THE ROLE OF THE OFFICE OF RESEARCH INTEGRITY IN CANCER CLINICAL TRIALS
Peter Abbrecht, MD, PhD, Nancy Davidian, PhD, Samuel Merrill, PhD and Alan R. Price, PhD
Office of Research Integrity, Department of Health and Human Services, Rockville, MD, USA
NOTE: The views expressed in this article are those of the authors and do not necessarily reflect those of the Office of Research Integrity, the United States Department of Health and Human Services, or any other Federal agency.
1. INTRODUCTION
This chapter stresses the importance of integrity in cancer clinical trials and provides examples of cases of research misconduct, handled by the Office of Research Integrity and its predecessor, the Office of Scientific Integrity, for the National Institutes of Health and the Department of Health and Human Services, in which clinical research coordinators, research nurses, and physicians did not maintain high standards of integrity in their research records.
2. BACKGROUND
In 1989, the National Institutes of Health (NM) created the Office of Scientific Integrity (OSI), in response to Congressional concerns about public reports of fraud in biomedical and clinical research supported by NM at major universities and research hospitals. Simultaneously, the Department of Health and Human Services (HHS) issued regulations for research institutions to deal with allegations of scientific misconduct (42 Code of Federal Regulations, Part 50, Subpart A). These regulations required institutions that receive NM and other U.S. Public Health Service (PHs) research funds to conduct inquiries and investigations when warranted, and to provide reports to OSI on such investigations, whether they found scientific misconduct (for falsification, fabrication, or plagiarism in research) or no misconduct, for further review or
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investigation by OSI. In 1992, HHS moved OSI into the Office of the HHS Secretary, and OSI was renamed the Office of Research Integrity (ORI). In 2000, based on recommendations from NIH and an HHS Review Group on Research Integrity, OR1 ceased under PHs policy to conduct independent investigations in the extramural or PHs intramural programs. Instead, OR1 depended on receiving institutional investigation reports, followed by thorough oversight by ORI, which negotiated voluntary agreements with respondents who committed misconduct or recommended findings of scientific misconduct to the HHS Assistant Secretary for Health (ASH) for charge letters of proposed misconduct findings, which could be appealed to the Departmental Appeals Board (DAB) for a formal public hearing before a DAB tribunal. In 2005, HHS published a revised regulation on research misconduct (42 Code of Federal Regulations, Part 93), effective June 16, 2005, in which OR1 negotiates with or makes findings of research misconduct against respondents, for falsification, fabrication, or plagiarism in proposing, performing, or reviewing research or in reporting research results. In the revised regulation, the former PHs term "scientific misconduct" was changed to "research misconduct" to be consistent with the Government-wide terminology developed by the Office of Science and Technology Policy. ORI's findings may be appealed to the DAB for a hearing before an administrative law judge, whose decision is provided to the ASH for decision and HHS action. ORIIHHS publishes formal notice of its findings of research misconduct, with the name of the respondent(s), hisfher title, the institution at which helshe committed research misconduct, and the HHS administrative actions taken against the respondent(s), including requirements for requesting correction or retraction of falsified papers, in several Federal publications: Federal Register, GSA Debarment List online (for debarment), NIH Guide for Grants and Contracts, and ORI's Website (http://ori.hhs.rzov), Newsletter, and Annual Report, all of which can be reached through Internet searches.
In the 16 years since 1989 under this system, over 700 formal cases involving inquiries and investigations have been handled by OSI and ORI. OSI made 25 findings through 1991, and OR1 has made 164 findings of scientific misconduct between 1992 and November 2005.
Of the OR1 findings, 14 involved cancer-related clinical trials (see Table). Of these, 12 addressed either cancer treatment or prevention, while one (Ms. Conrad) was a case control study of radon-related lung cancer and another (Dr. Fossel) was a study of the possible use of nuclear magnetic resonance (NMR) spectroscopy on blood to detect the presence of malignant disease. Only four of the respondents found by OR1 to have committed scientific misconduct in cancer clinical trials held degrees above the baccalaureate level, with three M.D. (Drs. Poisson, Tewari, and Herman) and one Ph.D. (Dr. Fossel) degrees. Except for the M.D.-Postdoctoral Fellow (Dr. Tewari), the remaining doctoral degree holders were all Principal Investigators (P.1.s) for the studies in which they committed misconduct. Three of the other respondents were registered nurses. The ten non-doctoral degree holders were all in positions of data manager, study coordinator, clinical research coordinator (CRA), or research program coordinator (one being designated a research assistant and another a research associate).
The majority of the trials listed in the Table (9 of 14) were sponsored by the National Cancer Institute (NCI), either through cooperative arrangements (National Surgical Adjuvant Breast and Bowel Project [NSABP] and the Southwest Oncology Group [SWOG]) or by individual N M research project grants. In addition, significant clinical cancer trial support was provided by the National Eye Institute (NEI), through its Collaborative Ocular Melanoma Study (COMS); by the National Institute of Environmental Health Sciences (NIEHS); and by the NIH Division of Research Resources (DRR) (now the National Center for Research Resources, NCRR) through its General Clinical Research Centers (GCRC) funding.
The instances of falsification and or fabrication in these cancer trials occurred either in an effort to enroll patients who did not meet all of the eligibility requirements for a study, an attempt to improve the apparent outcome of the study, or to provide data required for the protocol for research work that was not actually done.
Some examples of such OR1 clinical cancer research cases follow:
Roger Poisson, M.D., who was a surgeon at St. Luc Hospital in Montreal, Canada, had instructed his research staff to falsify or fabricate at least 177 records of laboratory tests and dates of procedures conducted between 1977 and 1990 for the NCI-supported mastectomy vs. lumpectomy cancer treatment trial of the NSABP. Instances of scientific misconduct included falsifying and failing to report conditions that would have disqualified a patient for trial entry (peau d'orange skin change in breast cancer, congestive heart failure in a patient enrolled in a trial with cardio-toxic drugs, inadequate white blood cell count for initiation of chemotherapy), misrepresentation of biopsy site for estrogedprogesterone receptor assays
234 Chapter 13 (primary tumor vs. axillary nodes), and fabrication of follow-up data, including continued reports of contacts with a patient who was deceased.
Dr. Poisson gave various explanations for his actions, such as "Our cardiologists felt that she was a good candidate and we accepted their words" for the patient with congestive failure. In 1993 Dr. Poisson was debarred by ORI/HHS from Federal funding and prohibited from serving on PHs advisory groups for 8 years.
Vicki Hanneken, R.N., who was a CRA at Decatur Memorial Hospital in Illinois, falsified or fabricated clinical and study records in 60 instances for 35 patients in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), funded by NCYNIH through SWOG. Prior to being appointed to the CRA position, Ms. Hanneken had worked for a decade as an oncology home care and hospice nurse, receiving outstanding evaluations. However, in her work on the SELECT trial, Ms. Hanneken apparently had difficulty in collecting the required patient data. Her acts of scientific misconduct included fabrication and falsification of patients' laboratory values on original and source documents, falsification of information on patients' clinical progress records, and alteration of visit and laboratory report dates to fit the protocol time windows. The falsifications were done to make it appear that the trial was being conducted in such a manner that protocol requirements were met for patient eligibility and continuation in the study.
Ms. Hanneken entered into a Voluntary Exclusion Agreement (VEA) in which she agreed to exclude herself from contracting or subcontracting with any U.S. Government agency and from serving in any advisory capacity for PHs for 3 years.
Eric Fossel, Ph.D., who was an Associate Professor of Radiology at Beth Israel Hospital and Harvard Medical School in Boston, altered NMR imaging data from a privately-funded Multi-Center Breast Trial and reported these falsified results in an NIH grant application, claiming a falsely high sensitivity for a diagnostic blood test for predisposition to malignancy or relapse. Although purportedly blinded to diagnoses, Dr. Fossel obtained the patients' diagnoses by reference to the patients' clinical records (through his wife, who was a co-investigator) and through access to the Hospital's electronic records. He then altered the line-width data to match the patients' diagnoses. In 1996, Dr. Fossel entered into a VEA with the PHs to exclude himself from contracting or subcontracting the Federal Government and from serving as a PHs advisor for 3 years.
Thomas Philpot, R.N., was an experienced research nurse who committed scientific misconduct while employed at two institutions, Rush-Presbyterian- St. Luke's Medical Center (RPSLMC) and MacNeal Cancer Center, an NSABP-affiliate of Northwestern University (NWU). According to the
record, he developed an exceptional rapport with his research patients and trained new personnel in the collection, documentation, and reporting of clinical research data. Mr. Philpot committed misconduct by fabricating telephone contacts with NSABP protocol patients and fabricating data on patient survival, treatment failure, and morbidity that were submitted to the NSABP Biostatistical Center. One of Mr. Philpot's misconduct incidents at RPSLMC was discovered by a routine computer check. The incident at MacNeal was uncovered during a routine audit of NSABP records by NWUINSABP staff. OR1 charged Mr. Philpot with scientific misconduct and required a 3-year supervisory plan for him in any PHS-supported clinical research.
Vivian Tanner, who was designated as the Clinic Coordinator for COMS research at the Cleveland Clinic Foundation (CCF), had to be certified by COMS. Her specific responsibilities, as set forth in the COMS Manual of Procedures, included scheduling patient visits and surgical procedures, maintaining and reviewing all CCF study documentation, and reporting the data to the COMS Data Coordinating Center (DCC). Misconduct by Ms.
Tanner was initially detected during a routine clinic monitoring visit at CCF by the COMS DCC. Over a number of years she falsified and fabricated research data (physical examination, blood test and chest X-ray results) for 21 of the 24 patients. HHS debarred her from participation in federal grants and contracts for a period of 3 years.
Terence Herman, M.D., was an Associate Professor of Radiation Therapy at Harvard Medical School (HMS), a staff member of the Joint Center for Radiation Therapy, and a member of the Division of Radiation Oncology at the Dana Farber Cancer Institute (DFCI). His misconduct occurred in a clinical trial of trimodality (cisplatin, hyperthermia, and radiation) treatment of superficial malignant tumors. The protocol called for the physician to make sequential measurements of two dimensions of each tumor during the course of treatment, and the response was to be assessed by the degree of measurable reduction in tumor size. However, Dr. Herman did not routinely measure tumors, by caliper, ruler, CT scan, or any other objective means, and he published fabricated or falsified measurements in a paper in the International Journal of Radiation Oncology~Biology*Physics in 1989, leading him to report a falsely large number and magnitude of positive responses to hyperthermia therapy. Suspicion of misconduct was raised by a co-worker and resulted in an internal audit of his protocol by the DFCI Quality Control Center, followed by a joint investigation by HMS and DFCI.
Dr. Herman entered into a VEA with OR1 to be supervised for a 3-year period for any PHS-sponsored research in which he was involved and to retract that portion of the questioned paper that dealt with tumor response.
236 Chapter 13 As illustrated in the cases described above, the administrative actions imposed by OR1 against respondents involve debarment from Federal funding, typically for 3 to 5 years; close supervision of their future research;
andlor special certification of their research. All of the respondents in the Table were also prohibited from serving on P H s advisory groups for a certain period.
The proportion of doctoral degree holders (29%) among those who committed misconduct in the small OR1 sample represented in the Table is markedly lower than that in the remainder of ORI's scientific misconduct findings cases (approximately 65%), reflecting the fact that the P.1.s on N M grants (generally doctoral degree holders) tend to be the respondents more frequently involved in non-clinical cases involving laboratory research than involved in clinical trials.
Although most of the respondents who committed misconduct in the cancer clinical trials were relatively low ranking staff members, rather than P.I.s, several of the institutional reports to OR1 noted that lack of supervision, training, oversight, and on-site presence by the P.I. may have contributed to the occurrence of or opportunity for misconduct.
In ORI's experience, most of the problems in clinical research, including cancer clinical trials, arise from overworked physicians/researchers who do not maintain careful oversight over trials; overloaded clinical research coordinators or research nurses, who did not have time to complete their work and paper requirements; poorly trained clinical research staff; pressure to enroll patients; other job-related problems; or personal/home problems.
The problems with clinical data integrity are reported by internal quality control groups; external quality control groups, like data coordinating centers or external auditors; co-workers and colleagues; direct supervisors;
and patients or their care-givers who contact the trial appointment desks.
These problems in clinical research go beyond the OR1 issues of falsification and fabrication of clinical and study records and reports. They lead to other non-OR1 matters, such as failing to report adverse events to the institutional review board (IRB), to the sponsor, or to the Food and Drug Administration (FDA); failing to obtain or to document informed consent;
deviating from the clinical trial protocol, such as including a subject who was ineligible or administering another drug that was off-protocol, so long as the patient and research records were accurately reported; failing to obtain IRB or FDA approval for changes made in a formally approved protocol;
forging a physician's signature on medical orders; or breaching a patient's or subject's confidentiality. While these are not OR1 issues, they fall under FDA or HHS Office for Human Research Protections (OHRP) authority and are addressed by those offices.
In addition, NCI's Clinical Trials Monitoring Branch (CTMB) expects all cooperative clinical trial groups and individual institutions to report any data
discrepancies or evidence of manipulation of clinical data or records.
NCYCTMB staff then notifies OR1 about pending audits of such trials, and OR1 staff often attend as observers, seeking to preserve any evidence of falsification or fabrication that may constitute research misconduct. OR1 may then work with the research university or hospital to ensure an appropriate inquiry andfor investigation if the evidence of significant misconduct is sufficient (OR1 does not expect or want cooperative clinical cancer groups themselves to try to investigate misconduct at their member institutions, where they generally lack administrative authority over the property or personnel in question).
OR1 remains interested in working with clinical research investigators and their staffs, including the critically important CRAs, to detect early or prevent such problems in clinical research, which may lead to research misconduct and public exposure. To that end, OR1 has sponsored several conferences (see htt~:Nori.hhs.novlconferences), including "Fostering Integrity in Clinical Research at Academic Medical Centers" in 2001 in Baltimore; "Enhancing Integrity in Clinical Research" in 2003 at the University of California at Los Angeles; "The Research Coordinator:
Strategies for Promoting Integrity in Clinical Research" in 2005 at the University of Pennsylvania; and ""CSI" for Clinical Investigators: Making the Case for Integrity and Examining the Causes of Misconduct in Research," an ORI/Physicians for Responsibility in Medicine and Research pre-conference workshop for clinical researchers in 2005 in Boston. OR1 welcomes expressions of interest from cancer clinical trials researchers and CRAs in further educational meetings.
3. CONCLUSION
This chapter stresses the importance of integrity in cancer clinical trials and provides examples of cases of research misconduct, handled by the Office of Research Integrity and its predecessor, the Office of Scientific Integrity, for the National Institutes of Health and the Department of Health and Human Services, in which clinical research coordinators, research nurses, and physicians did not maintain high standards of integrity in their research records.
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Table. OR1 findings of scientific misconduct in cancer-related clinical trial cases Respondent's
I
Anand
Catherine
err^
I-
Vivian N.
F
Gail L.
Daubert, RN Eric Fossel,
I-
Rankltitle of respondent Staff Surgeon
Postdoctoral Fellow, Surgery Research Assistant, Preventive Medicine Associate Professor, Radiation Therapy Data Manager
Data Coordinator
Program Coordinator Clinic Coordinator
Clinic Coordinator
Associate Professor of Radiology
Institution
St. Luc Hospital, Montreal Stanford University
University of 10 wa
Harvard Medical School and Dana Farber Cancer Inst.
St. Mary's Hospital, Montreal St. Mary's Hospital, Montreal University of Arizona Cleveland Clinic Foundation Northwestern University
Harvard Medical School, Beth Israel Hosp.
Sponsor1 funding agency NIH-NCI
NIH-DRR through the GCRC NIH- NIEHS
NIH-NCI
NIH-NCI
NIH-NCI
NIH-NCI NIH-NEI
NIH-NEI
Private foundation
& NCI grant
applications
Clinical cancer trial type NSABP- multisite breast cancer treatment Phase I interleukin- 1 fl
NSCLC treatment Radon exposure, as possible etiology of lung cancer Hyperthermia, single site cancer treatment NSABP multi-site breast cancer prevention NSABP multi-site breast cancer prevention
Breast cancer self-care COMS multi- site ocular melanoma treatment COMS multi- site ocular melanoma treatment NMR spectra use in cancer diagnosis and detection of recurrence
Year OR1 Closed
1993
1994
1995
1995
Ann Marie
~ u e l s k a m ~ "
Maria ~ i a z "
Thomas Philpot, l 3 RN, BSN
Vickie L.
Hanneken, l 4 RN
Research Program Coordinator
Data Manager
Data Manager
Clinical Research Associate
John Hopkins School of Medicine Rush Presbyterian St. Luke's Hospital
Rush Presbyterian, Northwestern University
Decatur Memorial Hospital
NIH-NCI
NIH-NCI
NIH-NCI
NIH-NCI
Metastatic breast cancer treatment and quality of patient life NSABP (breast cancer) and ECOG (lung cancer) prevention NSABP - several multi- site breast cancer treatment protocols SWOG SELECT prostate cancer prevention
REFERENCES
1. Poisson notice: http:Ngrants.nih.gov/grants/guide/notice-files/not93-177.html 2. Tewari notice: http:Ngrants.nih.gov/grants/guide/notice-files/not94-244.html 3. Conrad notice: http://grants.nih.gov/grants/guide/notice-files/not95- 138.html 4. Herman notice: http://grants.nih.gov/grants/guide/notice-files/not95-138.html
5 . Jones notice: http://grants.nih.gov/grants/guide/notice-les/not95-178.html
6. Kerr notice: http://grants.nih.gov/grants/guide/notice-files/not95-233.html 7. Santa Cruz notice: http://grants.nih.gov/grants/guide/notice-files/not96-002.html 8. Tanner: http://ori.dhhs.gov/documents/newsletters/vol3~no3.pdf
9. Daubert notice: http://grants.nih.gov/grants/guide/notice-files/not96-080.html 10. Fossel notice: http:Ngrants.nih.gov/grants/guide/notice-files/not96-160.html 1 1. Huelskamp notice: http:Ngrants.nih.gov/grants/guide/notice-files/not97-097.html 12. Diaz notice: http://grants.nih,gov/grants/guide/notice-files/not99-057.html 13. Philpot notice, http:Ngrants.nih.gov/grants/guide/notice-files/not99-028.html 14. Hanneken notice, http://grants.nih.gov/grants/guide/notice-files~OT-OD-04- 038.html
