University of Virginia Institutional Review Board - Health Sciences Research Guidelines for Researchers Using Gadolinium-Enhanced MRI in Research

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1 University of Virginia Institutional Review Board - Health Sciences Research Guidelines for Researchers Using Gadolinium-Enhanced MRI in Research Page 1 of 16

2 Table of Contents New Information:... 3 IRB-HSR Recommendations for past and future use of Gadolinium-enhanced MRI in Research:... 4 New exclusion criteria for protocol using gadolinium-enhanced MRI in research... 6 New risk language for the protocol using gadolinium-enhanced MRI in research... 7 Required Risk Language for the consent for New Studies or for studies that are Open to Enrollment but have not yet enrolled subjects:... 7 Addendum Template:... 9 Appendix A: FDA Public Health Advisory Appendix B: Recommendations from UVa Department of Nephrology for ESRD/dialysis patients requiring gadolinium as contrast Appendix C: Risk of Gadolinium Memo from the UVa Department of Radiology Dated: Thursday, April 19, Page 2 of 16

3 New Information: The FDA has recently released a warning about a new and rare disease called Nephrogenic Systemic Fibrosis (NSF) or Nephrogenic Fibrosing Dermopathy (NFD) that is linked with the use of Gadolinium in people with: 1. moderate chronic kidney disease (glomerular filtration rate (GFR) less than 60 ml/min) 2. end-stage kidney disease (GFR less than 15 ml/min). 3. receiving dialysis for acute or chronic kidney disease NSF/NFD causes fibrosis of the skin, connective tissues like muscles, tendons, ligaments, and blood vessels throughout the body. In addition, those who develop NSF/NFD may have scarring of their vital organs. The signs of NSF/NFD include: burning, itching, swelling, hardening and tightening of skin; red or dark patches on the skin; yellow spots on the whites of the eyes; stiffness in joints with trouble moving or straightening the arms, hands, legs or feet; pain deep in the hip bones or ribs; muscle weakness. In most of the cases reported to the FDA, symptoms of NSF/NFD started between 2 days to 18 months after exposure to the gadolinium-based contrast agent. NSF/NFD may be progressive (may worsen) and may be fatal. There is no known treatment for NSF/NFD. Skin biopsy is the only true means of diagnosis. A copy of the Public Health Advisory from the FDA is available in Appendix A of this document. On January 31, 2007, the UVa Department of Nephrology drafted recommendations related to the use of gadolinium in the presence of renal failure. These guidelines are available in Appendix B of this document and should be referenced for treating patients clinically. These recommendations were given to the UVa Department of Radiology. The Department of Radiology has established guidance for the use of gadolinium in clinical practice as well. The memo that was sent to clinicians earlier this year is provided for your reference in Appendix C of this document. All of these expert recommendations address the use of gadolinium in clinical practice; however these guidelines do not address the use of gadolinium in research. The purpose of this document to relate the IRB-HSR recommendation for the use of gadolinium in research. Page 3 of 16

4 IRB-HSR Recommendations for past and future use of Gadolinium-enhanced MRI in Research: 1. In general, the use of gadolinium-enhanced MRI for research purposes will not be approved in subjects with an estimated GFR of less than 60 ml/min. However, if the principal investigator wants to use gadolinium-enhanced MRI in research subjects with impaired renal function, the principal investigator must provide the IRB with a procedure to screen subjects, a risk/benefit analysis, a discussion of the potential for benefit of the MRI and a plan to minimize the risks. This information must be incorporated into the protocol. Based on review of this information, the IRB will then decide on a protocol by protocol basis whether there is an acceptable risk/benefit ratio. 2. For studies not yet approved by the IRB which utilize gadolinium-enhanced MRI the protocol and consent must list the risk of NSF/NFD and the protocol should list the new exclusion criteria unless otherwise approved by the IRB. Risk language has been approved by the Office of General Counsel and Health System Risk Management and is provided for you later in this document. 3. For studies previously approved by the IRB that utilized gadolinium-enhanced MRI for research the following steps must be taken:. If the study is Active ( e.g. not closed with the IRB) the following steps must be taken: o Add the new exclusion criteria and the recommended risk language and to the protocol (exact wording is given later in this document). o If the protocol is monitored by the GCRC Advisory Committee please contact them for review and approval. o If the protocol is investigator-initiated and overseen by the Cancer Center PRC please contact them to determine if PRC review is required. o Submit modified protocol to IRB for approval Page 4 of 16 o If the study is still open to enrollment: 1. Add the new risk section to the consent form (exact wording is given later in this document) 2. If the protocol is monitored by the GCRC Advisory Committee please contact them for review and approval. 3. If the protocol is investigator-initiated and overseen by the Cancer Center PRC please contact them to determine if PRC review is required. 4. Submit modified consent to IRB for approval 5. If subjects have already been enrolled take the following additional steps: 6. Create Consent Addendum (template attached to this document) 7. Submit Consent Addendum to IRB for approval 8. After IRB has approved consent addendum, send it to all subjects who have had a gadolinium-enhanced MRI within the last two years

5 9. The consent addendum should be mailed with a self-addressed envelope requesting that they sign the new addendum and return the form to the study team. The form should be signed by someone from the study team and a copy of the fully signed form should then be mailed to the participant. This should be done within 30 days following the modification approval. If the study is closed to enrollment and subjects were enrolled: 1. Create Consent Addendum (template attached to this document) 2. If the protocol is monitored by the GCRC Advisory Committee please contact them for review and approval. 3. If the protocol is investigator-initiated and overseen by the Cancer Center PRC please contact them to determine if PRC review is required. 4. Submit Consent Addendum to IRB for approval 5. After IRB has approved consent addendum, send it to all subjects who have had a gadolinium-enhanced MRI within the last two years 6. The consent addendum should be mailed with a self-addressed envelope requesting that they sign the new addendum and return the form to the study team. The form should be signed by someone from the study team and a copy of the fully signed form should then be mailed to the participant. This should be done within 30 days following the modification approval. If the study is Closed AND utilized gadolinium-enhanced MRI for research take the following steps: 1. Create Consent Addendum (template attached to this document) 2. If the protocol is monitored by the GCRC Advisory Committee please contact them for review and approval. 3. If the protocol is investigator-initiated and overseen by the Cancer Center PRC please contact them to determine if PRC review is required. 4. Submit Consent Addendum to IRB for approval 5. After IRB has approved consent addendum, mail it to all subjects who have had a gadolinium-enhanced MRI within the last two years 6. The consent addendum should be mailed with a self-addressed envelope requesting that they sign the new addendum and return the form to the study team. The form should be signed by someone from the study team and a copy of the fully signed form should then be mailed to the participant. This should be done within 30 days following the modification approval. The IRB administrative staff is available to help expedite the approval of the consent addendum. In addition the School of Medicine Clinical Trials Office is available to help with this process. Please contact Lori Elder at if assistance is needed. Page 5 of 16

6 New exclusion criteria for protocol using gadolinium-enhanced MRI in research Add the following recommended exclusion criteria to the protocol under the inclusion/exclusion criteria: Estimated GFR less than 60 ml/min based on a serum creatinine drawn within 90 days of the MRI if any of the following conditions exist: o Greater than 70 years of age o A history or indication of renal insufficiency o History of diabetes o History of paraproteinemia syndromes such as multiple myeloma o History of vascular disease (CAD, MI, carotid disease, PVD, or known visceral artery disease) Page 6 of 16

7 New risk language for the protocol using gadolinium-enhanced MRI in research 1. Required risk language for the protocol using gadolinium-enhanced MRI for research. Add the following recommended risk language to the protocol under the DSMP section 1.1: An extremely rare disease called Nephrogenic Systemic Fibrosis (NSF) or Nephrogenic Fibrosing Dermopathy (NFD) is linked with the use of gadolinium in people with: moderate chronic kidney disease (glomerular filtration rate (GFR) less than 60 ml/min) end-stage kidney disease (GFR less than 15 ml/min). receiving dialysis for acute or chronic kidney disease NSF/NFD causes hardening and thickening (fibrosis) of the skin, connective tissues like muscles, tendons, ligaments, and blood vessels throughout the body. In addition, those who develop NSF/NFD may have scaring of their body organs. NSF/NFD may be progressive (may worsen) and may be fatal. There is no known treatment for NSF/NFD. Skin biopsy is the only true means of diagnosis. Add the following recommended risk language to the protocol under the DSMP section 1.2: To minimize the risk of receiving gadolinium: In addition to the exclusion criteria in this protocol, all subjects will be screened by UVa Department of Radiology staff prior to receiving gadolinium. If radiology screening indicates that it might be unsafe for a subject to receive this contrast, then the subject should not be given the contrast for research purposes. If screening indicates that the subject may receive gadolinium, the subject will receive a brand of contrast that has thus far not been linked to reported cases of NSF per the FDA. Required Risk Language for the consent for New Studies or for studies that are Open to Enrollment but have not yet enrolled subjects: Place this information in the body of the consent form where risks of the study are discussed: Risk of using gadolinium: As part of the MRI/MRA you will receive a contrast called Gadolinium. This substance will help the tissues show up better. The FDA has received information about a new and extremely rare disease called Nephrogenic Systemic Fibrosis (NSF) or Nephrogenic Fibrosing Dermopathy (NFD) that is linked with the use of Gadolinium in people with moderate and severe kidney disease. Page 7 of 16

8 NSF/NFD causes hardening and thickening (fibrosis) of the skin, connective tissues like muscles, tendons, ligaments, and blood vessels throughout the body. In addition, those who develop NSF/NFD may have scaring of their body organs. The signs of NSF/NFD also include: burning, itching, swelling, hardening and tightening of skin; red or dark patches on the skin; yellow spots on the whites of the eyes; stiffness in joints with trouble moving or straightening the arms, hands, legs or feet; pain deep in the hip bones or ribs; Muscle weakness. In most of the cases reported to the FDA, symptoms of NSF/NFD started between 2 days to 18 months after a person received the Gadolinium-based contrast agent. NSF/NFD may get worse and may lead to death. There is no known treatment for NSF/NFD. IF you have any of the symptoms listed above after receiving Gadolinium-based contrast for a study MRI/MRA, please contact the study team immediately. The study team will review your symptoms and perhaps recommend a skin biopsy, which is the only way to determine if you actually have NSF/NDF. (Insert if appropriate) Because of this newly identified risk, study participants with moderate to severe renal failure will not receive Gadolinium based contrast agents before study MRI/MRA tests. (Insert if appropriate) Before you receive gadolinium/additional gadolinium for research: You will be screened by UVa Department of Radiology staff prior to getting gadolinium. If radiology screening shows that it might be unsafe for you to receive this contrast, then you will not be able to receive the contrast. (Add if necessary) You will not be allowed to enroll in the study. If your screening indicates that you may receive gadolinium, you will receive a brand(s) of contrast that has thus far not been linked to reported cases of NSF per the FDA. Page 8 of 16

9 Addendum Template: Use this template to communicate the risk for using gadolinium in research for studies that have enrolled subjects IRB-HSR #: Protocol Title Participant s Name Medical Record # Page 9 of 16 ADDENDUM TO CONSENT- Gadolinium This addendum to the consent form is to tell you about new information regarding the study in which you are enrolled. You received or are scheduled to receive a contrast agent called gadolinium before your study MRI/MRA exams. This contrast agent is given by IV and is useful because it helps the MRI/MRA pictures of the internal organs or blood vessels show up better. The FDA has received information about a new and extremely rare disease called Nephrogenic Systemic Fibrosis (NSF) or Nephrogenic Fibrosing Dermopathy (NFD) that is linked with the use of gadolinium in people with: moderate kidney failure (glomerular filtration rate (GFR) less than 60 ml/min) end-stage kidney disease (GFR less than 15 ml/min). NSF/NFD causes hardening and thickening (fibrosis) of the skin, connective tissues like muscles, tendons, ligaments, and blood vessels throughout the body. In addition, those who develop NSF/NFD may have scaring of their body organs. The signs of NSF/NFD also include: burning, itching, swelling, hardening and tightening of skin; red or dark patches on the skin; yellow spots on the whites of the eyes; stiffness in joints with trouble moving or straightening the arms, hands, legs or feet; pain deep in the hip bones or ribs; muscle weakness. In most of the cases reported to the FDA, symptoms of NSF/NFD started between 2 days to 18 months after exposure to the Gadolinium-based contrast agent. NSF/NFD may get worse and may lead to death. There is no known treatment for NSF/NFD. IF you had or have any of the symptoms listed above after receiving Gadolinium-based contrast for a study MRI/MRA, please contact the study team immediately. The study team will review your symptoms and perhaps recommend a skin biopsy, which is the only way to find out if you actually have NSF/NDF. The study team contact information is on page 2 of this document.

10 (Insert if appropriate) Because of this newly identified risk, study participants with moderate to severe renal failure will no longer receive Gadolinium based contrast agents before study MRI/MRA tests. (Insert if appropriate) Because of this newly identified risk, this study is being stopped, changed etc. Add details if study is being changed. Add information about final, or follow up visits. (Insert if appropriate) If you have not already received your MRI: You will be screened by UVa Department of Radiology staff prior to getting gadolinium. If radiology screening shows that it might be unsafe for you to receive this contrast, then you will not be able to receive the contrast. (Add if necessary) You will not be allowed to continue to be in the study. If your screening indicates that you may receive gadolinium, you will receive a brand(s) of contrast that has thus far not been linked to reported cases of NSF per the FDA. All other sections of the original consent form still apply. Please refer to it for any questions you might have. Contact Names and Numbers If you have any questions about this study, you should talk to (insert name and title) at (insert phone number) If you have any questions regarding research participants' rights, please contact the Chair of the Institutional Review Board for Health Sciences Research of the University of Virginia at (434) or the IRB-HSR staff at (434) Conclusion You will receive a signed copy of this form to keep. I HAVE READ, OR HAD READ TO ME, THE ABOVE INFORMATION BEFORE SIGNING THIS ADDENDUM. I HAVE BEEN OFFERED AN OPPORTUNITY TO ASK QUESTIONS AND HAVE RECEIVED ANSWERS THAT FULLY SATISFY THOSE QUESTIONS PARTICIPANT PARTICIPANT DATE (SIGNATURE) (PRINT) PERSON OBTAINING PERSON OBTAINING CONSENT DATE CONSENT (SIGNATURE) (PRINT) Page 10 of 16

11 Appendix A: FDA Public Health Advisory Update on Magnetic Resonance Imaging (MRI) Contrast Agents Containing Gadolinium and Nephrogenic Fibrosing Dermopathy The FDA has received additional information about a new disease, known as Nephrogenic Systemic Fibrosis or Nephrogenic Fibrosing Dermopathy (NSF/NFD), which may occur in patients with moderate to end-stage kidney disease after they have had a Magnetic Resonance Imaging (MRI) or Magnetic Resonance Angiography (MRA) scan with a gadolinium-based contrast agent. An MRI scan provides clear and detailed pictures of internal organs. An MRA test uses a gadolinium-based contrast agent to take detailed pictures of blood vessels. During some MRI scans and all MRA scans, a gadolinium-based contrast agent is injected into a patient s vein so blood vessels can be distinguished from other nearby tissues. As of December 21, 2006, FDA has received reports of 90 patients with moderate to end-stage kidney disease who developed NSF/NFD after they had an MRI or MRA with a gadolinium-based contrast agent. Their NSF/NFD began from 2 days to 18 months after exposure to the contrast agent. Many, but not all of these patients, received a high dose of the contrast agent; some received only one dose. In light of these reports, FDA is notifying health care providers and patients of the following: Patients with moderate to end-stage kidney disease who receive an MRI or MRA with a gadolinium-based contrast agent may get NSF/NFD which is debilitating and may cause death. Patients who believe they may have NSF/NFD should contact their doctor. Patients who develop NSF/NFD have areas of tight, rigid skin and may have scarring of their body organs. The signs of NSF/NFD also include: burning, itching, swelling, hardening and tightening of the skin; red or dark patches on the skin; yellow spots on the whites of the eyes; stiffness in joints with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. When a patient with moderate to end-stage kidney disease needs an imaging study, select imaging methods other than MRI or MRA with a gadolinium-based contrast agent for the study whenever possible. If these patients must receive a gadolinium-based contrast agent, prompt dialysis following the MRI or MRA should be considered. The FDA asks health care professionals and patients to report possible cases of NSF/NFD to the FDA through the MedWatch program by phone (1-800-FDA-1088) or by the Internet at Worldwide, about 215 patients with NSF/NFD have been reported. Of these reports, the medical histories of 75 of these patients were reviewed in detail, and all of the patients had received a gadolinium-based contrast agent for an MRI or MRA. Researchers have identified gadolinium in skin biopsies of patients with NSF/NFD. Page 11 of 16

12 Why NSF/NFD occurs in patients with moderate to end-stage kidney disease who receive gadoliniumbased contrast agent is not yet known. The FDA is working with expert scientists to gather additional information about NSF/NFD. Currently there are five FDA approved gadolinium-based contrast agents, Magnevist, MultiHance, Omniscan, OptiMARK, and ProHance. These contrast agents are FDA approved for use during an MRI scan, but not for use during an MRA scan. Although NSF/NFD has been reported for only 3 of the 5 gadolinium-based contrast agents, FDA believes that there is a potential for NSF/NFD to occur with the use of any of the approved gadolinium-based contrast agents. You can find more details about NSF/NFD and gadolinium-based contrast agents in FDA s Information for Healthcare Professionals. Page 12 of 16

13 Appendix B: Recommendations from UVa Department of Nephrology for ESRD/dialysis patients requiring gadolinium as contrast Introduction On 12/22/06 the FDA issued an alert stating that 90 cases of nephrogenic sclerosing fibrosis (NSFpreviously referred to as nephrogenic sclerosing dermopathy or nephrogenic fibrosing dermopathy) have been reported in patients with moderate chronic kidney disease or end stage kidney disease. All 90 patients had received gadolinium for MRI scans within 2 days to 18 months of developing the debilitating and potentially fatal condition. It is also possible that the most commonly used gadolinium preparation (gadodiamide-omniscan) is most likely to cause NSF Scattered cases of NSF have been previously reported, including 57 cases in Europe. All of these cases involved MRI. MRI, requires a high dose of gadolinium and it is thought that this combined with ESRD patients inability to rapidly excrete the agent likely contribute to the development of NSF. Gadolinium has been found in skin biopsies of patients with NSF. Investigation is ongoing. Gadolinium appears to be excreted totally by the kidney; hemodialysis is effective in removing gadolinium. The first hemodialysis treatment after gadolinium exposure removes approximately 70% of the gadolinium. The second and third post-exposure hemodialysis treatments remove 92% and 96% respectively (4). Recommendations--reducing the risk of NSF associated with MRI with gadolinium: 1. consider using another imaging modality or unenhanced MR in patients at risk of NSF ( ESRD patients and potentially those with GFR < 30) 2. Use gadolinium enhanced MRI only if clinically necessary 3. If using gadolinium in this population dialyze within 3 hours of the imaging procedure, and again at 24 and 48 hours. 4. Use the lowest possible dose of the agent that will still yield reliable diagnostic information 5. Inform patients in the target population of the risks and benefits and alternatives of the procedure 6. Report occurrences of NSF to nsf@esur.org and to the FDA Med Watch program. There is also an international NSF registry overseen by Shawn Cowper. (NFD/NSF website see REFERENCES 1.FDA (2006) Public Health Advisory: Gadolinium-containing Contrast Agents for Magnetic Resonance Imaging (MRI): Omniscan, Optimark, ProHance, and MultiHance. Available at 2 Nephrogenic Systemic Fibrosis (NSF): A disease recently associated with some of the Gadolinium contrast agents: a document prepared by the Contrast Medium Safety Committee of the European Society of Urogenital Radiology. Nov Cassels, C. Dialysis recommended to prevent NSF after Gadolinium based imaging in severe renal failure. Medscape medical news Information obtained from January 10, 2007 issue of the journal Radiology Page 13 of 16

14 4. Thomsen, H. S.et al Is there a causal relation between the administration of gadolinium based contrast media and the development of nephrogenic systemic fibrosis (NSF)? Clinical Radiology 2006; 61: Thomsen HS. Nephrogenic systemic fibrosis: a serious late adverse reaction to gadodiamide. Eur Radiol 2006; 16: Epub. 6. Maarckman P et al Nephrogenic systemic fibrosis: Suspected etiological role of gadodiamide used for contrast enhanced magnetic resonance imaging. J Am Soc Nephrol 2006; 17: University of Virginia Division of Nephrology January 31, 2007 JH/LN Page 14 of 16

15 Appendix C: Risk of Gadolinium Memo from the UVa Department of Radiology Dated: Thursday, April 19, 2007 Risks of gadolinium contrast Overall, MRI contrast agents have an excellent safety profile over 18 years and more than 200 million doses worldwide. However, recent reports have described an association between certain gadoliniumbased MR contrast agents and a rare but serious medial condition called Nephrogenic Systemic Fibrosis (NSF) or Nephrogenic Fibrosing Dermopathy (NFD). NSF/NFD was first described in 1997 and has only been observed as a side-effect in patients with chronic kidney disease. NSF/NFD causes thickening and hardening of the skin and may also affect the internal organs. The disease is progressive and may be fatal. There is currently no effective therapy for NSF/NFD. The cause and relationship to gadolinium based contrast agents are currently unknown. The following link provides some background on this topic: From the available and limited literature, with GFR or moderate kidney disease, it appears that the risk of developing NSF is greater than the general public, although this risk remains extremely low (<1% or less than 1 out of 100 patients). With GFR<30 or severe to end stage kidney disease, it again seems that the risk of developing NSF is very low, but more likely than either patients with no kidney disease, or moderate kidney disease, and perhaps as great as 1%. For patients on renal dialysis with renal failure, the risk of developing NSF seems much more significant, but is still likely to be low (less than 5%). For these patients, prompt dialysis is recommended following imaging studies using gadolinium-based contrast agents to reduce the contrast burden as a preventative measure. Implications In order to minimize the risk and ensure patients are well informed, it is recommended for all imaging studies that non-contrast protocols are optimized and contrast amount is reduced for protocols when this is feasible, while ensuring diagnostic integrity is maintained. For patients with existing renal disease, the decision and amount of contrast is a risk-benefit decision. In order to determine a patient's risk level, a screening form much like those currently used for CT contrast will be administered, and will identify those patients requiring labs. Additionally, this form will be used to document the radiologist's order for the administration of the contrast. For those patients requiring contrast, their risk will be stated for 3 distinct tiers: GFR 30-59, GFR <30 and Dialysis patients. For all patients in these 3 groups it is recommended that gadodiamide (Omniscan ) or gadoversetamide (OptiMARK ) not be used. Instead either gadopentetate dimeglumine (Magnevist ), gadoteridol (ProHance ), or gadobenate dimeglumine (MultiHance ) is recommended. When gadodiamide (Omniscan ) is used for patients without documented renal disease, it will be limited to weight based dosing (0.1mmol/kg) For Dialysis patients, the use of contrast is discouraged, but the choice to do so becomes a physician's risk-benefit assessment. Page 15 of 16

16 We will be implementing a consent form that will have a check box and description of risk for the 3 groups of relative increased risk. These consent forms will be "self administered" and the technologist will follow up with the patient to identify additional questions. Dialysis patients (for both CT and MRI) will be identified at time of scheduling along with when and where they are scheduled for dialysis and the scheduling of dialysis concurrent with the contrast administration will be facilitated by the radiology staff. Until we have a completed screening form and consent, it is recommended that patients identified as having potential or likely renal disease (based on technologist questioning) not be administered gadodiamide (Omniscan ). All patients on dialysis must be identified and cleared with the attending radiologist prior to contrast administration. For additional information please reference the UVa Department of Radiology Policy on Gadolinium Based Contrast ( Policy # PH006) Page 16 of 16