REPORT OF THE PROVOST S REVIEW PANEL Clinical Practices and Research in the Department of Neurological Surgery June 27, 2013 Executive Summary In August 2012 the Provost and Executive Vice Chancellor convened a special panel to conduct a review of the procedures and decision-making processes with regard to the treatment of patients with terminal glioblastomas by Drs. J. Paul Muizelaar and Rudolph Schrot. The review panel concludes that although the Institutional Review Board (IRB) responded appropriately and issued a letter of sanction, establishing formal lines of communication between the IRB and the Health Sciences administrators, particularly the Vice Chancellor and Dean and the Chief Medical Officer (CMO), would provide better oversight over cases involving research and innovative care. The review panel questions the decisions of academic administrators who did not pursue disciplinary action under the Faculty Code of Conduct after the IRB sanction and allowed Dr. Muizelaar to continue as chair of his department and subsequently receive an endowed chair. While there may be a difference of opinion about the results of the Medical Staff Peer Review process, the process was carried out promptly and in accordance with policy and practice. The review team recommends more rigorous academic oversight of clinical research and increased attention to supporting a culture of compliance at the health systems campus and throughout the research enterprise. The review team also notes that corrective actions are underway addressing improved communications protocols, practices for awarding endowed chairs and sharing of information between the Medical Staff Peer Review and Academic Affairs. There are additional investigations by The Joint Commission (TJC) and the California Department of Public Health (CDPH) addressing corrective action with regard to operating room protocols, issues that were not included in the scope of this review. The outcome of these reviews may provide additional recommendations to prevent recurrence of the issues identified in this case. Charge In August 2012, at the request of the Chancellor, the Provost and Executive Vice Chancellor convened a special panel to review the circumstances surrounding, and especially subsequent to, the period of time Drs. J. Paul Muizelaar and Rudolph Schrot were engaged in the treatment of patients with terminal glioblastomas and for which they were sanctioned by the Institutional Review Board (IRB) in a letter dated September 16, 2011. The charge was to undertake a broad review from a procedural perspective that examines internal review and decision-making processes during this period of time and make recommendations regarding communications and decision-making in order to determine if additional procedures might be required to exercise appropriate oversight in the future. Specifically this review was to address: [1] The IRB process, including communications into the IRB and out of the IRB, as well as the responses to inquiries, written and otherwise; [2] The administrative process that led to Dr. Muizelaar continuing in his role as department chair after the IRB findings and whether the IRB findings are sufficient reason to terminate his service as department chair;
[3] The review process in Academic Affairs (then Academic Personnel) regarding whether there was a violation of the Faculty Code of Conduct under APM-015; [4] The process through which concerns about patient care were referred to the Chief Medical Officer (CMO) for review by the Medical Staff Peer Review Committee and the decision not to refer the matter to the Medical Board of California; [5] The process leading to the creation of a new administrative endowed chair earmarked for the chair of the Department of Neurological Surgery and subsequently awarded to Dr. Muizelaar. The special panel conducted interviews with the CMO, the Vice Chancellor and Dean of the Medical School, the then-director of IRB, the then-vice Provost for Academic Personnel, the Director of Academic Employee and Labor Relations, and the two faculty chairs of the IRB clinical committees. The panel reviewed correspondence and emails relating to the surgeries and the IRB investigation, and also documents related to the accreditation survey by The Joint Commission (TJC) and Medicare Conditions of Participation (COPs) review performed by the California Department of Public Health on behalf of CMS. Background J. Paul Muizelaar, MD, is a Professor and was Chair of the UC Davis Health System s Department of Neurological Surgery. Rudolf J. Schrot, MD is an Associate Professor in the department. In 2008, Dr. Schrot, working under Dr. Muizelaar s direction, approached the FDA about the possibility of treating a patient with terminal glioblastoma by instilling bacteria to promote wound infection and hopefully extend the life. Glioblastoma is a common and deadly form of malignant brain tumor. At the time of this proposed treatment there was a belief that development of postoperative infection might confer a significant survival advantage to patients with glioblastoma. The response of the FDA was that the physicians could proceed with the intervention as innovative treatment if the bacteria were available locally. If it is not and only available under an IND, then the physicians would have to consult with CBER, which determined that animal studies would be required before proceeding with the use of the bacteria in humans. Dr. Schrot consulted with UCD IRB chair who concurred with the advice from the FDA that the treatment involving the use of a biologic agent in humans could not proceed without further animal testing. Dr. Schrot notified the IRB that the proposed protocol would be suspended. Drs. Muizelaar and Schrot continued to believe in the potential benefits of intervention with intentional wound infection and hired a graduate student to assist in preclinical study involving rats. The student worked in a campus research laboratory with cultured bacteria procured from ATCC of Virginia specified as not intended for human use. In 2010, Dr. Schrot, again acting under Dr. Muizelaar s direction, contacted the IRB with regard to the instillation of bacteria in a patient with glioblastoma. He represented to the IRB that this was to be a one-time procedure with no research aim, undertaken with bacteria cultured in a UCD lab. The IRB Director indicated via email that the proposed procedure could be undertaken as innovative care not subject to IRB or FDA oversight, but that approval should be sought from the CMO. The IRB Director also indicated that if the physicians intended to perform human subjects research, subsequent procedures using the bacteria might require a formal submission of the project to the IRB for review and approval. In response to this advice, Dr. Muizelaar informally notified the CMO of his plans. The CMO verbally authorized him to proceed, although with caution and documentation of clear and full informed consent from 2
the patient. On, the CMO sent a follow up email to the two doctors cautioning them to consider three issues in addition to informed consent: (i) procedures to be undertaken if there are complications to the innovative care, (ii) ethics committee review and (iii) a determination as to how the costs of care will be handled. In the email, the CMO indicated that he had informed the Chief Health System Counsel about the proposed plan and asked the doctors for written documentation that the IRB had authorized them to proceed. The operation was performed on and although early imaging showed promise, the patient failed to improve and died approximately 6 weeks later. Around this same time, Dr. Muizelaar encountered a second patient and asked Dr. Schrot to approach the IRB Director again. The IRB Director recommended FDA review with the understanding that no further patients would be treated. On the IRB Director offered assistance and resources to Dr. Schrot for preparing an IND for FDA approval. The doctors proceeded with a second surgery on, 2010 without submitting the IND for approval from the FDA. This patient experienced a reduction in tumor size and lived for close to a year after the surgery. Neither the IRB Director nor the CMO were aware of this surgery when it was performed, although Dr. Muizelaar informed the CMO some time after the procedure had been completed. In 2011, the doctors identified a third patient, a with newly diagnosed glioblastoma, and performed surgery on with the consent of the patient and family. The patient was stable in ICU for a week after surgery but developed sepsis and died on after the family elected to withdraw life support. During this period, the doctors convened an ad hoc ethics committee and presented them with a proposal to proceed with five additional patients without IRB or FDA approval. The ad hoc ethics committee concurred with the proposal and recommended continuing clinical activities with the understanding that an IRB-approved formal protocol would be developed as soon as possible. During this time, a pharmacist at the Medical Center raised a question in an email to Dr. Muizelaar about the plan to use the drug GMCSF on these patients after the surgeries, as it is not an FDA-approved indication for the drug. The email asking for supporting literature was cc d to the CMO. The Director of Pharmacy followed up with the CMO and the Director of Perioperative Services regarding concerns about the use of the drug and the underlying surgeries. On, the CMO responded to the e-mail indicating that the original messages were in his email trash so he did not find and review them until that time. On the same day the CMO issued a cease and desist order via email [protected under medical staff peer review pursuant to Evidence Code 1157] followed by a Letter of Warning and Expectation to Dr. Muizelaar with a copy to Dr. Schrot instructing them not to do any further surgeries that involved bacteria implantation without protocol review and approval by the IRB and with the full knowledge and approval from the CMO or Chief of Staff. They were also informed that the matter would be referred to the Medical Staff Peer Review committee. The email was copied to the Chief Health System s Counsel, the SOM Executive Associate Dean, and the UCD Chief Compliance Officer. The IRB initiated an investigation of these events in the of 2011 and issued a letter to Drs. Muizelaar and Schrot on September 16, 2011 informing them of the following findings: (1) with regard to the first patient, the incorrect information provided to IRB staff regarding the source of the bacteria led to an incorrect determination that no IRB review was required; (2) with regard to the second and third patient, the administration of bacteria constituted human research without IRB review and approval in violation of Policy 240. The IRB concluded that serious and continuing non-compliance occurred and required the two doctors to halt enrollment of human subjects in all research in which they serve as PI s and report within 10 days regarding all human 3
research for which they serve as study personnel and/or co-investigators. In addition, the IRB referred the case to the Committee on Biosafety to address issues related to the use of bacteria in humans, the UC Davis Health System to address how non-approved products were allowed into the surgical setting and to Academic Personnel for potential disciplinary action under Academic Personnel Manual (APM) 015, the Faculty Code of Conduct. Findings [1] The IRB Process and Communications The record indicates that the IRB, its staff and committees, communicated promptly and appropriately with the two doctors based on the information available to them. Upon notice of possible failure to follow IRB policies, an investigation was initiated and completed in a timely manner with an appropriate outcome. The failure of the IRB to intervene sooner to prevent the non-compliant activities can be traced to the failure of the two doctors to provide accurate information about the source of the bacteria in the first instance, and the subsequent failure to follow the advice of the IRB Director in the second and third surgeries. The doctors did not respond to the CMO s request for documentation of the IRB response at the time of the first surgery. There may have been points in time where direct communications between the CMO and the IRB would have increased the likelihood of timely intervention. At the time of these events there was no formal process for informing the Medical Staff or Medical Center staff (perioperative services) about patients who were to receive innovative care, the results of an IRB investigation or any decision to restrict physicians from performing research activities. The CMO indicated that the lines of communication relied on his personal efforts and relationships with the IRB chairs. Since these events, the Medical Center has developed a process for requiring that at the time of scheduling a surgical procedure, the physician must notify the operating room that a patient will receive innovative care or participate in a research protocol. While communication at the time of scheduling a surgical procedure may address some of the communication problems that occurred in this situation, a broader method for communication between the IRB, CMO and medical center staff regarding participation of any patient in a research protocol and its implications could prevent similar problems from occurring in other settings, including, but not limited to radiology and other procedural suites, as well as inpatient and ambulatory care settings. [2] Dr. Muizelaar s Continuing Role as Chair At the time of the surgical procedures, Dr. Muizelaar was the Chair of the Department of Neurological Surgery. The review panel believes that the findings set forth in the September 16, 2011 IRB letter support removing Dr. Muizelaar from his administrative position. They reflect conduct that is not consistent with the expectations of a department chair with respect to both academic and clinical responsibilities. [3] The Academic Personnel Review under APM-015 The Vice Provost for Academic Personnel reviewed the findings in the IRB letter and discussed the course of action with the campus counsel, the Health System counsel and the Associate Dean for Academic Affairs of the School of Medicine. Based on the information available at the time, they determined that the conduct primarily concerned clinical practice and as a result, the most appropriate venue for response was the Medical Staff Peer Review process. Because the matter 4
had been referred for Medical Staff Peer Review, the Office of Academic Personnel did not proceed with an investigation to determine whether the doctors conduct violated the Faculty Code of Conduct. After more information about the events came to light, the Office of Academic Personnel, now Academic Affairs, initiated an investigation under The Faculty Code of Conduct to determine whether additional disciplinary action is warranted. [4] The Peer Review Committee Process The actions of the physicians were reviewed under the Medical Staff Peer Review process, a process which is confidential and protected from disclosure under State law. (California Evidence Code 1156/1157). The Medical Staff Peer Review process in this case provided a timely review in accordance with proper procedures. Subsequently, the review panel understands that Dr. Muizelaar voluntarily took leave from clinical activities due to recently filed medical malpractice complaints. Dr. Schrot retained full medical staff privileges. [5] The Administrative Endowed Chair The Julian R. Youmans Chair in Neurological Surgery is an administrative endowed chair for the School of Medicine established pursuant to the procedures set forth in UCOP APM 191 and UC Davis APM UCD-191 governing endowed chairs. UCOP policy grants the President the authority to establish and name endowed chairs. (APM 191.B.1) The UCOP and UC Davis policies set forth two types of endowed chairs: (1) An endowed chair or professorship provides funds to a chair holder in support of his or her teaching, research, and service, and (2) an administrative endowed chair provides funds in support of the teaching, research, and service activities of the department, research unit, school, or college. The UC Davis implementing procedure at APM UCD-191-III.F, provides that an administrative endowed chair is one that is designated for a specific administrative position, for example, department chair The UC Davis internal checklist for the establishment and naming of an endowed chair describes a multi-step process. After a gift for an endowed chair has been secured and the position description incorporated into the Academic Plan, the request is forwarded to the Dean s Office. The Dean forwards the documentation to the Vice Provost for Academic Personnel who then submits it to the Committee on Academic Planning and Budget for their review and comment. The Vice Provost then forwards the documentation with a recommendation to the Chancellor. The Chancellor forwards the request for naming an Endowed Chair to the Office of the President. The Office of the President has final authority to approve the naming of the endowed chair. The Youmans chair was initiated in response to a private gift of $765,000 matched by $735,000 from the SOM Dean s Catalyst Fund. The purpose of the Youmans chair is to support the individual selected to serve as the academic leader of the Department of Neurological Surgery. In August 2011, the Dean of the School of Medicine submitted a request to establish the Youmans chair to the Chancellor. In accordance with UC Davis procedures, the Vice Provost Academic Affairs submitted the request to the Senate Committee on Planning and Budget (CPB) for their review and comment. In October, the chair of CPB sent a memo to the Vice Provost conveying the committee s support for the establishment of the Youmans chair. President Yudof approved the endowed chair in November 2011. In a letter to the Chancellor dated December 12, 2011 the 5
Dean wrote to request the appointment of Dr. Muizelaar to the Youmans chair, noting that the appointment is an administrative chair and would be concurrent with Dr. Muizelaar s appointment term as the Chair of the Department. The letter was signed with the notation recommend approval by the new Vice Provost of Academic Affairs on January 19, 2012 and by the Chancellor on January 19, 2012. In a letter dated January 20, 2012 the Chancellor invited Dr. Muizelaar to accept appointment as the holder of the Youmans chair noting that the appointment carries with it special responsibilities including excellence in teaching and creative activities, and also administrative duties as department chair. The letter also stated that it is expected that holders of endowed chairs will follow the Faculty Code of Conduct and conduct themselves consistent with the UC Davis Principles of Community. There is no evidence that the Chancellor was aware of the IRB investigation at this time. The Dean s decision to proceed with the request to the President to establish an endowed chair apparently was made after the Dean was aware that Dr. Muizelaar engaged in serious noncompliance with IRB policies. The Dean indicated that since the Youmans chair was established as an administrative chair, it is automatically provided to the current department chair. Because Dr. Muizelaar was continuing as department chair, there was no reason to question the award of the endowed chair. The Dean and the Vice Provost for Academic Affairs stated that although they were aware of the ongoing investigation, they felt that the compliance issues had been appropriately referred to and were being handled based on procedures in place for both the IRB investigation and the Medical Staff Peer Review. Since the chair was administrative and coterminous with the department chair position, the Dean was required to recommend the appointment of Dr. Muizelaar to the endowed chair. At that time, there was no pending disciplinary action under the Faculty Code of Conduct (APM 015). In 2012, the administration developed and implemented a procedure for conducting a Full Compliance Check for all appointments of significant academic leadership, including endowed chairs. Pursuant to that process Academic Affairs consults internal confidential records to determine whether there have been substantiated findings of policy violations regarding Research Misconduct, Sexual Harassment, Improper Governmental Activities (Whistleblower/Retaliation) or the Faculty Code of Conduct. The process also includes determining whether research protocols have been suspended by the offices of Institutional Animal Care and Animal Use (animal subjects research) or the Institutional Review Board (human subjects research), and whether the candidate is up-to-date on mandatory University training for Sexual Harassment Prevention, Conflict of Interest and Ethics and Compliance. For Medical School appointees, the compliance check includes whether there have been substantiated findings for violating Medical Center Policies and Procedures based on input from the Chief Medical Officer, Medical Staff office, Health System/School of Medicine Compliance Office or the School of Medicine offices of Academic Affairs and Human Resources. The review panel concludes that these new compliance check procedures are sufficient to address any issues related to previous or ongoing investigations that have not been adequately coordinated between various units on campus in the past. The compliance check provides strong assurance that compliance problems will be addressed prior to making any decisions regarding appointments to endowed chairs or other academic leadership positions. Recommendations 6
1. Improve Lines of Communication This review identified a number of issues related to lines of communication between the Davis campus and the Health Sciences campus in Sacramento as well as between units within the Health Science campus. The communication and coordination of clinical trials and their oversight is challenging for all health care systems. Situations such as this one emphasize the need for more formal lines of communication between the Director of Research Compliance, the IRB and the Medical Center (the Vice Chancellor and Dean, the CMO, appropriate Medical Staff committees, and Medical Center departments) related to clinical trials review and approval. For example, the CMO indicated to us that he has regular communications with the IRB chairs, but admitted that communication with the physicians and the IRB in this case was not optimal. As a result, the Medical Center staff members were unaware of the discussions with the IRB and the Director of Research Compliance. While the CMO and others interviewed indicated that more formal lines of communication have been established, a review of the report from TJC indicates that the communication is still not optimal. For example, the communications to the physicians regarding further use of bacterial implantation did not include formal notification to the CMO or others who might have a need to know of this restriction, but relied on personal communication. The CMS review identified that no information about the events and subsequent restrictions were entered into the credentials files for the physicians. The Vice Chancellor and Dean and the CMO should review the current formal lines of communication both within the Medical Center and with the IRB and other campus committees to minimize the likelihood of recurrence of events such as the ones that occurred in this case. The IRB should communicate directly with the Vice Chancellor and Dean when there is a compliance issue involving a faculty member. The Vice Chancellor and Dean may want to consider appointing a multidisciplinary task force to clarify lines of communication and coordination related to oversight of clinical research activities ands innovative therapies used in the clinical setting. In addition the Health System may benefit from better coordination of efforts between the Davis and Sacramento campuses to ensure a single standard of management for research activities, coordinated approaches to oversight of clinical and academic roles and responsibilities and appropriate coordination between campus counsel staffs. 2. Create More Rigorous Academic Oversight The lack of follow-through by the Office of Academic Personnel seems to represent a lack of understanding of the magnitude of the research misconduct and misrepresentation of the research activities as clinical activities under the jurisdiction of the Medical Staff. While this may have been an error in judgment in this specific instance, it could represent a larger issue regarding the role of the academic review process when questions arise regarding activities of the clinical faculty. To prevent a recurrence of this problem the process for review of faculty for whom there are questions about adherence to the Faculty Code of Conduct should be assessed; the roles of the Academic Affairs administrators at the Medical School and the campus, i.e. the Vice Chancellor and Dean, the Associate Dean for Academic Affairs, the Vice Provost for Academic Affairs, the Provost and Executive Vice Chancellor, in situations such as this one need to be clarified. A clarification of the communication protocols between Academic Affairs and the Medical Staff office would be useful to ensure that the review process is appropriate, comprehensive, fair and consistent with the Medical Staff Bylaws and Academic Personnel Manual. Coordination of the review and evaluation process will often require the guidance of campus counsel to ensure that the individual faculty member s rights have been maintained and University policies and procedures are appropriately followed. 3. Reinforce the Culture of Compliance and Highest Ethical Standards in Clinical Research and Patient Care 7
There are some broader issues with regard to culture and compliance that were identified during this review. The communication and coordination of compliance activities that involve both campus and Medical Center leadership could be improved in order to reinforce a culture that supports compliance. Based on some of the comments made by those faculty and staff interviewed, there is a perception that compliance with University policies and external regulatory requirements is not universally held as a value. While we found no evidence that the leadership on the Health Science campus intentionally wavers on its commitment to high ethical standards in research, improving the relationship between the Davis campus leadership and Health Science and Medical Center leadership may improve the climate for compliance and support the commitment to a culture of high ethical standards and compliance. As an example of an area that will benefit from improved coordination, it will be essential to clarify for the faculty the authority of the Medical Staff, the IRB, Academic Affairs and the Academic Senate regarding oversight and management of clinical trials. The CMO has emphasized the critical importance of maintaining the protections provided by the Medical Staff Peer Review process (California Evidence Code 1156/1157). To ensure that the leadership is aware of areas of concern on the part of the clinical faculty activities, it will be helpful to reevaluate the lines of communication and coordination to ensure that the peer review process is maintained while also ensuring responsible oversight of clinical research by appropriate campus administrative leadership and committees. The review panel understands that there is work underway to establish procedures for providing Academic Affairs with information about Medical Staff Peer Review findings that identify serious clinical deficiencies on a need to know basis without compromising the peer review protections. The review panel urges that the campus and Medical Center convene a task force of internal leadership to clarify the roles, responsibilities and communication procedures between Academic Affairs, the Office of Research, the Academic Senate and the Medical staff with regard to cases where clinical issues may also warrant consideration as a violation of the Faculty Code of Conduct. 4. Clarify Process for Awarding Endowed Chairs The decision to recommend Dr. Muizelaar for the endowed chair after findings of serious noncompliance with University policies related to clinical research was inappropriate. The review panel believes that the compliance check procedures developed by Academic Affairs at the request of the Chancellor provide a sufficient additional review to identify whether there is any record of substantial misconduct prior to recommending approval of awards for endowed chairs, administrative leadership appointments or other University honors. 5. Restore Department Leadership During this review, Dr. Muizelaar stepped down as Chair of the Department of Neurological Surgery pending the results of the Faculty Code of Conduct investigation. Further investigations were charged to address his ability to fulfill his responsibilities as a member of the faculty or medical staff. The review panel believes that it would be inappropriate for him to return to a leadership role. We understand that since completing our review, Dr. Muizelaar retired from the University. Neal Cohen Sheila O'Rourke 8