Select one of the two cases given below. In 2 pages, make a well-reasoned ethical argument that answers the question given at the end of the case.

Select one of the two cases given below. In 2 pages, make a well-reasoned ethical argument that answers the question given at the end of the case. Towards that end, our paper should demonstrate consideration of:

1. Ethical issues in the case
2. Interested parties and the rights, interests, and reasonable expectations of those parties
3. Legal standards, ethical principles, institutional policies, and other rules or guidelines relevant for analyzing the case
4. Two to four possible responses to the question (options on how to proceed)
5. Consequences of these possible responses/options you identify
6. An explanation(especially including ethical arguments) of the response/option you would select

Notes: Your case analysis should draw and cite at least 5 readings or media assigned for class.When you draw on course materials, you need to cite them appropriately.

Your essay should include in-text citations or footnotes and a bibliography or works cited list. You may use any major citation system you are comfortable with—MLA, APA, Chicago, etc. But, pick one system, know how to use it, and use it consistently. You are NOT expected to do research beyond the readings and other materials assigned for

class or presented in lecture or recitation. Citations to materials beyond course assignments are acceptable, if appropriately done, but do not count towards citing 5 course

sources.

On Form

Responses should be:

• Submitted via BlackBoard as a .DOC, .DOCX, or a .PDF file

•12 point font with a standard typeface with 1-inch margins

For grading criteria, refer to the rubric further down on this document.

BIO 416, Case Analysis 2

Case 1:

A group of researchers have studied the vulnerability of the U.S. milk supply to attacks. They have identified weak (unsecure) points in the milk supply and have developed a

mathematical model that predicts how many people will be killed when different amounts of the toxin are dumped into the supply at different points. They have submitted their work for publication in a top-tier journal. The National Institutes of Health (NIH), which funded the research, has contacted the editors and asked them to stop the publication. The agency is concerned that the publication will provide information that terrorists can use for an attack. The editors of the journal want to go ahead with publishing the article, because they feel that the benefits of the research will out weigh the risks. The editors believe that publishing the research will alert milk suppliers and public health officials to the significance of the problem and motivate them to take effective action to secure the milk supply. The editors and officials from NIH have a meeting to discuss these issues.How should the researchers, editors, and NIH officials handle publication of this research?

Shamoo, Adil E.; Resnik, David B.Responsible Conduct of Research (p. 299). Oxford University Press. Kindle Edition.

Case 2: The Translational Omics Case at Duke

Omics is the study of molecules in cells, such as DNA sequences (genomics) and proteins (proteomics). Translational omics research seeks to apply this new knowledge to the creation of diagnostic tests that better detect disease and determine individualized treatment. Translational omics involves several significant challenges. Research "generates complex high-dimensional data" and resulting diagnostics are characterized by "difficulty in defining the biological rationale...based on multiple individual biomarkers" (IOM, 2012). In addition, diagnostic tests differ from drugs and other medical technologies regarding regulatory oversight; tests may be reviewed by the Food and Drug Administration, or be validated in a CLIA-certified laboratory (Clinical Laboratory Improvement Act).Beginning in 2006, a series of papers appearing in major journals such as Nature Medicine and the New England Journal of Medicine purported to show that the gene activity in a patient's tumor cells could be used to determine which chemotherapy drugs would be most effective for that patient. This capability would enable significant advances in cancer treatment. Since individual reactions to these drugs are heterogeneous, the drugs that are effective for one person may not be effective for another. The lead author of the papers was cancer researcher Anil Potti, who worked at Duke University in the lab of Joseph Nevins.Soon after the first papers were published, Keith Baggerly, Kevin Coombes, and Jing Wang, bioinformaticians at the M. D. Anderson Cancer Center of the University of Texas, began working to replicate the results. They immediately encountered difficulties using the data made publicly available with the paper, and began communicating with Potti and Nevins. Data provided by the Duke team to Baggerly, Coombes, and Wang contained numerous anomalies and obvious errors, making it impossible to replicate or verify the results. A correspondence by the M. D. Anderson researchers submitted to Nature Medicine in 2007 raising these issues was quickly rebutted by Potti and Nevins (Coombes et al., 2007; Potti and Nevins, 2007). However, when Baggerly, Coombes, and Wang examined additional information provided by the Duke team they found that there were still significant problems. For example, in some cases, sensitive and resistant labels for cell lines were reversed, which would lead to patients being treated with the least effective chemotherapy drug if the tests were used to direct treatment, rather than the most effective.

Over the next several years, in response to interest expressed by M. D. Anderson clinicians in utilizing the advances that continued to be reported by Potti and Nevins, Baggerly and Coombes worked with the data. In several cases where they discovered clearly incorrect results, they submitted correspondence to journals such as Lancet Oncology, Journal of Clinical Oncology, and Nature Medicine, but these were rejected without explanation (Baggerly, 2012; Baggerly, 2010).

Committee on Science, Engineering, and Public Policy, Policy and Global Affairs, and National Academies of Sciences, Engineering, and Medicine, Fostering Integrity in Research (Washington, D.C.: National Academies Press, 2017), doi:10.17226/21896, p. 234-240.

In 2007, at the same time questions were being raised about the data underlying the Nevins-Potti research, Duke University and Duke University Medical Center investigators not associated with Nevins or Potti launched three clinical trials based on the results, and an additional trial was launched at Moffitt Cancer Center (IOM, 2012). Duke also applied for patents, and several companies were working to commercialize the research, including one in which Potti served as a director and secretary (Reich, 2010b; Tracer, 2010). Learning about the trials in June 2009,Baggerly and Coombes prepared a critical analysis of the Duke work, which was published in the Annals of Applied Statistics after it had been rejected by a biomedical journal (Baggerly and Coombes, 2009). In January 2015, the the Cancer Letter, a specialist newsletter, reported that Bradford Perez, a third-year medical student who was working with Potti in the Nevins lab, became very concerned about the methodology and reliability of the research (Goldberg, 2015). He shared these concerns in a detailed memo with Potti, Nevins, and several Duke administrators in the spring of 2008 (Goldberg, 2015). In addition to providing specifics about a number of concerning factors, he asked that his name be removed from four papers based on the work he had contributed to, including a paper submitted to the Journal of Clinical Oncology, and left the Nevins-Potti laboratory (Perez, 2008). Rather than catalyzing any independent assessment of the serious

concerns raised by Perez about the quality of the research, Duke administrators referred him back to Nevins with no apparent follow-up by any institutional official. Nevins and Potti committed to revalidate all of their work, but it appears that this did not happen. Perez left the Nevins lab knowing he would repeat a year of his medical education, in his words, "to gain a more meaningful research experience" (Perez, 2008). As noted in a 2012 Institute of Medicine (IOM) report discussed further below, Duke "did not

institute extra oversight or launch formal investigations of the three trials during the first 3 years after the original publications triggered widely known controversy about the scientific claims and after concerns started to develop about the possible premature early initiation of clinical trials" (IOM, 2012). Not only did Duke's administration fail to act decisively on Perez's suspicions, but an administrator who counseled Perez on the matter did not even inform the IOM committee that Perez had come forward years earlier (Goldberg, 2015; IOM, 2012). In response to the 2015 revelations by the Cancer Letter, Duke Medicine officials did not answer specific questions, but did state that "there are many aspects of this situation that would have been handled differently had there been more complete information at the time decisions were made" (Goldberg, 2015).

National Cancer Institute (NCI) researcher Lisa McShane had also been unsuccessful in attempts to replicate the work (Economist, 2011). In the fall of 2009, NCI expressed concern about the clinical trials at Duke as well as the parallel trial at Moffitt. The trials were suspended, and Duke's Institutional Review Board formed an external review panel to evaluate the concerns. The Duke trials were restarted in early 2010 after the review panel concluded that the approaches used in the trials were "viable and likely to succeed" (IOM, 2012). During the first half of 2010, NCI continued to raise questions about the research. Through a Freedom of Information Act request submitted by the Cancer Letter it was revealed that the external review panel was not provided with several critical pieces of information, including a detailed description of the statistical methods used in the original research, and a new critique from Baggerly and Coombes based on analysis of updated data posted by Potti and Nevins (Duke University, 2009; Baggerly, 2010). About that material, the 2012 IOM report notes that it "was never forwarded to the external statistical reviewers because of the university leadership's

concerns that it might 'bias' the committee's review" (IOM, 2012).Several developments in July 2010 brought matters to a head. It was reported that Potti's claim on

his resume that he had been a Rhodes Scholar was exaggerated, and this was confirmed by the University of Oxford(Goldberg, 2010; Singer, 2010). Also, several dozen prominent biostatisticians wrote to NCI director Harold Varmus to request that the clinical trials based on the Duke research be suspended until the science could be publicly clarified (Barón et.al., 2010;Singer, 2010). Duke suspended the trials and suspended Anil Potti's employment in response. The trials were ultimately terminated and Potti left Duke. Starting in the fall of 2010, a number of the papers reporting the Duke results have been retracted.Over the time since the trials were suspended, there have been several significant developments.NCI asked the Institute of Medicine to develop principles for evaluating omicsbased tests, and IOM released its report in 2012 (IOM, 2012). Drawing on lessons from the Duke case and informed by the development of other omics-based tests, the IOM report lays out a recommended development and evaluation process for these tests, and makes specific implementation recommendations to researchers, institutions, agencies, and journals (IOM, 2012).Duke University has also taken steps to respond (Califf, 2012). Its Translational Medicine Quality Framework emphasizes new science and management approaches to ensure data provenance and

integrity, the incorporation of adequate quantitative expertise, explicit management accountability in the institution beyond the individual lab for research affecting patient care, and enhanced conflict-of-interest reviews.In 2015, ORI concluded that Potti had "engaged in research misconduct by including false research data," citing specific examples of Potti's data that had been reversed, switched, or changed in a number of (now retracted) articles and other submissions (ORI, 2015). While Potti did not "admit

nor deny ORI's findings of research misconduct," he has expressed that he has no intention of applying for PHS (Public Health Service)-funded research, but agreed that if he is engaged with any PHS-funded research in the future, his research will be supervised for 5 years (ORI, 2015).In this case, just about all the scientific checks and balances intended to uncover incorrect or fabricated research and protect human subjects failed over the course of several years. A summary of these failings illustrates some of the US research enterprise's key vulnerabilities regarding integrity. Effective steps on the part of Duke to address the problems with Potti's work and investigate possible misconduct were delayed for years, and were finally triggered only by the disclosure of Potti's resume falsification. Those pointing out these problems were appropriately cautious about making formal allegations of misconduct, since there was a possibility that the problems were due to error or extreme sloppiness rather than falsification. Another contributing factor was the willingness of Joseph Nevins, a highly prestigious researcher, to vouch for the work and advocate for Potti with university administrators and others. Individual Researchers Anil Potti's misbehavior is at the center of the case. Prior to ORI's conclusion of research misconduct, Joseph Nevins and Robert Califf had both said that it is highly likely that Potti intentionally fabricated or falsified data (CBS News, 2012). In addition, Baggerly, Coombes, and Wang had documented many instances of sloppy or careless data analysis, and Perez documented use of unreliable predictors and omission of data not showing desired results. The negative impact of such sloppy and careless practices on the ability to replicate results and ultimately on patient care might be similar to the impact of fabrication or falsification.In addition to problems with data and analysis, the IOM committee described a number of poor practices related to the clinical trials for the tests, including trials being undertaken simultaneously with preliminary studies (IOM, 2012). Potti's collaborators also share responsibility. For example, despite being principal investigator of

the lab where the research was undertaken, as well as Potti's mentor and coauthor, Joseph Nevins did not thoroughly check the original data files until after it was revealed that Potti had exaggerated his credentials in July 2010, more than 3 years after the data issues were originally raised (CBS News, 2012). Moreover, we now know from a deposition cited in court documents that Nevins "pleaded with Perez not to send a letter about his concerns to the Howard Hughes Medical Institute, which was supporting him, because it would trigger an investigation at Duke" (Kaiser, 2015). Indeed, Duke administrators testified to the IOM that none of Potti's coauthors (a total of 162 for 40 papers) raised any questions or concerns about the papers or tests until they were contacted by Duke at the start of the process of determining which papers should be

retracted (IOM, 2012). Bradford Perez, the medical student described above, did raise concerns and removed his name from the papers that he contributed to, so his documented concerns were apparently not considered when that statement was made. Nevins remained on faculty as a department chair until his retirement in 2013, the year after the IOM report was released.Institutional Policies and Procedures In addition to the failures of individual researchers, lessons can be drawn from the responses by

Duke as an institution during the controversy. Institutional shortcomings in policies and procedures, structure, systems, and oversight contributed to delays in recognizing that the science underlying the Nevins-Potti research was unsound. First, Duke's Institute for Genomic Science and Policy and its component Center for Applied Genomics and Technology, where Nevins and Potti worked, instituted its own system for undertaking clinical trials, separate from the extensive existing infrastructure of the Duke Cancer Center (IOM, 2012). This parallel pathway lacked the normal checks and balances as well as clear lines of authority and oversight. In addition, systems for managing conflicts of interest at the individual and institutional levels were inadequate (IOM, 2012). For example, the IOM committee found evidence that researchers involved with undertaking the clinical trials had unreported financial or professional conflicts of interest. Some investigators held patents on one or more of the tests, or had links with one of the

companies founded to market the tests. The institution itself, through its licensing relationships, had a financial interest in the success of the tests, as well as a reputational interest in having generated such an important new technology. It is of note that the institution had created a set of video and print materials featuring the research (CBS News, 2012; Singer, 2010). As noted in the 2012 IOM report, as a "responsible party" for assuring the integrity of the science conducted under their auspices, universities have particularly important responsibilities. These include responsibility for the hiring and promotion of the faculty members conducting research, the establishment and maintenance of oversight structures, and responsibilities for properly responding to and resolving questions about the validity of research or allegations of misconduct

when they arise. It also includes the responsibility for ensuring the existence of an organizational culture and climate that sets expectations for research integrity that "are transmitted by the institution and modeled by its leadership. Institutional culture starts with the dean, senior leaders,and members of their team stating how research is to be

conducted, with integrity and transparency, and with clarity that shortcuts will not be tolerated and that dishonesty is the basis for dismissal" (IOM, 2012). The evidence now available, some that has come to light only after Freedom of Information Act r quests and court depositions, suggests that Duke University and its leadership failed in virtually

all of these responsibilities: from undertaking clinical studies outside the established review structures; for the failure to pursue internal investigation of serious, documented concerns until forced by outside forces to do so; for withholding from an external committee the full Baggerly/Coombes critique; to referring responsibility for rechecking Potti's work back to the laboratory of his (explicitly conflicted) principal investigator, Joseph Nevins; to failing to employ the full set of institutional checks and balances that were in place; and to either incomplete or factually unsupportable statements made to the IOM Committee charged with examining the issue.The breadth and depth of these institutional failings are disappointing. Occurring in an institution of Duke's stature and resources, they raise troubling questions about the ability of research institutions, without more support and reinforcement, to manage complex cases when directed against prominent institutional researchers.Duke suspended the trials and launched an investigation in the fall of 2009 in response to NCI concerns. However, this investigation had several serious flaws. Although the trials were resumed based on the report of the two external statistical experts, as noted above, these experts were not provided with several critical pieces of information. The IOM report also raises the possibility that

Nevins was improperly in direct contact with the reviewers during the inquiry (IOM, 2012). As for the clinical trials that were undertaken based on the fabricated work, 117 patients were ultimately enrolled. Duke later faced a lawsuit brought by the families of eight of these patients, which was settled in May 2015. The terms of the settlement were not disclosed (Ramkumar, 2015). In its Translational Medicine Quality Framework activity, Duke also identified an environment that might discourage postdocs or grad students from raising concerns with research within the lab or taking their concerns to others at the university as a possible problem. The university reported that it has established an ombudsman's office and taken other steps to address this. Taken together, these institutional failings raise the question of whether, in addition to

strengthening policies and procedures to the extent possible, research institutions should explore new mechanisms for bringing in outside perspectives in cases where it might be difficult for an institution to objectively address allegations of misconduct or other challenges to the soundness of science. In 2016, four members of the IOM committee published a piece critical of how Duke handled the case as an institution (DeMets et al., 2016). Journal Policies and Practices Although Nature Medicine and the Journal of Clinical Oncology did publish letters from Baggerly, Coombes, and Wang questioning the validity of data, along with responses from Potti, they rejected further questioning of the Duke results.This is likely the result of the common journal practice of not publishing additional comments on an article that appear to repeat concerns

already raised in a previously published comment, so as to avoid involving the journal in an ongoing dispute. Further, other journals that had published other articles reporting the Nevins-Potti work were not responsive to questions raised by Baggerly and Coombes. This stance contributed to delays in recognizing the nature and extent of the problems with the papers. The translational omics case raises issues of how scholarly publishers, institutions, and the broader community should respond when the work underlying numerous papers in a variety of journals is questioned.Sponsor and Regulator Policies and Practices The IOM report identifies some ambiguities in Food and Drug Administration requirements for launching clinical trials on diagnostics as possibly contributing to the clinical trials being launched prematurely and to delays in finally shutting them down (IOM, 2012). The IOM report also points out that NCI felt constrained in communicating what it knew and the extent of its concerns with

Duke and others early in the case, particularly before officials were aware that the agency was supporting aspects of the clinical trials (IOM, 2012). More direct and complete communication would be helpful in future cases.This case has numerous ethical failings in respect to misconduct, research with human subjects, and social responsibility and on the part of the reserachers,the university, and the journals. Which failings were most severe? Identify at least 3 ethical failures in this case and analyze their relative severity. Rank the violations by importance /seriousness (severity) and make an ethical argument to explain your order. Note: In making a rational argument you will want to avoid phrases such as "I think" or "I feel" and instead say something like "I chose this because...."