DEPARTMENT OF HEALTH & HUMAN SERVICES Food and Drug Administration Silver Spring. MD 20983 June 24, 2009 Jeffrey R. Garber, MD, FACP, FACE President American Association of Clinical Endocrinologists 245 Riverside Avenue, Suite 200 Jacksonville, FL. 32202 Dear Dr. Garber: This is in response to your May 26 letter concerning the performance of blood glucose testing, meters. ‘The Food and Drug Administration (FDA) values its interactions with professional organizations such as the American Association of Clinical Endocrinologists (AACE). We appreciate hearing your thoughts on important issues such as performance requirements for blood glucose meter and test strip systems (in this letter we will refer to them as self monitoring of blood glucose devices [SMBG devices] to differentiate them from other point-of-care systems that do not use strip technology). FDA recognizes how important itis to have accurate and reliable glucose readings in order to optimize diabetes care and ensure patient safety. Lasked FDA’s Center for Devices and Radiological Health to address your specific concerns. Enclosed is the Center’s response. FDA’s Office of Special Health Issues (OSHI), which serves, as a liaison between health professional organizations and the various components within FDA, informed me that they have been interacting with AACE. If you need help having your concerns heard or connecting with the appropriate FDA staff please contact OSHI’s Director, Theresa Toigo, RPh, MBA, at 301-827-4460 or by e-mail at theresa.toigo@fda.hhs. gov. The care of diabetics is one of FDA's highest priorities. The FDA believes that by working, organizations such as AACE, we will continue to see improvements in SMBG devices and better educate users about SMBG device best practices. We would appreciate any opportunities where we might collaborate with you on initiatives in these areas. | look forward to working with you in the future, and thank you again for sharing your thoughts. A similar letter is being sent to Drs. Daniel Duick and Richard Hellman. RECEIVED JUN 29 2008 a % % a4 ner of Food , Enclosure‘The FDA’s Center for Devices and Radiological Health’s Response Self monitoring blood of glucose devices (SMBG devices) are used by millions diabetic patients in the U.S. every day. These devices have gotten smaller, faster, and more accurate over the past 3 decades and now allow for better glycemic control by diabeties than in the past. Glucose meters are not only used by diabetics at home, but they are also used by healthcare providers in a variety of settings such as hospitals, emergency response units, nursing homes, and physicians” offices Frequent monitoring of blood glucose levels facilitates better patient outcomes. However, because SMBG devices appear to be simple devices, many believe they are immune from errors. This is an unfortunate misconception that we believe often results in operators not exercising proper care when using SMBG devices. However, despite the known problems associated with SMBG devices, we continue to believe that the benefits outweigh the risks. Clinical trials have provided evidence that SMBG devices have a positive impact in management of type | diabetes. ‘The Diabetes Control and Complications Trial (DCCT)', for example, showed that patient managed tight glycemic control, which included frequent use of SMBG devices by diabetic patients to monitor their glucose levels, resulted in a 76 percent reduetion in the risk for the development of retinopathy, a 54 percent reduction in the risk of albuminuria, and a 60 percent reduction in the risk of clinical neuropathy when compared to periodic use of SMBG devices. FDA receives reports of several deaths and thousands of potentially device-related failures every year associated with SMBG device use. Over the years, FDA has worked hard with ‘manufacturers to address those failures that could be clearly identified as device failures, but a large number of the reports that the FDA receives point to user error. Because the awareness of SMBG device related errors is too low, FDA has participated in a variety of outreach activities to ‘educate operators about the proper use and limitations of glucose meter systems. Some examples include: + Presentations at professional meetings such as those sponsored by the Diabetes Technology Society and the American Association of Clinical Chemistry on the problems associated with glucose meters. + Educating lay users through presentations, focus groups and poster sessions at meetings sponsored by consumer groups such as the Children With Diabetes organization, the largest on-line consumer group in the country. + Posting Safety Tips on our Web site such as “Common Problems with the Use of Glucose Meters” and “Useful Tips to Increase Accuracy and Reduce Errors in Test Results from Glucose Meters.” + A brochure published by our Home Health Care Committee entitled, “Blood Glucose Meters: Getting the Most Out of Your Meter- Testing Your Blood Glucose Accurately.” + Several initiatives to make the public aware of falsely elevated glucose results when patients, ‘were receiving therapies which contained the interfering sugar, maltose. ‘These included an ' The Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type | diabetes mellitus. JAMA, 2002;287:2563-2569on-air FDA Patient Safety News broadcast entitled, “Potentially Fatal Glucose Monitoring Errors with Icodextrin,” Web site postings of publications entitled, “FDA Reminders For Falsely Elevated Glucose Readings From Use of Inappropriate Test Method,” and “Eatal Iatrogenic Hypoglycemia: Falsely Elevated Blood Glucose Readings with a Point-of-Care Meter Due to a Maltose-Containing Intravenous Immune Globulin Product,” and the issue of a MedWatch Safety Alert. + A special link on FDA’s Web site for reporting blood glucose meter problems + An October 29, 2001 FDA Advisory Panel Meeting on Alternative Site Testing to gather and share information about the erroneous results being seen when samples are collected from sites other than the fingertip. + Participation in a project with the Centers for Disease Control and Prevention to find a calibration material for standardizing whole blood glucose meters. We acknowledge the importance of the concerns you communicated in your letter and discuss them below. Standards for Accuracy and Precision of SMBG Devices You expressed concern about current standards for the accuracy and precision of SMBG devices. Setting minimum performance requirements is a difficult task and one which FDA does not take lightly. It requires consideration of what is medically appropriate for the intended use of the device, what is attainable by current technology, the consequenees of not allowing products on the market, and the risks associated with real world use of the device. As you are probably aware, the United States is one of a few countries worldwide that reviews the performance of in vitro diagnostic devices before they are allowed to be marketed, The International Standard Organization (ISO) document 15197 titled “In vitro diagnostic test systems- Requirements for blood-glucose monitoring systems for self-testing in managing diabetes mellitus,” is an important and valuable document that standardizes the way glucose meter performance is established. According to this document, which was drafted 7 years ago, the minimum performance criteria to be satisfied for marketing SMBG devices in the European Community provides that 9Spercent of meter values be within 20 percent of the reference method, when reference method glucose values are > 75 mg/dL, and that 9Spercent of meter values must fall within 15 mg/dL when reference method values are <75 my/dL. FDA, in fact, argued strongly in support of stricter criteria when the document was in development and even considered voting against the standard, but in the end there were parts of the document that were valuable, and we determined that we needed to balance our recommendations with those from the international community and the available scientific evidence to support the recommendation. The ISO committee, following an open standard process thet included government authorities, manufacturers, and professional societies, determined these criteria were appropriate after considering expert medical opinion which existed in the literature; existing product standards; the effectiveness of existing SMBG devices as demonstrated in clinical outcome studies; and the state-of-the-art of existing available technology. ISO 15197 is currently being reviewed to determine if'a revision is necessary. FDA is recommending the revision of the current standards of accuracy in light of new technological advancements. The involvement of professional societies, such as yours, in the revision of thisISO standard would clearly add an important perspective, Therefore, we urge you to contact the ISO group to request inclusion in the current discussions, We understand that Ron Quicho” has been identified as the contact person for this revision, If the ISO standard for accuracy is not revised, the agency would consider taking action to no longer recognize that part of the standard, and may instead recognize other (higher) performance standards for SMBG devices for management of diabetes. As has been pointed out previously, the DCCT' demonstrated that current meters used by diabetics for self management, despite their poor accuracy, have a major positive impact on long term patient outcomes. Furthermore, a global consensus conference on self monitoring blood glucose, hosted by the Intemational Diabetes Center, a World Health Organization Collaborating Center for Diabetes Education and Translation, was convened in Minneapolis, Minnesota, on October 29 -30, 2004, to develop a consensus in the use of SMBG devices.’ The conference reached consensus on the importance of frequent use of SMBG devices to improve glycemic control, and found the method to be critical for diabetics not only in evaluating glucose control but also in helping patients learn how various medications and/or lifestyle choices affect their glucose levels, Yet, itis reasonable to stipulate that improvement in the accuracy of the meters will result in improved outcomes, as ong as frequency of testing is not decreased. During development of the existing ISO standard, manufacturers argued that very tight accuracy standards may be technologically achievable but it would be costly. Since on average diabetics pay more than twice in healthcare costs yearly than non-diabetics*, there are large socioeconomic disparities in care of diabetics®, and there are studies demonstrating the correlation of price® of testing with frequency of use, the FDA is very concerned that sudden large increases in prices could have a detrimental effect on diabetes care. However, a review of the last 31 SMBG devices the FDA has cleared shows that about haif of the meters could meet a tighter standard (within 10 mg/dL if reference reading is less than 75 mg/dL and within 15 percent when reference readings are above 75 mg/dL). Other Issues FDA Considers When Clearing SMBG Devices While the standards for accuracy and precision are important considerations when determining whether a SMBG device meets standards for marketing, FDA is also concerned with other factors which can significantly impact test results. Adverse event reports we receive through our post market surveillance system indicate that many of the erroneous glucose results resulting in harm to patients are associated with other aspects of device performance and use. Although SMBG devices are small and appear relatively simple to operate, their performance may be adversely affected by a number of factors which are not always obvious to the user. For example, erroneous results are observed during a variety of physiological conditions such as diabetic ketoacidosis, shock, or acid-base imbalance; when patients have abnormal hematocrit, Ron Quicho, Standards Administrator, Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, PA 19087, phone: 610-688-0100, ? Bergenstal, RM; MD, Gavin JR, MD, Am J Medicine 2005;118:1$-6S 4 CDC National Diabetes Fact Sheet, 2007 * Department for Health and Human Services report on Health Disparities: A Case for Closing the Gap; see bttp://www.healthreform.gov/reportshealthdisparities/index html "Fox KM, Grandy S, Curr Med Res Opin 2008, 24, 3323-9triglyceride or urate levels; when other sugars are present, such as maltose or xylose; when patients are taking Jarge doses of Vitamin C or medications such as acetaminophen or L-Dopa; when abnormal environmental conditions exist such as extreme temperatures or humidity, or high altitude; when patients collect samples from alternative sample sites (such as the forearm or thigh), use improper techniques to collect the sample (such as “milking”), or they fail to wash their hands before testing; when operators use a test strip that is not appropriate for their meter; when operators use expired test strips; and when operators do not follow directions such as properly cleaning and maintaining the meter, performing quality control measures, or properly storing test strips Because of the number of critical errors associated with the improper operation of the meters, FDA encourages built-in safety features to address the risk of these adverse events and the potential for common misuses. SMBG Device Labeling and Human Factors Compounding the challenges related to the use of SMBG devices is the fact that users vary areatly in theit cognitive abilities, training and skill level. FDA works to ensure that labeling is comprehensive, captures all of the necessary instructions for use, performance information, and appropriately warns users about meter limitations. We believe that all of this information is necessary to ensure the safe use of these systems; however we know that this information may be to0 technical or overwhelming for some users, even when instructions are written at the seventh grade reading level. We also recognize that not all healthcare settings are capable of providing adequate training and orientation to use of these systems. You mentioned one situation where a user in an isolated location was unable to test her blood sugar because she only had access to expired strips. Her SMBG device was programmed not to read expired strips, but the patient was unaware of this feature and did not anticipate it. This type of feature was introduced to prevent what had been a major problem resulting in erroneous results, but clearly the manufacturer should have properly described the feature in the package labeling, Please help us by encouraging users to report these types of problems to us so that we can investigate and take appropriate action. We welcome any suggestions which AACE may have to address the problem of making glucose meters easier to use or to make the labeling more user friendly. Independent Assessment of SMBG Device Performance You also suggested that a third party organization could test and verify that the performance of SMBG devices is within a specified, stricter standard. Similar programs exist in other areas, such as cholesterol testing. The Cholesterol Reference Method Laboratory Network (CRMLN) certifies manufacturers of clinical diagnostic products that measure total cholesterol, HDL-C, and LDL-C. The CRMLN laboratories use reference methods or designated comparison ‘methods that are rigorously standardized to the CDC reference methods.’ Similarly, the National Glycohemoglobin Standardization Program (NGSP)* is a group that has developed criteria for evaluating and improving the performance of assays for measuring glycosylated hemoglobin for the monitoring of glycemic control in patients with diabetes, While FDA’s ability to use such 7 htop:siwww.cde.gowlabstandards/crmin_elinical.htm * upsliwww.ngsp.orgyprograms as a substitute for regulatory review is constrained, the agency can recognize such standards and does monitor device labeling so that only those that in fact meet the third party accreditation standards can claim that they have done so. The requirements that labeling be aecurate, combined with professional societies’ recommendations, are typically strong incentives for device improvement. Other Cost Related Concerns You expressed concem that SMBG devices are chosen on the basis of cost alone, that patients receive inadequate instruction on the use of SMBG devices, and that there is a lack of interoperability among different manufacturer's devices and test strips. We appreciate and share these concems. We are aware of these problems and work with stakeholders to improve healthcare in these areas, while continuing to support development of innovative products. Hospital Use of SMBG Devices Use of SMBG devices in the hospital is of great concern not only to you but to the FDA, and it is perhaps the area in which there is the most misunderstanding. The landmark trial of intensive insulin therapy (IIT) by Ban den Berghe et al.” demonstrated a reduction in surgical critical care mortality, and several other studies showed similar benefits of glycemic control in other patient populations. These publications led to the recommendation that intensive insulin therapy be the standard of care for critically ill patients by the American Diabetes Association’? and the American Association of Clinical Endocrinologists", and in general a recommendation for active ‘inpatient glycemic control. More recent data, however, including the termination of two large European trials due to an increased risk of severe hypoglycemia and the findings of the Normoglycemia in Intensive Care Evaluation —Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study of increased mortality in the group with tight glycemic control (81 to 108 mg/dL), are clearly leading professional organizations such as yours to take a more measured stand." FDA is concerned that hospitals have been implementing protocols for tight glycemic control using SMBG devices. FDA agrees that tight performance standards are warranted for any technology that measures glucose when it is being used as a biomarker to diagnose disease or when it is used to maintain tight glycemic control of diabetic and non-diabetic patients in the hospital environment. FDA has cleared laboratory-based and bench-top point-of -care devices that provide accurate glucose test results with a fast tum around time. Meters such as the HemoCue Glucose 201 RT system and the i-Stat system, which are not strip based technologies, have accuracies approaching those ° Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in eriticaly il patients. N Engl J Med 2001;345:1359-67. ‘° american Diabetes Association. Standards of medical care in diabetes — 2008, Diabetes Care 2008;3(Suppl p:S12-54 "' AACE Diabetes Mellitus Clinical Practice Guidelines Task Force, American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus, Endocr Pract 2007;13(Suppl 1):1-68 Moghissi, E, Korytkowski, M, DiNardo, M, Einhorn, D, Hellman, R, etal, American Association of Clinical Endocrinologists and American Diabetes Association Consensus Statement on Inpatient Glycemic Control, Endocrine Practice, 15(4):1-17, 2009of laboratory methods'’. Nevertheless, many hospitals continue to use SMBG devices, cleared only gs aids in the management of diabetic patients, in these settings, even though they are not FDA cleared to diagnose disease or to maintain tight glycemic control of diabetic and non- diabetic patients in the hospital environment. This practice can be problematic. Where hospitalized patients are sicker (such as those in the ICU), any inaccuracies in the meters would pose different risks of greater magnitude than expected in the population and use for which the SMBG devices are cleared, We would encourage AACE to participate in the development of clinical guidelines for inpatient glycemic control, which would take into account the greater accuracy of laboratory-based and bench-top point-of-care devices. Furthermore, FDA is considering putting together a public workshop to discuss issues related to point of care glucose measurements and best practices. In the last 3 years, FDA, along with the National Institutes of Health and the Juvenile Diabetes Research Foundation, have conducted two very successful workshops that dealt with development of the Artificial Pancreas", A similar workshop that allows for discussion between academics, clinicians, regulators, and industry can lead to a better understanding of the issues and a coordinated plan on how to address them. Future Efforts Although we have been working to encourage improvements in meter technology and participating in outreach activities to educate users about glucose meters, we will continue to explore options to create new incentives for product developers. FDA is committed to exploring new opportunities to interactively engage the public to solve the remaining problems associated with these important devices. In addition, FDA is exploring mechanisms for working with the community and encouraging advancements in technology so that greater levels of accuracy and reproducibility can be achieved. The agency is also encouraged that there are new technologies such as continuous glucose sensors and the artificial pancreas that have the promise of making some of the issues addressed in this letter obsolete. For example, several companies are exploring the use of continuous glucose sensors in hospitals to use in intensive insulin therapy. "FDA publishes a summary of the data used to clear all in vitro diagnostic devices, The suramary for the most recent clearance of the HemoCue Glucose 201 RT system can be viewed at hitpd/www.accessdata {da goviedrh_docs/reviews/K060765.pdf. Performance data for the STAT and other point (of care glucose instruments is similar. See http://www.blsmeetings.net/h1368-4/intro.cfim