IRB University of South Florida

3500 East Fletcher Avenue, Suite 300

December 19, 2005 IRB MEETING MINUTES

The Chair, Dr. Bercu, called the Institutional Review meeting to order on December 19, 2005 at 2:30 p.m.

Members present:          

Barry Bercu, M.D., Chairperson, University of South Florida, Pediatrics

Kenneth Berg, B.S., Non-Affiliated, Non-scientist, Community member

Mortimer Brown, Ph.D., Non-Affiliated

Cathie DeLuna, R.N., Tampa General Hospital, Nursing Linda Detman, Ph.D., USF

Clement Gwede, Ph.D., MPH, R.N., USF/Moffitt Cancer Center, Nursing/Health Outcomes

Pamela Munster, M.D., USF, MCC, Medical Oncology Jennifer Powe, RN, VA, Cardiothoracic

 Patti Simmons, Manager, Research and Sponsored Projects, TGH, Ex-Officio

Members absent:           

Ray Dielman, N.D., NA, Radiation Medicine, Natural Hygiene

Hiram Green, B.A. USF Non-scientist, Diversity/Community Affairs Adriana Hung, M.D., VA, Nephrology

Nagi Kumar, Ph.D., USF, MCC, Nutrition

Richard Lush, Ph.D., USF, MCC, Pharmacology/therapeutics John Merritt, M.D. FACP, USF, VA, Internal Medicine

Daniel Sullivan, M.D. USF, MCC, Medical oncology/biochemistry

Administrative Staff:

Laurie A. Tozier, Sr. Grants Specialist

Henry Zych, IRB Coordinator

Guests:        Lorraine Hickson, MCC, Anthony Kirkpatrick, MD

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 cannot be counted towards the quorum. The excused member can be recalled to provide information that is requested by the IRB.

New Protocol

104237 Kirkpatrick, Anthony

A Pilot Study of a 5-Day Infusion of Ketamine for Intractable Complex Regional Pain Syndrome

The PI came to the meeting to present the study to the board.

The study is looking at what is called complex regional pain syndrome or CRPS which is characterized by a lot of ups and downs in pain levels leaving the determination of efficacy a problem. Usually the pain does not go away completely and patients experience chronic pain which lingers after some treatments. Patients are only provided temporary relief of pain.

The PI stated that his practice has now been limited to this CRPS patient population from all over the world and treats those with the most serious/worse cases where the syndrome has spread to multiple extremities, is progressing rapidly and other treatments have failed. The treatments currently given include medications, synthetic nerve blocks, sometimes amputhecotmy if appropriate, spinal cord stimulation, surgeries, implanting devices and invasive procedures to provide some measure of relief.

A national scientific advisory committee was created to set up the first clinical practice guidelines for the diagnosis and treatment of RSD that is now used by the Social Security Administration of adjudicated cases involving this syndrome. The cases seen by the PI have basically run out of options for treatment. The patients that have gone overseas to have this treatment were basically flat on their backs and have gone through all the invasive interventions. The PI stated that when these patients returned they were literally changed people. After the high dose treatment some patients sometimes also need to be given a booster of low dose ketamine.

The PIs goal is to take this treatment out of Germany, bring it here, treat this population and find ways to improve the safety, comfort and tolerability factor for these subjects and hopefully generate enough data to serve as a stepping stone to a controlled study with an active control.

The issues to be dealt with by the PI from an ethical standpoint is the cost of this study and treatment. The patients that have gone to Germany so far have spent more than 30k. The plan is to try to get some funding to help these patients with the costs involved. The PI will be communicating with Travelers Insurance and St. Pauls to solicit some funds. The costs are estimated with no complications for 5 days of infusion and 2 days of recovery in the hospital for a total of 27k, and this does not include any consults that could occur during the stay outside of the hospital expenses.

The board asked if any of these patients have been treated with the low dose of ketamine. The PIs response was that he had just read the manuscript for 4 patients that were put on the low dose (and noted that the board keep in mind these patients are basically debilitated and flat on their backs) of 100 mg per hour and the study is using 3-4 times higher doses. When the subjects were given this dosage for 10 days the pain comes back. There is something about the higher dose intervention for 5 days that works. The hypothesis is basically an overload of the receptors.

The PI also stated that before a patient is enrolled into the study he will contact their insurance company and explain what treatments have been done to date and what he proposes and will request them to cover the treatment or at least part of it. The low dose boosters are being covered by the insurance companies at this time.

A board member stated that ketamine has been used in other settings for long periods of time and asked the PI to comment on this.

His response states that there have been studies done where subjects with severe head trauma received long term anesthesia for more than 5 days with ketamine. The advantage of ketamine is that it supports blood pressure and gives better GI function than with opioids. What was found was that blood pressure was maintained in these patients and was a statistically significant advantage over using narcotics in these head injury patients. Most anesthesiologists generally stay away from ketamine for head injury patients because of the increase in intracranial pressure but in that study it was not a problem.

Another comment of the board was that there will be a group of people that will not be able to come up with the initial 27k making this option not available to everyone. It was also noted that the investigators involved will be waiving their fees for the study to help reduce cost.

The PI also stated that there will be special in-services for these patients and continuous monitoring and oversight. He also stated he would be accessible 24 hours a day by phone, and/or pager. The patients may end up staying in the hospital for more than 7 days especially if the disease is in the lower extremities as it may take longer to get up and get around walking and moving as they will be weak but the PI will have them doing exercises such as using a pool to regain their strength.

The PI noted that he would also like to make a change to the protocol at this time. He would like to only perform the neuropsychological testing at 3 and 6 months for the study instead of at every visit as currently stated in the protocol. The board agreed to this change.

[Tape #1, side A, 28 minutes]

Dr. Kirkpatrick leaves the meeting. Discussion of the board.

A board member stated that the charges are not clearly defined. The TGH representative stated that when the study was reviewed at TGH they were asked to consider the rates comparable to current Medicade rates but TGH denied this because they would lose money. Because of the time needed in the ICU and the days on the surgical floor it will be a high cost study for a patient with no complications. The risks of complications in this patient population is very high and will add to the cost of their overall care and extend their hospital stay. Based on the financial projections for the 7 days not including the consult fees it was determined the best option was 27k and an additional 35% of gross charges that exceed 70k. The hospital has no control over the consultation and other outside fees.

The Board requested that perhaps the PI can provide the IRB with some numbers of the costs that are involved after the first patient is treated. It was stated that many of these patient do not have insurance because they are unable to keep health coverage and do not qualify for medicade either but, fall into a category where they cannot get Financial help and do not have the funds to pay.

The primary reviewer stated that the background was heard from the PI and these patients have very few options available to them. The reviewer stated that the most challenging aspect of the study is the cost issue. The procedure is being done elsewhere and there is some experience with the long term anesthesia.

The issues noted were that the protocol did not state what the prevalence is of this problem, and should be added to the background. The reviewer agreed with the staff comments and revisions.

The application changes needed include the number of subjects. It should be stated as I subject, then re-review, then 3 subjects and DSMB review, and then 7 subjects and so on. The ethnic origin/population needs to be at least estimated in section 7C. The application and protocol are not consistent with each other and they need to change that.

The IND section is appropriate in the application. Section 16.1 and 16.2 has missing information that can be found in the protocol. In the consent form the PI may want to include more of the key people to the first page of the consent form. There should be more information added to the section of why the study is being done. The cost section needs to be much more specific about the charges that could be involved while in the hospital.

[Tape #1, side A, 38 minutes, Tape ends]

[Tape #1, side B, Tape begins]

The secondary reviewer stated their concerns. The consent form should state that this procedure does not help all patients and that the pain can return. The percentage of the risks should be included in the consent. The information gathered from the study in Germany should be included. (Ten subjects received this treatment in Germany and 7 are free from pain, etc). All the risks of all the procedures being done in the study need to be included in the consent. The washout period should also be described in the consent and application. Also, if these subjects are on chronic narcotics for pain control can they truly sign informed consent. The risks of the ketamine versed should also be explained in the consent form.

The reviewer noted that there is an abstract but this study has not been published. It was stated that ketamine is a PCP derivative and wondered if it can be addictive and will the subjects need to keep getting boosters because of this. The exclusion criteria should include anyone on a nitrate because of chronic ischemia. The labs involved should be done everyday during the study. It is mentioned in several places that they will be done every other day but need to be done everyday.

Another board member wanted to know what happens if the costs become so high the subject cannot pay the charges. These patients will lose their homes and the potential to lose everything for a chance to be pain free.

Also noted is that all four of the members of the DSMB are on the protocol. There should be an independent review of this study by an independent board or group of people with no one from the study involved. It was stated that all the data collected after the first subject has completed the study will be reviewed by TGH and the IRB before another subject can be treated.

The risk is greater than minimal risk with the potential of benefit to the subject. A board member noted that the beneficence of this study is not quite clear. These subjects are in tremendous pain and under the influence of narcotics so are they in the right frame of mind to be consented and understand the ramifications of this protocol. Secondly, what about justice of these patients, only those that have money can be in the study or those without money? Choosing is not providing justice. The PI should try to find a sponsor for this study. The hospital should not be expected to swallow the costs of this study and it is very likely these patients will spend more than 7 days in the hospital. The costs are too vaguely defined when it is very possible this could cost half a million dollars.

The dilemma is that any PI cannot get a sponsor without data to present. The study in Germany has not even been published and they are basing everything on the study in Germany. The board asked that the data collected from the German study be reviewed.

It was suggested that perhaps the PI could be more definitive in his exclusion criteria to help reduce the potential risks while in the hospital. The majority of the board did not agree with that suggestion.

Again if some independent anesthesiologists could review this study it could give another point of view. The board wanted to know why this study has not been done in Philadelphia where the booster doses are given.

The reviewer asked for the data from the German experiment and what was the criteria for selecting those patients and what are the characteristics of those patients previously treated.

Dr. Kirkpatrick entered the meeting again.

The question raised to the PI was why this study is not being done in Philadelphia. The PI response states that Dr. Swartzman has a lot of protocols going on presently. He is conducting the low dose study and simply cannot do it due to time.

A board member asked about the Orphan drug Act that was mentioned in the study and the PI stated he has not contacted them yet for funding. The board told the PI that they will want the data from the study done in Germany. The PI will provide a copy of the 4 patients with severe RSD that went on the low dose regimen. The pain these patients experience is a subjective and the way it is measured is more by performance such as daily performance of walking or returning to work.

Overall, this study presents a very significant ethical dilemma for the IRB and has been the most difficult protocol that has been reviewed to date by this Board. The Board also requested that an outside review be done by independent persons.

A motion was made to withhold approval (defer) of the study pending submission of substantive changes. The motion was seconded and carried unanimously.

The IRB voted For - 8 Against - 0 Abstain - 0 (Total present - 8)

Tape #1, side B, 47 min, Tape ends]

March 27, 2006 IRB MEETING MINUTES

The Vice-Chair, Dr. Sullivan, called the Institutional Review meeting to order on March 27, 2006 at 2:35 p.m.

Kenneth Berg, B.S., Non-Affiliated, Non-scientist, Community member

Barry Bercu, M.D., Chairperson, University of South Florida, Pediatrics

Norma Epley, Assistant Director, Division of Research Compliance, Ex-Officio

Administrative Staff:

Laurie A. Tozier; Henry Zych

Guest(s):                           

Jeff Jorski, MCC, Lori Barctel, TGH

 Approval of Minutes

A motion was made to approve the January 23, 2006 minutes. The motion was

The IRB voted For - 10                   Against - 0             Abstain - 0           (Total present - 10)

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 involves putting patients with chronic pain (CRPS) under 5 days of general anesthesia using the drug Ketamine in the ICU at Tampa General Hospital. There were multiple unresolved issues when this study was previously reviewed with the major issue being that the patients are required to provide $27,000 up front prior to enrolling.

The reviewer stated that the PI did a lot of work on the revisions. However, he needs to correct the pager number on the consent as it does not match what is listed in the application. He should also expand on the difference in the standard of care versus this study treatment. The risk profile of Ketamine is not actually described only that it is well established. The PI revised the exclusion criteria but should also add significant history of cardiac ischemic disease to these criteria.

The protocol and application also need to state that the labs for the study will be taken every day. There was a note included about the suggestion of using a rotating bed to decrease risk of pneumonia but it was not stated if it will actually be used so this needs to be clarified and will it be part of the $27,000 fee. Another issue was the ICU nurses titrating the ketamine and there was a question if the nurses would be getting in-services prior to the enrollment. It was not stated in the application. This is very important to the study and the nurses need to be given in-services training.

[Tape #2A, 5 minutes]

Since the drug ketamine is being used for a non-approved use does the PI need to apply for a IND? The PI should clarify this. The IRB requested that a copy of the guarantor agreement also be submitted. The reviewer also tried to call the finance department using the number listed in the consent form and could not get in touch with anyone.

The PI also needs to include in the consent form the percentages of relief from pain that patients experienced in the German study. He should also state what the average length of stay for those subjects were in the German study. Clarification regarding who decides the health care surrogate for the patient is needed. The consent form indicates that the PI is assigning the surrogate instead of the patient themselves.

The procedures of the study and what is covered by the $27,000 should be given in the consent form in more detail. The IRB had requested a review done by an outside clinician who is a pain doctor. Her overall point of view was that this study could be done at a lower dose of Ketamine that does not require general anesthesia for 5 days in the ICU and with less risk.

There was further discussion regarding the study being very expensive for patients and would the patients have the means to pay, and if they do, how is this being just to other populations. It was stated that the patient will pay 35% of the hospital costs up to $70,000. Another point of view expressed that although this is very expensive to the patient how can they be denied the opportunity to be pain free even if they need to take out loans to pay for this.

The Board would like the PI to provide a best case cost scenario and a worse case cost scenario so the subject is informed. The PI will also know what the costs will be after 1 patient has completed the study and he will be able to revise his information for the subsequent subjects.

Although the German study is not published it is a well known study in the pain anesthesia field and the outside reviewer knew of the study immediately when it was mentioned. The Board requested that 2 other outside anesthesiologists review the study and give their opinions.

One reviewer stated that there is possible potential for some good in this study but it is questionable whether the benefit outweighs the risk given the cost and risk of being under anesthesia for 5 days and all the possible complications that could occur. Given the situation of this study the PI needs to give extremely specific cost information and provide all the data in the consent form on the 30 patients that have been treated to date in Germany. He needs to address all the issues discussed today, the IRB will solicit the outside expert reviewers opinions. After review of these opinions, then maybe the study could enroll one patient.

[Tape #2A, 26 minutes]

A board member stated that even with outside reviewer's opinions the excessive cost and risk will not be diminished. Another Board member stated that, although this is true, an expert opinion can bring some valuable information to show this IRB that there is a reasonable benefit to the cost.

The Committee had no further questions or discussion on this study. A motion was made to DEFER this study pending major revisions. The motion was seconded and carried unanimously.

The IRB voted For - 8   Against - 2  Abstain - 0  (Total present - 10)

[Tape #2A, 36 minutes, Tape ends]

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

Members absent:             

Mortimer Brown, Ph.D., Non-Affiliated

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]

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

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.

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.

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]