Kinsman Conference Workshop A-3 - Responsible research: IRBs, consent and conflicts of interest Elizabeth Steiner MD, Associate Professor of Family Medicine, Co-Chair, Institutional Review Board, OHSU Case 1 A New Device: when does an investigator s investment in a commercial enterprise result in conflict of interest? Key points 1. What is non-significant risk? Can it be different for the same device when used for a different condition? 2. Who decides if a device is non-significant risk? 3. Can members of a DMSB separate their interests? LAY LANGUAGE PROTOCOL SUMMARY Study/Protocol Title: Sub-Acute Stroke Rehabilitation with AMES Please answer all of the following questions using lay language, similar to the language used in a consent form. Please number your responses. 1. Briefly describe the purpose of this protocol. The purpose of this study is to see how the AMES device can be used to aid in the recovery of arm or leg weakness/paralysis caused by damage to the brain from a stroke. 2. Briefly summarize how participants are recruited. Participants will be recruited from the PI s stroke clinic. Those subjects that meet inclusion criteria will be asked if they would like to participate. The general public will be recruited through an advertisement the general public will also be enrolled through the PI s clinic. 3. Briefly describe the procedures subjects will undergo. Subjects will undergo various physical exercises/movement routines aided by the investigational device. These tests will measure the tightness, strength, and ability to control movement in the subject s arm and/or leg. Subjects will be tested 2-3 times per week, for 6-14 weeks. Each visit will last about 45 minutes for each limb treated, with 30 minutes of actual testing being done. Subjects will be randomized to receive either an ultrasonic vibration through the study device, or no vibration. The vibration can t be felt, heard or seen by the subject or investigator. The study is looking at the effect this vibration has on the rehabilitation of stroke subjects with weakness or paralysis caused by the stroke. 4. If applicable, briefly describe survey/interview instruments used. Document Title: Investigational Protocol Document Number: COD0101 Revision: E Page 1 of 44 Effective Date: 10-10-07 Issued By:
Subjects will be asked about how they feel their stroke has reduced their ability to move. 5. If this is a clinical trial using an experimental drug and/or device, or an approved drug and/or device used for an unapproved purpose, briefly describe the drug and/or device. The AMES device is an external device designed to treat all four appendages from either a four-legged chair or a wheel chair. The device is highly adjustable so that it can be properly fit to each subject s affected arm and/or leg. The study device has a motor for rotating the affected joint(s) and vibrators to vibrate muscle tendons. A computer in the study device will run a program that provides the arm and leg tests. 6. Briefly describe how the data will be analyzed to address the purpose of the protocol. Data will be analyzed by Sponsor, not the study team. Sponsor will compare pre- and post-treatment difference of the Fugl-Meyer score between Test and Control Groups using an independent two-sample test. EXCERPT FROM PROTOCOL 1. Introduction 1.1 Purpose of the Study The AMES device is a non-significant risk investigational therapeutic device used to rotate cyclically the hand, wrist, or ankle, while tendon vibrators stimulate sensory receptors in the muscles antagonistic to the joint rotation. As part of the AMES therapy, the patient assists the passive motion imposed on the limb. In effect, the device provides assisted movement of a joint and enhanced sensation (i.e., AMES) of that movement. The purpose of this document is to describe the procedures to be used in a controlled study of sub-acute (<6 months) stroke subjects treated with AMES. No other use of the AMES device is allowed in this study. 1.2 Historical Background Approximately 700,000 U.S. citizens have a stroke each year, making stroke the leading cause of long-term disability in the U.S. There are an estimated 5 million stroke survivors in the U.S., of whom about half end up with significant motor disabilities. Disability associated with hemiplegic stroke is most often associated with motor dysfunction. Paresis, rigidity, dyssynergia, and loss of sensation combine to cause motor disability in individuals suffering strokes. Paresis, or in its severest form, plegia, results from damage to descending motor pathways, from joint rigidity, and from dyssynergia. Joint rigidity is caused by contracture, hypertonia, and spasticity. Cocontraction during attempted voluntary movement is a form of dyssynergia that contributes to paresis. Loss of sensation also interferes with the initiation of movement and is often associated with hemineglect. This constellation of sensory and motor symptoms interacts in multiple ways to impede movement and to hamper therapeutic measures intended to restore movement by alleviating individual symptoms. For example, plegia, sometimes observed in ankle dorsiflexion following stroke, may have multiple causes, and the alleviation of just one of these causes may be insufficient to
restore functional movement and eliminate foot-drop during gait. The most obvious cause of foot drop is muscle weakness due to damage to descending motor pathways from the brain. However, contracture, hypertonia, spasticity, dyssynergia, and muscle atrophy can all prevent ankle dorsiflexion, even if descending pathways are partly intact and the patient is able to voluntarily contract the ankle dorsiflexors. Some therapeutic interventions improve one symptom while worsening others. For example, ankle-foot orthoses (AFOs) prevent foot drop, but cause muscle atrophy. Botox injections reduce spasticity and hypertonia, but weaken connectivity between voluntary motor centers of the brain and the muscle. Until the early 1990s, most physical rehabilitation was based on passive ranging of the joints, massage, and isolated sensory stimulation. Current evidence suggests that these approaches appear not to enhance recovery of function much beyond that which would be achieved with spontaneous recovery. However, the last 15 years has seen the development of a number of new rehabilitative approaches, based in part upon the recognition that the adult brain is plastic and can be changed by active training and sensory stimulation. Purely physical approaches, such as constraint-induced therapy, progressive resistance training, repetitive active movement, and higher-level occupational therapy have produced some encouraging results, with improvements in limb range of motion and functionality reported in some stroke patients. Other approaches have employed methods, such as assistive/resistive motion robots, EMG biofeedback, and electrical stimulation of muscles, nerves and the motor cortex. Most of these recently developed approaches seem to be most effective in stroke patients with significant residual function and minimal joint rigidity. Treatment for spasticity and hypertonia continues to focus on pharmacological approaches, especially those involving anti-spasmodics and Botox. Clearly, the model for stroke therapy is undergoing transformation, influenced by rigorous research and newly developed technology. The trend over the last 15 years for the treatment of paresis has been to focus more on active participation of the patient and to involve more sensory stimulation. Correspondingly, the AMES therapy approach was designed to induce functional plasticity in the stroke patient s brain by the repetitive and synchronous activation of cortico-motor and cortico-sensory neurons. New treatments that significantly improve the long-term prognosis of stroke survivors will have major financial and societal impacts in the U.S. and the rest of the world. 1.3 AMES History This study is based on more than 20 years of research on muscle vibration and motor function. Initially, the goal of this research was to improve basic understanding of sensorimotor control and, more recently, to apply this basic understanding to clinical problems. In clinical research conducted over the last 5 years, the AMES device has been used to treat subjects with chronic stroke, sub-acute stroke, incomplete spinal cord injury, traumatic brain injury, and essential tremor. Results thus far indicate that AMES treatment leads to a significant and permanent restoration of functional movement in the upper and lower extremities of chronic stroke subjects (2-16 years post-stroke), most of whom had less than 30% residual strength and range of motion in the treated limb. Preliminary studies have been completed in 22 chronic stroke subjects with treatment of the lower extremity (n = 15), and upper extremity (n = 14). Of the 22 subjects, 7 used a device for both the upper and lower extremity at different times. The prototype upper- and lower-extremity devices used in these studies assist the movement of a joint(s) and vibrate the tendons of the flexors and extensors crossing the treated joint(s). There have been no significant safety issues over the 5 years of this
research. A majority ( 70%) of the subjects have experienced significant improvement in strength, joint rigidity, and functional movement of the affected limb after 6 months of treatment. These improvements in function were most profound in the treated joints, but significant improvements were also found in the more proximal joints of the treated limb. Follow-up on these subjects has typically shown retention of improved function and, in some cases, continued improvement in function up to 6 months post treatment. Most importantly, no subject achieving functional improvement by the end of 6 months of AMES treatment experienced a decrease in function after treatment was discontinued. During this study, chronic stroke subjects used the prototype AMES devices in the home setting. The therapeutic regimen consisted of 30 min of therapy per day over a 6- month period. The therapy was self-applied. Most subjects were able to get into and out of the device, turn it on and off, and perform all tests and therapy without assistance. 1.4 AMES Device AMES Technology, Inc. has developed a Beta-version of the AMES device, to be employed in a clinical trial on sub-acute stroke patients. Whereas the prototype version of the AMES device was difficult to adjust to different user sizes, the Beta device will be highly adjustable, suitable for application in the clinic where a large number of patients will be using the device. The Beta device will accommodate patients treated from a wheelchair or from a conventional 4-legged chair. Each Beta system will consist of a base unit and 2 appendages designed to treat all 4 extremities. Each base unit will contain all of the electronic and computer hardware necessary to operate the appendages. A flat panel display will provide a user interface for both the patient and therapist. The Beta device will incorporate mechanical, electrical, and software safety features, including an emergency panic switch within reach of the users. Figure 1. AMES Beta device set up for treatment
1.5 AMES Hypothesis AMES is designed to produce functional cortical plasticity through: (1) the facilitation of agonist muscle activity by assisting the subject as he/she attempts to move the limb (assisted movement) and (2) the enhancement of movement sensation by vibrating the tendons of the antagonist muscles during movement (enhanced sensation). The goal of assisted movement is to increase the activation of cortical motoneurons during attempted voluntary movement, and the goal of vibration is to increase the feedback to cortical sensory neurons associated with that movement. AMES is based on the hypothesis that assisted movement and enhanced sensation, used together, promotes the functional reorganization (plasticity) of sensorimotor pathways in the brain. In this proposed study, we hypothesize that the combination of assisted movement and enhanced sensation from antagonist muscles can enhance motor rehabilitation of individuals disabled by a stroke. 1.6 Investigational Objectives The main objectives of the planned study are: 1) to substantiate the efficacy of AMES therapy in a sub-acute stroke population based on the change in Fugl-Meyer score; 2) to develop guidelines for optimal device usage in a clinic setting; 3) to evaluate the Beta device in order to plan for design improvements for the commercially available device. Case 2: A New Procedure: When does an investigator s belief in a procedure interfere with his ability to provide true informed consent? Key points 1. How does one distinguish between standard of care, innovative care, and research? 2. How do we inform patients and subjects properly about these distinctions? 3. How does an institution learn about what is truly standard of care across the country? LAY LANGUAGE PROTOCOL SUMMARY Study/Protocol Title: Ovarian Tissue Cryopreservation Foundational Study and Database Development Please answer all of the following questions using lay language, similar to the language used in a consent form. Please number your responses. 1. Briefly describe the purpose of this protocol. The purpose of this study is offer an alternative method to women who wish to preserve the possibility of fertility, as well as to learn more about the ability of human eggs to survive and function after long term storage in frozen ovaries (ovarian tissue crypreservation).
With this Foundational Study submission, we are transitioning this procedure from one that is performed under the Research Integrity Innovative Care Allowance, to being offered solely through this research protocol. 2. Briefly summarize how participants are recruited. We will retrospectively enroll women who have already undergone this procedure by contacting them by mail and offering participation in our ovarian tissue cryopreservation database. Please see Waiver of Authorization for details on this contact. Women who have not yet undergone this procedure, and who present to the Fertility Consultants desiring fertility preservation, will be offered participation in the study. 3. Briefly describe the procedures subjects will undergo. Subjects will undergo an initial visit which will include a blood draw, ultrasound, and any additional tests or exams that are medically indicated for the subject s diagnosis in preparation for surgery. Subjects will then undergo an oophorectomy surgery (removal of one or both ovaries). Following removal, subjects ovarian tissue will be cryopreserved (frozen) and stored for possible future use. We also plan to collect subjects medical history information to enter into a research database. Subjects will be followed until they decide to use their tissue for fertility purposes. 4. Briefly describe how the data will be analyzed to address the purpose of the protocol. There is no quantitative data analysis planned for the purpose of this protocol, as the main objective is to offer a clinical service to patients. Excerpt from IRB review memo IRB CLARIFICATIONS: Please clarify if ovarian tissue has been or will be collected from pre-menarchal subjects at this or any other site. The IRB is requiring a separate consent form for pre-menarchal subjects. The following must be included: o The increase in risk of the procedure to remove the tissue. o The lack of information for any success of future use of the tissue in this group. o Possible shelf life issues of the preserved tissue. Are there any data on the shelf life of frozen ovarian tissue? This issue must also be addressed in the risk section of the consent form. PROTOCOL: An OHSU research protocol must be submitted for this study. The protocol provided is not sufficient and the following must be included: o Descriptions of the different surgeries for tissue removal. Would it be open or laparoscopic? Are there contingencies that determine the type of surgery? o Clearly define the inclusion and exclusion criteria. Is there an age range?
o o What about consult with the oncologist? What if surgery would delay cancer treatment? What determines if only one or both ovaries are removed? Would you ever remove two in children? What if women are capable of having eggs collected and frozen prior to starting cancer treatment? Where will the tissue be stored at OHSU should subjects choose not to participate in the sub-study? Please comment on the status of the lab to maintain these samples. Does the lab have CLIA approval for this level of storage? The age range rationale and data, if there are any, on pre-menarchal preservation. Confirm who will be performing surgeries on the very young. CONSENT FORM: This study involves banking of tissue for future use. Based on this the HIPAA information must be removed from the consent form. The new HIPAA Research Authorization forms must indicate banking as a purpose category in Q.8. Purpose section: o The purpose of this study is to potentially preserve the possibility of having children in the future. o At the end of the third paragraph, include a statement regarding that future use will be under a research protocol and additional consent will be required at that time. Risk section: o All of the risks of de novo surgery must be listed. o Address the issue of shelf life of the preserved tissue. o Address the issue of the possibility of the tissue being compromised before or after preservation. o Add the risk of loss of ovarian hormone effects when both ovaries are removed. o Add the possibility of delayed cancer treatment. Signatures: o The signature options for this study are very confusing. Please simplify and clarify. There are comments in the tracked consent form. o Some of this information should be discussed earlier in the consent form, in the procedures section. DSMP: Q.4 on the form indicates a DSMP is not applicable. Please revise. LAY PROTOCOL SUMMARY: Clarify that the purpose is to potentially preserve the possibility of fertility.