (2009), as described below, applies to all
three clinical trials and related tests (docetaxel and doxorubicin chemo-
sensitivity tests used in NCT00636441, cisplatin chemosensitivity test used in
NCT00509366, pemetrexed chemosensitivity test used in NCT00545948).
No information is available about the vinorelbine test.
In September 2009, NCI was in the process of reviewing a revised
clinical trial protocol from the Cancer and Leukemia Group B cooperative
group (CALGB-30702), which was proposing to use six of the Duke che-
mosensitivity tests in a clinical trial for patients with advanced lung cancer.
The reviewers had noted serious discrepancies in the information presented
in the protocol and a lack of validation of the tests on human lung tumor
samples, and NCI disapproved that protocol. However, the protocol also
mentioned several Duke trials already under way using several of the tests.
The concerns generated by this protocol, along with the publication of the
Baggerly and Coombes paper (2009), led NCI to contact leadership at Duke
University, and ultimately resulted in suspension of the trials and launch of
the external review in early October 2009.
These events prompted NCI to further scrutinize another test devel-
oped by Nevins and Potti (but not one of the tests being studied in the
three clinical trials listed in the committee’s statement of task), the Lung
Metagene Score (LMS), for which a clinical trial had already opened. In
that trial, CALGB-30506, the LMS test was being used as a stratification
factor for randomization of trial participants. During the protocol review
process for CALGB-30506, NCI decided that, while the LMS test appeared
to have some promise, there were concerns that laboratory batch effects
might influence its performance. Therefore, NCI insisted on a change in the
originally proposed design of the trial so that the test would not be used
to direct therapy in the trial. Although results of the test were kept blinded
and were not being used to guide therapy in the trial, evaluation of the
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APPENDIX B
test was a co-primary aim of the trial. In November 2009, NCI’s Cancer
Therapy Evaluation Program (CTEP) made a request to CALGB for data
and computer code to reevaluate that test and information that had been
provided to CTEP during its original protocol review process for that trial
2 years earlier, when NCI did not have access to the data and computer
code. With data and computer code in hand, NCI’s reevaluation was able
to identify a number of problems with the version of the LMS test that had
been the basis for the trial approval and a supporting publication (Potti et
al., 2006b). The problems included an unstable computational model and
an inability to reproduce findings from a prevalidation exercise that had
taken place during the trial approval process (McShane, 2010a). Eventu-
ally, the New England Journal of Medicine article was retracted because of
“failure to reproduce results supporting the validation of the lung metagene
model described in the article using a sample set from a study by the Ameri-
can College of Surgeons Oncology Group (ACOSOG) and a collection of
samples from a study by CALGB” (Potti et al., 2011b, p. 1176).
In contrast to NCI’s reviews, oversight committees at Duke did not
recognize significant problems with the other Duke chemosensitivity tests,
and allowed them to be used to direct therapy selection in clinical trials. It
is not known if the Cancer Protocol Review Committee (CPRC) and Duke
Institutional Review Board (IRB), who were responsible for approving and
overseeing the Duke trials, were fully aware of the extent of problems with
the published papers or aware of contradictory statements being made
about the validation status of some of the tests. For example, the IOM com-
mittee received conflicting information about validation of the pemetrexed
test. Information supporting the lack of validation included correspondence
between Potti and NCI. In Potti’s submission of R01-CA131049-01A1 in
March 2008, Potti stated: “we have only been able to validate the accuracy
of the cisplatin test in independent patient samples . . ., not the pemetrexed
test . . . it is probably a little bit premature to employ the pemetrexed test
to stratify patients” (NCI, 2010a). Potti also mentioned the “premature”
status of the pemetrexed test in his 4/14/10 response to NCI’s letter dated
4/13/10 requesting information about his grant.2 Information suggesting
that the tests had been validated was included in the protocol for the
TOP0703 that was using the pemetrexed and vinorelbine tests. In Sec-
tion 1.4.2 of the 4/21/08 version of the trial protocol, it is stated, “Using
Affymetrix gene expression data with corresponding in vitro drug response
data for vinorelbine and pemetrexed, our group has developed robust gene
expression based models predictive of vinorelbine and pemetrexed sensitiv-
ity. These multigene models were validated with an accuracy of greater than
2 Communication from Anil Potti, Duke University, to William Timmer, National Cancer
Institute, RE: R01CA131049-01A1 Information Request, April 14, 2010.
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270 EVOLUTION OF TRANSLATIONAL OMICS
TABLE B-2 Continued
Date Event
January 2007 Letters to the editor and author reply related to the NEJM paper (Potti
et al., 2006b) published (Larsen et al., 2007; Potti et al., 2007b; Singh
and Dhindsa, 2007; Sun and Yang, 2007).
Correction to Potti et al. (2006b) published in NEJM (Correction,
2007).
February 2007 Journal of Clinical Oncology publishes “An integrated genomic-based
approach to individualized treatment of patients with advanced-stage
ovarian cancer” (Dressman et al., 2007).
April 2007 William Barry joins IGSP (Kornbluth and Dzau, 2011).
July 2007 Study Using a Genomic Predictor of Platinum Resistance to Guide
Therapy in Stage IIIB/IV Non-Small Cell Lung Cancer (TOP0602)
entered on ClinicalTrials.gov (Identifier NCT00509366).
October 2007 Journal of Clinical Oncology publishes “Pharmacogenomic strategies
provide a rational approach to the treatment of cisplatin-resistant
patients with advanced cancer” (Hsu et al., 2007).
Adjuvant Cisplatin With Either Genomic-Guided Vinorelbine or
Pemetrexed for Early Stage Non-Small Cell Lung Cancer (TOP0703)
entered on ClinicalTrials.gov (Identifier NCT00545948).
November 2007 Publication of a letter by Coombes et al. in Nature Medicine critiquing
the Potti et al. (2006a) paper, together with a rebuttal (Coombes et al.,
2007; Potti and Nevins, 2007).
Baggerly et al. submit a letter, “Pharmacogenomic strategies may not
provide a rational approach to the treatment of cisplatin-resistant
patients with advanced lung cancer,” to Journal of Clinical Oncology.
It is rejected (Baggerly, 2011).
December 2007 Lancet Oncology publishes “Validation of gene signatures that predict
the response of breast cancer to neoadjuvant chemotherapy: A substudy
of the EORTC 10994/BIG 00-01 clinical trial” (Bonnefoi et al., 2007).
March 2008 Trial to Evaluate Genomic Expression Profiles to Direct Preoperative
Chemotherapy in Early Stage Breast Cancer entered on ClinicalTrials.gov
(Identifier NCT00636441).
Potti et al. submit revised R01 grant proposal, “Prospective Validation
of Genomic Signatures of Chemosensitivity in NSCLC” (CA131049-
01A1), which is linked to a Phase II trial using the cisplatin
chemosensitivity test to direct therapy for advanced-stage lung cancer
patients. The trial was later identified as NCT00509366, which began
enrolling patients in June 2007 (McShane, 2010b).
Publication of a letter to the editor by Baggerly et al. “Run batch effects
potentially compromise the usefulness of genomic signatures for ovarian
cancer” (Baggerly et al., 2008), a comment on Dressman et al. (2007),
and an author reply in the Journal of Clinical Oncology (Dressman et
al., 2008).
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271
APPENDIX B
TABLE B-2 Continued
Date Event
May 2008 Baggerly and Coombes submit a letter to the editor of Nature Medicine,
“Microarrays: Retracing steps (again).”a
Baggerly and Coombes submit a letter to the editor of Lancet Oncology,
“Have gene signatures that predict the response of breast cancer to
neoadjuvant chemotherapy been validated?” (Baggerly, 2011).
June 2008 Nature Medicine requests that Baggerly and Coombes 5/08 letter be sent
to Potti and coauthors.b
Nature Medicine rejects letter.c Lancet Oncology rejects letter.d
July 2008 Genomic Directed Salvage Chemotherapy with Either Liposomal
Doxorubicin or Topotecan entered on ClinicalTrials.gov (Identifier
NCT00720096).
July 2009 Cancer and Leukemia Group B (CALGB) submits revised
CALGB-30702 protocol (Genome-Guided Chemotherapy for Untreated
and Treated Advanced Stage Non-Small Cell Lung Cancer: A Limited
Institution, Randomized Phase II Study).e
Current Oncology Reports publishes “Translating genomics into clinical
practice: Applications in lung cancer” (Jolly Graham and Potti, 2009).
September 2009 Annals of Applied Statistics publishes online: “Deriving chemosensitivity
from cell lines: Forensic bioinformatics and reproducible research in
high-throughput biology” (Baggerly and Coombes, 2009).
The National Cancer Institute (NCI) contacts Duke to ask that the
university carefully consider the validity of the work and its
extrapolation to the clinic (McShane, 2010a).
October 2009 10/2 — The Cancer Letter first covers the story; Nevins asserts that the
approach has been shown to work in a blinded validation by Bonnefoi
et al. (2007) (Goldberg, 2009a).
The Data Safety Monitoring Board and Duke Cancer Protocol Review
Committee conclude that issues raised by Baggerly and Coombes (2009)
presented no immediate increased risks to study patients already on
therapy (Kornbluth and Dzau, 2011).
Enrollment in the three trials is suspended (Duke University, 2007a,b,
2008). Patients already enrolled in the trials are informed of the
controversy and reconsented (Kornbluth and Cuffe, 2010).
Duke IRB commissions an independent, external two-person review of
the scientific methodology in question. NCI provides assistance in
identifying potential external experts (Kornbluth and Dzau, 2011;
McShane, 2010a).
Baggerly and Coombes’ data analysis and questions from the Annals of
Applied Statistics paper were shared with the Duke IRB and principal
investigators of the three clinical trials (Kornbluth and Dzau, 2011).
10/23 — The Cancer Letter reports statements from coauthors of the
Lancet Oncology study that the validation was never blinded (Goldberg,
2009b).
continued
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272 EVOLUTION OF TRANSLATIONAL OMICS
TABLE B-2 Continued
Date Event
November 2009 11/9 — Baggerly sends a report highlighting problems with data posted
on a webpage on the cisplatin and pemetrexed tests to Kornbluth at
Duke. This report was shared with Nevins, who asked that it be
withheld from the external reviewers; Duke leadership decided to honor
Nevins’ request (Kornbluth and Dzau, 2011).
11/9 — Claudio Dansky Ullmann of NCI submits the review of revised
CALGB-30702 protocol (Genome-Guided Chemotherapy for Untreated
and Treated Advanced Stage Non-Small Cell Lung Cancer: A Limited
Institution, Randomized Phase II Study) to NCI’s Cancer Therapy
Evaluation Program (CTEP) Protocol and Information Office and
forwards the review and disapproval letter to CALGB.f,g
11/16 — Lisa McShane and Jeffrey Abrams of NCI contact CALGB
requesting re-evaluation of the Lung Metagene Score (LMS) test for
CALGB-30506.h
Ullmann and McShane contribute to an erratum published in Current
Oncology Reports to Jolly Graham and Potti (2009).
December 2009 External reviewers find that “In summary we believe the predictors are
scientifically valid and with a few additions can be fully responsive to
the comments of Baggerly and Coombes” (Review of genomic
predictors for clinical trials from Nevins, Potti, and Barry, 2009).
January 2010 Letter submitted to NCI on 1/7/2010, accompanied by the report from
the external reviewers (Kornbluth and Dzau, 2011; McShane, 2010a;
Review of genomic predictors for clinical trials from Nevins, Potti, and
Barry, 2009).
Duke restarts the three trials (NCT00545948, NCT00509366, and
NCT00636441) (ClinicalTrials.gov, 2011a,b,c).
February 2010 NCI completes reevaluation of supporting data for the CALGB-30506
trial (NCI, 2010b).
March 2010 Nevins et al. send a letter to McShane in response to some of her
concerns about the LMS used in CALGB-30506.i
McShane and Abrams reply with the conclusions of their analysis of the
LMS in the CALGB-30506 clinical trial: The test should not remain as a
stratification factor, and the coprimary aim to evaluate its performance
should be removed from the study.j
April 2010 CTEP requests data and computer code from Potti regarding R01 grant
CA131049-01A1 titled “Prospective validation of genomic signatures of
chemosensitivity in NSCLC” (cisplatin and pemetrexed tests).k
Potti responds to CTEP.l
The Cancer Letter obtains a copy of Duke University’s external review
report from NCI via a Freedom of Information Act request and
publishes the document (Goldberg, 2010a).
May 2010 CTEP sends follow-up questions to Potti regarding their response to the
April 2010 request regarding the cisplatin and pemetrexed tests. Potti
responds.m
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273
APPENDIX B
TABLE B-2 Continued
Date Event
June 2010 NCI completes its reevaluation of the cisplatin chemosensitivity test
(McShane, 2010c).
NCI hosts Duke researchers to discuss the gene expression–based tests
developed at Duke. NCI states that it is not satisfied, and directs Potti
and Nevins to conduct a search of their labs to supply the data and
code reproducing the results in Hsu et al. (2007) and justifying the trials
under way. Duke statistician William Barry is tasked with checking the
cisplatin/pemetrexed tests and verifying the data (Kornbluth and Dzau,
2011; NCI, 2010a; TMQF Committee, 2011b).
July 2010 7/16 — The Cancer Letter reports that Anil Potti incorrectly stated his
credentials. Duke places Potti on administrative leave while the
University investigates allegations of inaccuracies in his curriculum vitae
and in the research with Nevins (Goldberg, 2010b).
7/19 — Thirty-one biostatisticians and bioinformatics experts from
around the world send a letter, “Concerns about prediction models used
in Duke clinical trials,” to NCI director Harold Varmus. This letter is
later signed by two additional statisticians (Baron et al., 2010).
7/23 — Lancet Oncology issues an expression of concern for
“Validation of gene signatures that predict the response of breast cancer
to neoadjuvant chemotherapy: A substudy of the EORTC 10994/BIG
00-01 clinical trial” (Bonnefoi et al., 2007).
NCT00545948, NCT00509366, and NCT00636441 trials suspended a
second time (ClinicalTrials.gov, 2011a,b,c).
7/30 — NCI and Duke request assistance from the Institute of Medicine
(IOM) in assessing the scientific foundation of the three clinical trials
and identifying appropriate evaluation criteria for future tests based on
omics technologies.
August 2010 8/27 — Duke completes its review of Potti’s credentials; identifies issues
of substantial concern resulting in corresponding sanctions. Potti
remains on administrative leave (Duke Today, 2010).
October 2010 10/22 — Duke officials inform NCI that they have determined that
several datasets reported to have been used to validate the cisplatin test
were found to be flawed. The Hsu et al. (2007) paper would be
retracted. Investigation into other datasets was ongoing (McShane,
2010a).
November 2010 NCT00545948, NCT00509366, and NCT00636441 trials terminated
in ClinicalTrials.gov (ClinicalTrials.gov, 2011a,b,c).
11/16 — Journal of Clinical Oncology retracts “Pharmacogenomic
strategies provide a rational approach to the treatment of cisplatin-
resistant patients with advanced cancer” (Hsu et al., 2007, 2010)
11/19 — Anil Potti resigns from his position at Duke (DukeHealth.org,
2010), later taking a position as an oncologist in South Carolina
(Cancer Letter, 2010) with strong endorsement from some Duke faculty
members (Duke.Fact.Checker, 2011).
continued
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274 EVOLUTION OF TRANSLATIONAL OMICS
TABLE B-2 Continued
Date Event
December 2010 12/20 — McShane describes to the IOM committee the NCI interactions
with the Duke investigators pertaining to the gene expression–based
tests, and supplies documentation to the committee. This is the first
public explanation of why NCI thought problems with the LMS were
severe enough to warrant pulling it from CALGB 30506. This publicly
calls the NEJM paper into question. In addition, she reveals that NCI
had discovered that it had been providing partial funding to the trial
NCT00509366 through an R01 grant awarded to Anil Potti. She
describes her unsuccessful attempts to reproduce the results reported in
the Hsu et al. (2007) paper for the cisplatin test and how that eventually
led to discovery of several corrupted datasets (McShane, 2010a).
January 2011 IGSP Center for Applied Genomics and Technology is dissolved
(Goldberg, 2011; Havele, 2011).
Nature Medicine retraction (Potti et al., 2011a).
1/31 — The Food and Drug Administration (FDA) conducts an
inspection at Duke University to detemune the rationale for the IRB’s
initial non-significant risk decision regarding an investigational device
exemption (IDE) (FDA, 2011).
February 2011 Lancet Oncology retraction (Bonnefoi et al., 2011).
March 2011 NEJM retraction (Potti et al., 2011b).
Draft document, A framework for the quality of translational medicine
with a focus on human genomic studies: Principles from the Duke
Medicine Translational Medicine Quality Framework [TMQF]
committee, released. Final draft is released in May 2011.
July 2011 Duke sends the IOM committee a list of identified problems, missed
signals, and proposed solutions based on the work of the TMQF
committee (TMQF Committee, 2011b).
August 2011 8/22 — Duke representatives meet with the IOM committee: Robert
Califf, Sally Kornbluth, Michael Cuffe, Ross McKinney, John Falletta,
Geoff Ginsburg, Michael Kelley, and William Barry.
January 2012 1/25 — FDA posts documents on its website indicating that it informed
Duke in 2009 that an IDE should have been obtained for the three trials
(Chan, 2009; FDA, 2011; Potti, 2009).
Journal of Clinical Oncology retracts “An integrated genomic-based
approach to individualized treatment of patients with advanced-stage
ovarian cancer” (Dressman et al, 2007; JCO, 2012).
aCommunication from Michael Burns, Nature Medicine, to Keith Baggerly, MD Anderson
Cancer Center. Receipt of NMED-LE40837, May 30, 2008.
bCommunication from Alison Farrell, Nature Medicine, to Keith Baggerly, MD Anderson
Cancer Center. NMED-LE40837, June 2, 2008.
cCommunication from Alison Farrell, Nature Medicine, to Keith Baggerly, MD Anderson
Cancer Center. Decision on NMED-LE40837, June 11, 2008.
dCommunication from David Collingridge, Lancet Oncology, to Keith Baggerly, MD Anderson
Cancer Center. Your submission to the Lancet Oncology, September 6, 2008.
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275
APPENDIX B
TABLE B-2 Continued
eCommunication from Olwen Hahn, CALGB, to Michael Montello, National Cancer Institute.
RE: CALGB 30702, July 28, 2009.
fCommunication from Claudio Dansky Ullmann, National Cancer Institute, to CTEP Protocol
and Information Office. Consensus review of revised protocol CALGB 30702: Genome-guided
chemotherapy for untreated and treated advanced stage non-small cell lung cancer: A limited
institution, randomized phase II study, November 9, 2009.
gCommunication from Claudio Dansky Ullmann, National Cancer Institute, to Richard
Schilsky, CALGB. Reference number PCALBG-30702#R01PDISAPP01, November 9, 2009.
hCommunication from Jeffrey Abrams and Lisa McShane, National Cancer Institute, to
Richard Schilsky, CALGB. Important computer code and data request for CALGB-30506,
November 16, 2009.
iCommunication from Joseph R. Nevins, Anil Potti, William Barry, and David Harpole, Duke
University. Response to the NCI re-evaluation of supporting data for the CALGB-30506 trial,
March 8, 2010.
jCommunication from Lisa McShane and Jeffrey Abrams, National Cancer Institute, to Joseph
R. Nevins, Anil Potti, William Barry, and David Harpole, Duke University. RE: Nevins,
Potti, Barry, and Harpole response to the NCI re-evaluation of supporting data for the
CALGB-30506 trial, March 26, 2010.
kCommunication from William C. Timmer, National Cancer Institute, to Anil Potti, Duke
University. RE: R01CA131049-01A1 information request, April 13, 2010.
lCommunication from Anil Potti, Duke University, to William C. Timmer, National Cancer
Institute. RE: R01CA131049-01A1 information request, April 29, 2010.
mCommunication from Lisa McShane, National Cancer Institute, to Anil Potti, Duke Univer-
sity. RE: R01CA131049-01A1 information request, May 17, 2010.
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276 EVOLUTION OF TRANSLATIONAL OMICS
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