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 statisticians 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 Computational 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 Technology (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 analyses 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 developed 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 presentation and statistical analysis. Eventually, concerns were raised by statisticians about the validity of the tests and about potential harm to patients enrolled in the trials.



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 239
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

OCR for page 239
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:

OCR for page 239
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.

OCR for page 239
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.

OCR for page 239
243 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-

OCR for page 239
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

OCR for page 239
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).

OCR for page 239
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

OCR for page 239
247 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

OCR for page 239
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

OCR for page 239
249 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.

OCR for page 239
242 270 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).

OCR for page 239
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

OCR for page 239
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

OCR for page 239
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

OCR for page 239
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.

OCR for page 239
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.

OCR for page 239
276 EVOLUTION OF TRANSLATIONAL OMICS REFERENCES Baggerly, K. A. 2011. Forensics Bioinformatics. Presentation to the Workshop of the IOM Committee on the Review of Omics-Based Tests for Predicting Patient Outcomes in Clinical Trials, Washington, DC, March 30-31. Baggerly, K. A., and K. R. Coombes. 2009. Deriving chemosensitivity from cell lines: Forensic bioinformatics and reproducible research in high-throughput biology. Annals of Applied Statistics 3(4):1309-1334. Baggerly, K. A., K. R. Coombes, and E. S. Neeley. 2008. Run batch effects potentially compro- mise the usefulness of genomic signatures of ovarian cancer. Journal of Clinical Oncology 26(7):1186-1187. Baron, A. E., K. Bandeen-Roche, D. A. Berry, J. Bryan, V. J. Carey, K. Chaloner, M. Delorenzi, B. Efron, R. C. Elston, D. Ghosh, J. D. Goldberg, S. Goodman, F. E. Harrell, S. Galloway Hilsenbeck, W. Huber, R. A. Irizarry, C. Kendziorski, M. R. Kosorok, T. A. Louis, J. S. Marron, M. Newton, M. Ochs, J. Quackenbush, G. L. Rosner, I. Ruczinski, S. Skates, T. P. Speed, J. D. Storey, Z. Szallasi, R. Tibshirani, and S. Zeger. 2010. Letter to Harold Varmus: Concerns about Prediction Models Used in Duke Clinical Trials. Bethesda, MD, July 19. Bild, A. H., G. Yao, J. T. Chang, Q. Wang, A. Potti, D. Chasse, M. B. Joshi, D. Harpole, J. M. Lancaster, A. Berchuck, J. A. Olson, Jr., J. R. Marks, H. K. Dressman, M. West, and J. R. Nevins. 2006. Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature 439(7074):353-357. Bonnefoi, H., A. Potti, M. Delorenzi, L. Mauriac, M. Campone, M. Tubiana-Hulin, T. Petit, P. Rouanet, J. Jassem, E. Blot, V. Becette, P. Farmer, S. Andre, C. R. Acharya, S. Mukherjee, D. Cameron, J. Bergh, J. R. Nevins, and R. D. Iggo. 2007. 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. Lancet Oncology 8(12):1071-1078. Bonnefoi, H., A. Potti, M. Delorenzi, L. Mauriac, M. Campone, M. Tubiana-Hulin, T. Petit, P. Rouanet, J. Jassem, E. Blot, V. Becette, P. Farmer, S. Andre, C. Acharya, S. Mukherjee, D. Cameron, J. Bergh, J. R. Nevins, and R. D. Iggo. 2011. Retraction: 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. Lancet Oncology 12(2):116. Califf, R. M. 2011. Discussion at Discovery of Process Working Group Meeting with Repre- sentatives of Duke Faculty and Administration, Washington, DC, August 22. Cancer Letter. 2011. In the cancer centers. 37(22):1. Chan, M. M. 2009. Letter to Division of Medical Oncology, Duke University Medical Center. http://www.fda.gov/downloads/MedicalDevices/ProductsandMedicalProcedures/ InVitroDiagnostics/UCM289102.pdf (accessed February 9, 2012). ClinicalTrials.gov. 2011a. History of NCT00509366. http://clinicaltrials.gov/archive/ NCT00509366 (accessed December 12, 2011). ClinicalTrials.gov. 2011b. History of NCT00545948. http://clinicaltrials.gov/archive/ NCT00545948 (accessed December 12, 2011). ClinicalTrials.gov. 2011c. History of NCT00636441. http://clinicaltrials.gov/archive/ NCT00636441 (accessed December 12, 2011). ClinicalTrials.gov. 2011d. Genomic Directed Salvage Chemotherapy with Either Liposomal Doxorubicin or Topotecan. http://clinicaltrials.gov/ct2/show/NCT00720096?term=NCT 00720096&rank=1 (accessed October 11, 2011). Coombes, K. R., J. Wang, and K. A. Baggerly. 2007. Microarrays: Retracing steps. Nature Medicine 13(11):1276-1277. Correction. 2007. New England Journal of Medicine 356(2):201-202.

OCR for page 239
277 APPENDIX B Cuffe, M. 2011. Discussion at Discovery of Process Working Group Meeting with Representa- tives of Duke Faculty and Administration, Washington, DC, August 22. Dressman, H. K., A. Berchuck, G. Chan, J. Zhai, A. Bild, R. Sayer, J. Cragun, J. Clarke, R. S. Whitaker, L. Li, G. Gray, J. Marks, G. S. Ginsburg, A. Potti, M. West, J. R. Nevins, and J. M. Lancaster. 2007. An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer. Journal of Clinical Oncology 25(5):517-525. Dressman, H. K., A. Potti, J. R. Nevins, and J. M. Lancaster. 2008. In reply. Journal of Clinical Oncology 26(7):1187-1188. Duke Today. 2010. Duke Updates Response to Potti Allegations. http://today.duke.edu/2010/08/ pottiresponse.html (accessed December 12, 2011). Duke University. 2007a. Adjuvant Cisplatin with Either Genomic-Guided Vinorelbine or Pemetrexed for Early Stage Non-Small-Cell Lung Cancer (TOP0703). http://clinicaltrials. gov/ct2/show/NCT00545948?term=nct00545948&rank=1 (accessed November 23, 2011). Duke University. 2007b. Study Using a Genomic Predictor of Platinum Resistance to Guide Therapy in Stage IIIB/IV Non-Small Cell Lung Cancer (TOP0602). http://clinicaltrials. gov/ct2/show/NCT00509366?term=nct00509366&rank=1 (accessed November 23, 2011). Duke University. 2008. Trial to Evaluate Genomic Expression Profiles to Direct Preoperative Chemotherapy in Early Stage Breast Cancer. http://clinicaltrials.gov/show/NCT00636441 (accessed November 22, 2011). Duke.Fact.Checker. 2011. Texts of Letters of Recommendation for Dr. Anil Potti. http:// dukefactchecker.blogspot.com/2011/06/texts-of-letters-of-recommendation-for.html (ac- cessed December 12, 2011). DukeHealth.org. 2010. Duke Accepts Potti Resignation; Retraction Process Initiated with Nature Medicine. http://www.dukehealth.org/health_library/news/duke-accepts-potti- resignation-retraction-process-initiated-with-nature-medicine (accessed December 12, 2011). Falletta, J. 2011. Discussion at Discovery of Process Working Group Meeting with Represen- tatives of Duke Faculty and Administration, Washington, DC, August 22. Food and Drug Administration (FDA). 2011. FDA Establishment Inspection Report, Duke University Medical Center. http://www.fda.gov/downloads/MedicalDevices/ ProductsandMedicalProcedures/InVitroDiagnostics/UCM289106.pdf (accessed Febru- ary 9, 2012). Ginsburg, G. S. 2011. Discussion at Discovery of Process Working Group Meeting with Rep- resentatives of Duke Faculty and Administration, Washington, DC, August 22. Goldberg, P. 2009a. A biostatistic paper alleges potential harm to patients in two Duke clinical studies. Cancer Letter 35(36):1-5. Goldberg, P. 2009b. Duke halts third trial; coauthor disputes claim that data validation was blinded. Cancer Letter 35(39):1-4. Goldberg, P. 2010a. NCI raises new questions about Duke genomics research, cuts assay from trial. Cancer Letter 36(18):1-7. Goldberg, P. 2010b. Prominent Duke scientist claimed prizes he didn’t win, including Rhodes Scholarship. Cancer Letter 36(27):1-7. Goldberg, P. 2011. FDA auditors spend two weeks at Duke; Nevins loses position in reorga- nization. Cancer Letter 37(4):1-2, 4-5. Gyorffy, B., P. Surowiak, O. Kiesslich, C. Denkert, R. Schafer, M. Dietel, and H. Lage. 2006. Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. International Journal of Cancer 118(7):1699-1712.

OCR for page 239
278 EVOLUTION OF TRANSLATIONAL OMICS H. Lee Moffitt Cancer Center & Research Institute. 2007. NCT00720096 Protocol version 10, October 19. H. Lee Moffitt Cancer Center & Research Institute. 2008a. NCT00720096 Protocol version 13, January 10. H. Lee Moffitt Cancer Center & Research Institute. 2008b. NCT00720096 Protocol version 14, July 14. H. Lee Moffitt Cancer Center & Research Institute. 2009. NCT00720096 Protocol version 15, July 26. Havele, S. 2011. IGSP reviews organization, future plans. Chronicle, January 21. http://duke- chronicle.com/article/igsp-reviews-organization-future-plans (accessed January 13, 2012). Hsu, D. S., B. S. Balakumaran, C. R. Acharya, V. Vlahovic, K. S. Walters, K. Garman, C. Anders, R. F. Riedel, J. Lancaster, D. Harpole, H. K. Dressman, J. R. Nevins, P. G. Febbo, and A. Potti. 2007. Pharmacogenomic strategies provide a rational approach to the treatment of cisplatin-resistant patients with advanced cancer. Journal of Clinical Oncology 25(28):4350-4357. Hsu, D. S., B. S. Balakumaran, C. R. Acharya, V. Vlahovic, K. S. Walters, K. Garman, C. Anders, R. F. Riedel, J. Lancaster, D. Harpole, H. K. Dressman, J. R. Nevins, P. G. Febbo, and A. Potti. 2010. Retraction: Pharmacogenomic strategies provide a rational approach to the treatment of cisplatin-resistant patients with advanced cancer. Journal of Clinical Oncology 28(35):5229. JCO (Journal of Clinical Oncology). 2012. An Integrated Genomic-Based Approach to In- dividualized Treatment of Patients with Advanced-Stage Ovarian Cancer: Retraction. http://jco.ascopubs.org/content/25/5/517/suppl/DC1 (accessed January 30, 2012). Jolly Graham, A., and A. Potti. 2009. Translating genomics into clinical practice: Applications in lung cancer. Current Oncology Reports 11(4):263-268. Kornbluth, S. A. 2011. Discussion at Discovery of Process Working Group Meeting with Representatives of Duke Faculty and Administration, Washington, DC, August 22. Kornbluth, S. A., and M. Cuffe. 2010. Preliminary Accounting of Events at Duke University. Durham, NC: Duke University. Kornbluth, S. A., and V. Dzau. 2011. Predictors of Chemotherapy Response: Background Information: Draft. Duke University. Lancaster, J. M. 2008. Molecular Profiling to Predict Response to Chemotherapy, 5R33CA110499-05. http://projectreporter.nih.gov/project_info_description.cfm?aid=8101020&icde=10060731 (accessed October 11, 2011). Larsen, J. E., K. M. Fong, and N. K. Hayward. 2007. To the editor: Refining prognosis in non-small-cell lung cancer. New England Journal of Medicine 356(2):190. Marcom, P. K. 2008. A Randomized Phase II Trial Evaluating the Performance of Genomic Expression Profiles to Direct the Use of Preoperative Chemotherapy for Early Stage Breast Cancer. Durham, NC: Duke Institute for Genome Sciences and Policy. McKinney, R. 2011. Discussion at Discovery of Process Working Group Meeting with Repre- sentatives of Duke Faculty and Administration, Washington, DC, August 22. McShane, L. M. 2010a. NCI Address to Institute of Medicine Committee on the Review of Omics-Based Tests for Predicting Patient Outcomes in Clinical Trials. Presentation at Meeting 1. Washington, DC, December 20. McShane, L. M. 2010b. Notes from June 29 meeting with Duke investigators. McShane, L. M. 2010c. Re-analysis Report for Cisplatin Chemosensitivity Predictor. Bethesda, MD: National Cancer Institute. NCI (National Cancer Institute). 2010a. Discussion of Genomic Predictors Developed at Duke University. Presented at the National Cancer Institute, Rockville, MD June 29. NCI. 2010b. Executive Summary: NCI Re-evaluation of Supporting Data for the CALGB-30506 Trial. Bethesda, MD: National Cancer Institute.

OCR for page 239
279 APPENDIX B Nevins, J. 2011. Genomic Strategies to Address the Challenge of Personalizing Cancer Ther- apy. Presentation at the Workshop of the IOM Committee on the Review of Omics-Based Tests for Predicting Patient Outcomes in Clinical Trials, Washington, DC, March 30-31. Pittman, J. E. Huang, J. Nevins, Q. Wang, and M. West. 2004. Bayesian analysis of binary prediction tree models for retrospectively sampled outcomes. Biostatistics 5(4):587-601. Potti, A. 2009. Letter to FDA’s CDER from Division of Medical Oncology, Duke University Medi- cal Center. http://www.fda.gov/downloads/MedicalDevices/ProductsandMedicalProcedures/ InVitroDiagnostics/UCM289103.pdf (accessed February 9, 2012). Potti, A., and J. R. Nevins. 2007. Potti et al. reply. Nature Medicine 13(11):1277-1278. Potti, A., H. K. Dressman, A. Bild, R. F. Riedel, G. Chan, R. Sayer, J. Cragun, H. Cottrill, M. J. Kelley, R. Petersen, D. Harpole, J. Marks, A. Berchuck, G. S. Ginsburg, P. Febbo, J. Lancaster, and J. R. Nevins. 2006a. Genomic signatures to guide the use of chemo- therapeutics. Nature Medicine 12(11):1294-1300. Potti, A., S. Mukherjee, R. Petersen, H. K. Dressman, A. Bild, J. Koontz, R. Kratzke, M. A. Watson, M. Kelley, G. S. Ginsburg, M. West, D. H. Harpole, and J. R. Nevins. 2006b. A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. New England Journal of Medicine 355(6):570-580. Potti, A., H. K. Dressman, A. Bild, R. F. Riedel, G. Chan, R. Sayer, J. Cragun, H. Cottrill, M. J. Kelley, R. Petersen, D. Harpole, J. Marks, A. Berchuck, G. S. Ginsburg, P. Febbo, J. Lancaster, and J. R. Nevins. 2007a. Corrigendum: Genomic signatures to guide the use of chemotherapeutics. Nature Medicine 13(11):1388. Potti, A., D. Harpole, and J. R. Nevins. 2007b. The authors reply: Refining prognosis in non- small-cell lung cancer. New England Journal of Medicine 356(2):190-191. Potti, A., H. K. Dressman, A. Bild, R. F. Riedel, G. Chan, R. Sayer, J. Cragun, H. Cottrill, M. J. Kelley, R. Petersen, D. Harpole, J. Marks, A. Berchuck, G. S. Ginsburg, P. Febbo, J. Lancaster, and J. R. Nevins. 2008. Corrigendum: Genomic signatures to guide the use of chemotherapeutics. Nature Medicine 14(8):889. Potti, A., H. K. Dressman, A. Bild, G. Chan, R. Sayer, J. Cragun, H. Cottrill, M. J. Kelley, R. Petersen, D. Harpole, J. Marks, A. Berchuck, G. S. Ginsburg, P. Febbo, J. Lancaster, and J. R. Nevins. 2011a. Retraction: Genomic signatures to guide the use of chemo- therapeutics. Nature Medicine 17(1):135. Potti, A., S. Mukherjee, R. Petersen, H. K. Dressman, A. Bild, J. Koontz, R. Kratzke, M. A. Watson, M. Kelley, G. S. Ginsburg, M. West, D. H. Harpole, Jr., and J. R. Nevins. 2011b. Retraction: A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. New England Journal of Medicine 364(12):1176. Ready, N. 2010. Phase II Prospective Study Evaluating the Role of Directed Cisplatin Based Chemotherapy with Either Vinorelbine or Pemetrexed for the Adjuvant Treatment of Early Stage Non-Small Cell Lung Cancer (NSCLC) in Patients Using Genomic Expres- sion Profiles of Chemotherapy Sensitivity to Guide Therapy. Durham, NC: Duke Uni- versity Medical Center. Review of Genomic Predictors for Clinical Trials from Nevins, Potti, and Barry. 2009. Durham, NC: Duke University. Singh, T., and J. Dhindsa. 2007. To the editor: Refining prognosis in non-small-cell lung cancer. New England Journal of Medicine 356(2):190. Sun, Z., and P. Yang. 2007. To the editor: Refining prognosis in non-small-cell lung cancer. New England Journal of Medicine 356(2):189-190. TMQF (Translational Medicine Quality Framework) Committee. 2011a. Draft Table of Cat- egories and Areas of Improvement Related to TMQF. Durham, NC: Duke University. TMQF Committee. 2011b. A Framework for the Quality of Translational Medicine with a Focus on Human Genomic Studies: Principles from the Duke Medicine Translational Medicine Quality Framework Committee. Durham, NC: Duke University.

OCR for page 239
280 EVOLUTION OF TRANSLATIONAL OMICS Vlahovic, V. 2010. Phase II Prospective Study Evaluating the Role of Personalized Chemo- therapy 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. Durham, NC: Duke University Medical Center. Zuiker, A. 2008. Building a Just Culture. http://inside.duke.edu/article.php?IssueID=183& ParentID=17859 (accessed November 22, 2011).