April 24, 2006 IRB MEETING MINUTES The Chair, Dr. Bercu, called the Institutional Review meeting to order on April 24, 2006 at 2:27 p.m. Members present: Barry Bercu, M.D., Chairperson, University of South Florida, Pediatrics
Kenneth Berg, B.S., Non-Affiliated, Non-scientist, Community member Cathie DeLuna, R.N., Tampa General Hospital, Nursing Linda Detman, Ph.D., USF Hiram Green, B.A. USF Non-scientist, Diversity/Community Affairs Clement Gwede, Ph.D., MPH, R.N., USF/Moffitt Cancer Center, Nursing/Health Outcomes Arzu Ilercil, MD, USF, TGH, Cardiology Nagi Kumar, Ph.D., USF, MCC, Nutrition Richard Lush, Ph.D., USF, MCC, Pharmacology/therapeutics John Merritt, M.D. FACP, USF, VA, Internal Medicine Pamela Munster, M.D., USF, MCC, Medical Oncology Jennifer (Powe) Darter, RN, VA, Cardiothoracic Daniel Sullivan, M.D. USF, MCC, Medical oncology/biochemistry Norma Epley, Assistant Director, Division of Research Compliance, Ex-Officio Members absent: Mortimer Brown, Ph.D., Non-Affiliated
Ray Dielman, N.D., NA, Radiation Medicine, Natural Hygiene Patti Simmons, Manager, Research and Sponsored Projects, TGH, Ex-Officio
Administrative Staff: Laurie A. Tozier; IRB Staff, Henry Zych, IRB Coordinator Guests: Anthony Kirkpatrick, MD, TGH, Thomas Freeman, MD, TGH The IRB chair stated before the board that no member may participate in the review, discussion or vote of a project or activity in which she/he has a conflicting interest. The IRB member must leave the room prior to discussion, review and vote of the project and 104237 Kirkpatrick, Anthony A Pilot Study of a 5-Day Infusion of Ketamine for Intractable Complex Regional Pain Syndrome The reviewer presented the study. This study is to use 5 day general anesthetic induced coma to treat complex regional pain syndrome. Eligible patients will be put under general anesthetic at TGH and after 5 days will be weened down until they are conscious. The expectation is this procedure will control the intractable pain. In some cases it is shown to have a 30% permanent remission and about another third of the patients have about 6 months of control of pain. [Tape #3A, 4 minutes] Based on the study done in Germany which has not been published, and based on previous use of ketamine to control pain related to burns the PI is trying to replicate the German study. The want to determine the safety and efficacy of the 5 day induced coma using ketamine to reduce significant pain and disability. The investigator is specifically asking to enroll 1 patient and will then review the experience and enroll 2 more patients. TGH has approved this study for 1 patient and then the PI is to resubmit the data collected to TGH and the IRB for another approval before continuing. [Tape #3A, 7 minutes]
The PI has answered most of the questions even though there were many issues raised. The IRB asked that 2 outside anesthesiologists review the study and provide a response. The independent reviewers stated that the risk benefit ratio was acceptable; the risks to subjects are minimized but suggested that the subjects be given prophylactic antibiotics as a precaution; they also recommended the dose titration of the ketamine be better specified in the protocol. The IRB reviewer agreed with the outside reviewers comments.
Going back to the initial review regarding the justification for charging the subjects to participate in the study there was some FDA language the PI included that states that an investigator and/or sponsor can charge in a research study as long as it is not being commercialized or recovering more than the cost of the study procedures. Another issue noted in the PI response states that the CRA has left and the PI will resume those duties as part of the study. The PI should hire and train a CRA before he enrolls any subject to the study. The IRB did not feel comfortable with the PI taking on those duties that a CRA would be responsible for in addition to his regular role as PI. The reviewer stated the risks are described fairly well but, they should include more information in the consent and application as to how the side effects are minimized such as stating how the high blood pressure is being controlled. Additional clarification is needed regarding the financial aspect of the study for the patient in the promissory note. The actual cost numbers for this particular study will need to be in spelled out in the promissory note. It was stated that the PI was also able to procure some free housing for the family members of the subjects and has an agreement with radiology for tests to be done free or at cost. Given this information there is still a significant financial burden to the subject and it is unclear how the PI will choose the first patient for the study. The secondary reviewer stated that the outside reviews gave realistic suggestions and had no other major concerns. The reviewer stated that if the PI can make the changes noted today then he could go forth and enroll 1 subject. [Tape #3A, 16 minutes] Further discussion noted that the study in Germany did try to use a broad spectrum antibiotic and it was dropped from the study because it was found that there were much better results when the subject first begins to develop symptoms of an infection they took a culture immediately and treated the infection aggressively with specific antibiotics. They have found that infection rate has now been reduced by about 40% treating this way. [Tape #3A, 19 minutes] Another board member stated that the PI should apply for a IND exemption. The FDA can then decide if the study qualifies for exemption. It was also mentioned that the IRB also has to consider the potential benefit the subject may receive from the study even though the cost is a definite drawback. The IRB should also consider the cost these individuals would undergo getting this treatment in some other place. It was brought up that one of the outside reviewers also suggested that the patient be seen by 2 other independent pain practitioners who will say that every possible treatment has been done for these patients and they need this study to get relief from their pain. [Tape #3A, 25 minutes] A board member stated that this population is in terrible pain, very suicidal and desperate for some help because they've failed everything else. *** Dr. Kirkpatrick and Dr. Freeman enter the meeting. *** The issue of the promissory note was brought up and Dr. Freeman had spoken with TGH financial administration on this very day. He stated that the agreement made is for 35% of the gross hospital total charges which is extremely low. He explained that from $27,000 up to $70,000 they will pay 35% of the gross charges, which is the $27,000. Since the last review the PI has been able to obtain commitments for at least 10 categories of free services for this study. The PI will also on a case by case basis be contacting the subject's insurance company to see if they will help pay some of the costs. A board member asked for clarification that if the costs go over the expected $70,000 then the patient will be charged for 35% over the $70,000. Dr. Freeman replied yes, that is correct. Dr. Freeman stated that the confusion is with the term "gross charges" and charges that the patient is responsible for. What is needed is for the TGH finance department to make clear to the subject the actual charges they will be responsible for. The chair stated that there were 2 outside reviewers that made recommendations that the IRB wants incorporated and there was also 2 different points of view whether or not to use a broad spectrum of antibiotics. Therefore, the IRB will ask you to go to one of the infectious disease faculty for another opinion and provide that to the IRB. [Tape #3A, 41 minutes, Tape ends] [Tape #3B, Begins] Dr. Freeman stated that this was not included in the protocol because it is not considered standard of care at TGH. The rational of the outside reviewer was because of the high incidence of pneumonia in the German study it may help reduce the risk. Dr. Kirkpatrick addressed this issue: When the first 10 patients were done in the German study about half had pneumonia and about half had a UTI. At this time 30 patients have participated in the German study and there has been a total of 8 with evidence of pulmonary infection. The key to decrease the risk is with closer oversight and treatment specific antibiotics. Dr. Freeman stated that he would have an ID person at TGH look at the study and give an opinion for the prophylactic antibiotics. [Tape #3B, 2 minutes]
Again the IND issue was discussed. Dr. Kirkpatrick stated that he felt he met all the requirements of the FDA for exemption.
The chair stated the IRB felt very strongly about submitting for an IND which would force the FDA to interpret the guidelines and take a position if your study should be exempt. In the long run this will be to the Pls advantage for future research as well as a safeguard for the investigator to have something in writing from the FDA. [Editor's Note: The tape recording (upon which the minutes are based) shows different sequences of events and interpretations than what was documented in the minutes: For example, on the tape recording, Dr. Bercu informs Dr. Kirkpatrick, for the first time, that he must submit his study to the FDA for the purpose of obtaining an exemption to an IND. Then, Dr. Kirkpatrick objects to Dr. Bercu's demand by stating his study meets all the requirements for an IND exemption. Then, Dr. Bercu proceeds to justify his demand for a decision by the FDA, e.g., to "force" the FDA to interpret its guidelines, to force the FDA to take a position, to create an "advantage" for the PI for future research, to "safeguard" the PI, etc ] [Tape #3B, 7 minutes] The IRB also restated to the PI that a research coordinator needs to be hired for this study before enrollment can begin. Dr. Kirkpatrick stated that he has someone who is now the research manager that will take on those duties. He named Chris Jackson as the research coordinator and stated he is very familiar with research. Dr. Kirkpatrick also stated that in previous communication it was asked if a rotator bed would be used for this study. Dr. Freeman will address this issue. Dr. Freeman stated that the rotating beds are commonly used in patients with spinal cord injuries to minimize bed sores. The shorter period of hospital time as with this study is not standard of care for use of this bed. It is more of a long term use type of bed so it will not be used in this study. A board member asked the PI how he plans to address the fact that TGH is at maximum bed capacity for this study. Dr. Freeman stated that no more than 1 patient will be scheduled at one time with a minimum of 2 weeks in between each subject so there is no overlap of subjects. It was also noted that the rooms will be single rooms allowing for better air quality to reduce risks to the patients. [Tape #3B, 13:00 minutes] Drs. Freeman and Kirkpatrick leave the meeting. A motion was made to approve the study pending minor revisions as discussed. The revisions are as follows: Provide in writing the opinion of an Infectious Disease doctor regarding the suggestion to use prophylactic antibiotics as a standard for the subjects to be enrolled into the study. - Please explain how the first patient to be enrolled into the study will be identified.
- Please submit an application for a IND to the FDA.
- Provide the name and qualifications of the Clinical Research Coordinator for the study.
- Please state in the risk section on page 10 of the consent form under heart and circulatory system that clonidine is used to control this side effect.
- In the exclusion criteria of the application please delete the word "significant" from history of ischemic heart disease, and delete the word "recent" from MI and alcohol abuse.
- Please give more specific detail for the ketamine dose titration in the protocol.
- The inclusion criteria should be more specific to state that the subject "must have failed all available treatment as determined by at least two independent pain practitioners".
- Give more clarification in the exclusion criteria regarding the use of Actiq.
- In the protocol under section 3.4 please state that BIS monitoring will be continuous and include values for notification of the research physicians.
- Please state in the consent form that there is a possibility of awareness and recall during the general anesthesia portion of the research.
- Please provide a copy of the promissory note with the actual corresponding figures for this study that the patient will sign prior to enrollment in this study.
When the IRB chair reviews the response from the PI he will make the determination if all the revisions are clear and he can approve the study or if the revisions will come back before the convened IRB. The Committee had no further questions or discussion on this study. A motion was made to withhold approval pending minor revisions. The motion was seconded and carried unanimously. The IRB voted For - 8 Against - 4 Abstain - 0 (Total present -12) Mr. Green leaves the room. Ms. DeLuna leaves the room. Dr. Merritt leaves the room. [Tape #3B, 23 minutes, Tape ends] [Tape #3C, Tape for IRB meeting on March 26, 2007, Tape begins] Minutes Pending [Tape #3C, Tape for IRB meeting on March 26, 2007, 16 minutes, Tape ends] | 
