News from the Staff

University of Oklahoma at Tulsa

To: Christiana Care Research Community
From: Jerry Castellano, PharmD
Date:7/11/2000

In the first disciplinary action by the newly elevated Office for Human Research Protections (OHRP) formerly OPRR, the University of Oklahoma at Tulsa was ordered to cease all research programs.The story has first appeared in yesterday's USA Today and has been subsequently picked up by the major news organizations.

Copies of the letter are available from the IRB Office upon request.

U.S. Halts Cancer Tests In Oklahoma

By Rick Weiss and Deborah Nelson
Washington Post Staff Writers
Tuesday, July 11, 2000; Page A01

Federal regulators have shut down all government-funded human medical experiments at the University of Oklahoma Health Sciences Center in Tulsa amid evidence that researchers there broke multiple rules designed to protect patients and then tried to cover up their lapses by withholding information from university overseers and patients.

Among the concerns that led to the unusually severe disciplinary action were that dozens of cancer patients may have been injected with experimental cancer-fighting vaccines contaminated with dangerous bacteria or viruses; that 11 of the first 18 patients to get the vaccines were not eligible for the study; and that the informed-consent form given to volunteers overstated the possible benefits of the experiment and understated the risks.

University officials said yesterday they were looking into the lapses but had found no evidence that any patients had been harmed.

The research suspension, which affects about 75 studies on campus, represents the first major disciplinary action by the newly constituted federal Office for Human Research Protections (OHRP). Health and Human Services Secretary Donna E. Shalala created the office in the past month in response to a growing recognition of the need for enhanced federal oversight of human clinical studies.

Michael Carome, OHRP's chief of compliance, sent a 17-page letter to University of Oklahoma officials on June 29, outlining a plethora of patient protection failings. Most were related to a study of the experimental cancer vaccine, which had been approved for use in 40 patients with advanced melanoma--a deadly form of skin cancer--but which was actually injected into at least 90 patients. The study was led by Michael McGee, who was vice chairman of the university's department of surgery until recently, when he was relieved of that status.

According to OHRP's letter, first described yesterday in USA Today and obtained by The Washington Post, McGee's department asked a private consulting group to conduct an independent audit of the work early this year.

Among that group's March findings: The university researchers making the cancer vaccine were not qualified to do so; the techniques used could not ensure that the vaccine doses were produced free of contamination; the vaccines were being shipped to remote locations for injection into patients without proper assurance that they remained cold enough and were administered properly; and there was no reliable system for determining whether illnesses experienced by vaccine recipients--indeed, whether any of the 26 deaths that occurred among those patients--were due to the vaccine.

The auditors recommended that the experiment, which they said suffered from "egregious" lapses, be discontinued immediately, "since adequate precautions to protect the safety of patients have not been taken." The auditors also noted that "liability and public relations issues could surface as a result of this trial," according to a subsequent memo from McGee's boss, the chairman of surgery, to the university's dean.

But certain key details of that report, including the possibility that patients may have been harmed by the vaccine, were not immediately forwarded to the university's Institutional Review Board (IRB), which is responsible for ensuring patient safety in clinical studies, or to surviving patients, as is required by federal regulations and international principles of human medical research.

Instead, in an April 10 letter to participating researchers and surviving patients, and in a May 17 report to the IRB, McGee wrote that the study had been suspended because so many patients had expressed interest in the study that they had run out of vaccine. McGee also wrote that there "are no significant safety issues."

In a telephone interview yesterday, Ken Lackey, president of the university's Tulsa campus, said the school had recently hired consultants to review each patient's medical chart and look for evidence that any may have been harmed by the vaccine. "It certainly appears from that review that all the deaths were from the natural consequences of their diseases," he said.

As for the vaccine samples themselves, he said, "they were all tested and found to be free of contamination."

This past weekend, fulfilling one of OHRP's "required corrective actions," the university sent out new letters to doctors involved in the study, the surviving participants' primary care physicians and the closest known relatives of deceased patients, explaining the truth about why the study was suspended.

Lackey said he had disbanded the university's IRB and relieved two high-ranking research oversight officials of their administrative duties while the university completes its own internal investigation and prepares to come back into compliance with federal regulations.

Staff researcher Alice Crites contributed to this report.

© 2000 The Washington Post Company

Actions OU is taking to correct problems with its research programs in Tulsa

Corrective Actions

1. The University fully complied by June 16, 2000, with the request for documents listed in the OHRP letter of June 12, 2000 (see document 2).

2. The University initiated an independent investigation led by Dr. Michael Hensley of Quintiles (see document 1).

3. The University promptly curtailed the function on June 20, 2000, of the Tulsa IRB pending the results of the investigation (see document 3). Theses actions included; (a) deferring consideration of all new protocols, (b) deferring consideration of all new protocol amendments, and (c) suspending recruitment of all new patients into any of the protocols for which Dr. Michael McGee was principal investigator.

4. The University took several immediate actions upon receipt of the letter of June 29, 2000 (see document 4): a. The Tulsa IRB was immediately suspended. b. Enrollment of new subjects was ceased in all studies of any kind involving human subjects, no only the federally-funded studies as requested by OHRP. c. All active protocols were requested for review by the OUHSC-Oklahoma City IRB. d. Direction was given to limit the continuation of research activities involving previously enrolled subjects to cases in which it is in the best interest of the individual subject.

5. The chairs of the IRBs for each of the four major hospitals in Tulsa were notified by telephone on June 30, 2000, of the suspension of the OUHSC-Tulsa IRB, and were provided a copy of document 4.

6. Dr. Daniel Plunket was removed as the Chair of the OUHSC-Tulsa IRB on July 3, 2000 (see document 5).

7. Dr. Ed Wortham was removed as Director of the Office of Research Administration for the OUHSC-Tulsa on July 3, 2000 (see document 6).

8. Dr. Michael McGee was again instructed not to enroll new patients in any research project and was removed as Vise-Chair of the Department of Surgery for the OUHSC-Tulsa on July 3, 2000 (see document 7).

9. A letter was sent to Cherlynn Mathias, R.N., on July 3, 2000, reaffirming that the University of Oklahoma does not sanction any retaliation in response to her actions (see document 8). This letter reassured her of her protections afforded by all the policies of the University of Oklahoma. It also provided a contact for her should she have any questions about University policy.

10. The University completed required corrective actions 1, 2, and 3 listed on pages 15 and 16 of the letter of June 29, 2000, from OHRP. Corrective actions include a detailed plan for informing surviving patients and the relatives of deceased patients (see document 9). These actions were submitted to OHRP on July 7, 2000. The actions were approved and/or acknowledged by OHRP on July 7, 2000.

11. The University forwarded correspondence on July 7, 2000, to the remote site investigators and IRBs to inform them of the events as requested by OHRP in its letter of June 29, 2000 (see document 10). 1

2. The University immediately began contacting and informing surviving patients of the events that led to the termination of the melanoma vaccine research upon receipt of approval of our plan by OHRP on July 7, 2000 (see document 9).

13. The Oklahoma City IRB implemented a plan on July 7, 2000, for review of previously enrolled subjects in clinical research protocols at the OUHSC-Tulsa campus (see document 11).

14. The University of Oklahoma Health Sciences Center prepared a revised MPA document and is submitting that document with this correspondence (see document 12). The University adopted the recommendation of OHRP that the Senior Vice President and Provost be the sole authorized institutional official for all components of the Health Sciences Center (both the Oklahoma City and Tulsa campuses.). The revised MPA document indicates the addition of a second IRB {IRB-02} in Oklahoma City. The second IRB will be chaired by Dr. Karen Beckman, an experienced IRB member, and previously Vice-Chair of the Oklahoma City IRB {IRB-01}. The IRB membership rosters (see Appendix C of document 12) have been constructed around specific clinical disciplines, and each IRB has community representatives from both Oklahoma City and Tulsa. These IRBs will review all research involving human subjects from both the Oklahoma City and Tulsa campuses. IRB-01 will review protocols primarily form the disciplines of oncology, gynecology, surgery, pulmonary, urology, infectious diseases, and pediatrics. IRB-02 will review protocols primarily from the disciplines of cardiology, neurology, vascular, psychiatry, public health, nursing, dermatology, and ophthalmology. The membership rosters have purposely integrated new members with experienced members on both committees to provide the opportunity for mentoring of new members. Each IRB will meet two times per month.

15. The IRB staff in Oklahoma City is being increased from two full-time positions to five full-time positions. This action was in progress prior to receipt of the letter from OHRP on June 12, 2000. The staff will include a full-time IRB manager {Elizabeth Cothran}, a full-time IRB coordinator, and three full-time clerical staff.

16. All active IRB files from the OUHSC-Tulsa have been transferred to Oklahoma City. All of the active protocols will be reviewed by IRB-01 or IRB-02 in Oklahoma City, before resuming subject enrollment, if OHRP approves this action.

17. The University has scheduled Public Responsibility in Medicine and Research {PRIMR} to conduct a full-day educational session for IRB members on site at the University of Oklahoma Health Sciences Center in Oklahoma City in January 2001. This action had already been taken in May 2000 prior to receipt of the letter from OHRP on June 12, 2000. The date for PRIMR to visit in January was the earliest possible date based on their current waiting list for IRB educational events.

18. University of Oklahoma President David Boren has appointed a university-wide task force chaired by Joseph Harroz, Jr., General Counsel, and co-chaired by Internal Auditor Kenneth Rowe, in pursuit of the highest possible level of adherence to all regulatory requirements for the protection of human subjects in research and for all other federal programs.

Actions That Will Be Taken

The University plans to implement the following elements outlined in the "Human Research Subject Protection Act of 2000" {H.R. 4605 introduced by Ms. DeGette in the House of Representatives on June 8, 2000} (hereinafter "the Act"). Actions 1-4 below will be implemented without waiting for the Act to pass Congress. Modifications and/or additional actions will be implemented in accordance with the final Act.

1. Independent accreditation of the IRB. The Act recommends accreditation of the IRB by a non-profit private entity to be implemented within two years after the date of enactment of the Act. We plan to contract as soon as possible with a non-profit entity for on-going independent accreditation of our IRB.

2. Written attestation by all investigators engaged in research involving human subjects of their familiarity and agreement to comply with Chapter 45 CFR part 46, sub-parts A-D. We propose to have this policy in place at the University of Oklahoma Health Sciences Center by October 1, 2000.

3. Enhanced monitoring of human subject research by independent Data Safety Monotorizing boards (DSMB). We plan to establish, as policy for the University of Oklahoma Health Sciences Center, that for all investigator-initiated research involving human subjects, including federally-funded research, the IRB may request establishment of an independent DSMB as a condition of approval. This will include a process for appointing members to a DSMB and the development of a charter for the DSMB before commencing the research, which outlines its role, responsibilities, and frequency of reporting to the IRB. We plan to have our policy developed and in place by December 31, 2000. Our policy will be modified in accordance with any regulations developed by the Secretary of Health and Human Services as indicated in the Act.

4. Enhanced data collection for the IRB. We will immediately begin to compile annual data on the number of new research proposals reviewed, the number of continuing research projects reviewed, the number of human subjects involved in approved research and other appropriate information. For this action, we have dedicated a full-time information technology position to assist the Associate Vice President for Clinical Research and the IRB chairs and staff for refining the existing database, data collection, and analysis.

The University of Oklahoma Health Sciences Center will take the following additional actions:

1. The University will require mandatory certifications of researchers and research staff involved in human subjects research. This will be done in two phases. In phase one, all researchers and research staff will be provided a copy of the book "Protecting Study Volunteers in Research-A Manual for Investigative Sites" by Dunn and Chadwick {Center Watch Inc., Boston, NA 1999}. They will be required to complete and pass all parts of the examination contained with this book and obtain a certificate from the University of Rochester School of Medicine Industry, Office of Continuing Professional Education. The first phase of this certification will be implemented by October 1, 2000. The second phase will be to establish the minimum requirements for ongoing education and filing, at least yearly, of evidence that minimum ongoing educational requirements have been completed. We will develop and complete the second phase of this policy for certification by December 31, 2000.

2. The University will develop and implement a program for enhanced quality assurance auditing of research involving human subjects. As part of this program we will implement a full-time position of "Compliance Officer" within the Office of Research Administration in Oklahoma City. This position will be dedicated to the oversight of compliance with all Federal, State, and University regulations governing clinical research, and the coordination of experience and a track record of quality work in the field of quality assurance of clinical research, to help design and implement our quality projects, since most of the industry-sponsored contract clinical trials are already undergoing monitoring of 100% of patients enrolled. Nevertheless, we will also develop a process for enhanced oversight of these industry-sponsored projects by a central receipt and review of the monitoring reports submitted either by the sponsor or the contract research organization doing the monitoring. A plan will be developed and implemented by November 1, 2000.

3. The University will implement immediately a policy for submission of investigator-initiated Investigational New Drug (IND) applications, and Investigational Device Exemptions (IDE). Two levels of approval will be required before such applications may be submitted by faculty. These are (1) IRB approval, and (2) approval by the Senior Vice President and Provost. It should be noted that the OUHSC-OKC IRB refused approval of two such investigator-initiated protocols during the past year. The added level of approval is designed to prevent submission of an IND or IDE for which the University may not be able to meet certain regulatory standards, particularly GMP or GLP.

4. The University will establish immediately a "no-fault" phone line for contact by researchers and research staff regarding any issues or problems related to human subjects research. These contacts will be reported directly to the Associate Vice President for Clinical Research.

5. The University will hire a full-time staff member based within the Office of the Associate Vice President for Clinical Research to coordinate ongoing educational efforts for research staff related to the protection of human subjects.