Implications of FDA Guidance "Diabetes Mellitus: Efficacy Endpoints for Clinical Trials Investigating Antidiabetic Drugs and Biological Products"
On May 26th, 2023 the FDA published its draft guidance “Diabetes Mellitus: Efficacy Endpoints for Clinical Trials Investigating Antidiabetic Drugs and Biological Products”.? What are the implications for Sponsors, patients, sites and CROs??
Christian Born Djurhuus MD, PhD, BSc, Djurhuus Consulting. Former VP of Insulin & Devices and Chief Digital Officer at Novo Nordisk?
Jonathan Goldman, MD MBA , CEO Clinical ink.???
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Summary?
The 2023 FDA guidance reconfirmed the importance of HbA1c as a surrogate efficacy endpoint but introduces the importance of risk/benefit and measurement of hypoglycemia as an endpoint in many cases.? This has implications for the use of patient reported outcomes and food diaries and requires the application of continuous glucose monitoring (CGM).? Patients, sites, CROs and sponsors will require near real time access to complex data sets to ensure patient safety and the ability to provide contextual Investigator and Sponsor oversight.?
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Discussion?
The 2023 FDA guidance is a further update to the 2020 and 2022 FDA guidance regarding the development of medical products (drugs and devices) to treat and manage diabetes. ?
People living with diabetes, both Type 1 and Type 2 diabetes, use different medications to manage their disease. Because some antidiabetic therapies, such as insulins, which are developed to treat hyperglycemia, have an inherent risk of causing hypoglycemia, it is the integrated Benefit / Risk evaluation that ultimately will form the basis for approval by regulators. ? ?
In the recent guideline, the agency maintains that HbA1c (A1c) is a validated efficacy surrogate marker of diabetes complications and hence a suitable primary endpoint for clinical studies in diabetes. ?
FDA emphasizes that hypoglycemia is a relevant endpoint?
What is new, is the establishment of hypoglycemia as a novel efficacy endpoint where relevant. The agency uses the recently established definitions of hypoglycemia from the International Hypoglycemia Study Group, which has harmonized the definitions globally as follows:?
Level 1: Blood glucose levels less than 70 milligrams/deciliter (mg/dL) (3.9 millimoles/liter (mmol/L)) and greater than or equal to 54 mg/dL (3 mmol/L). This threshold is an alert value at which patients should take action to avoid continued decline in blood glucose. ?
Level 2: Blood glucose levels less than 54 mg/dL (3 mmol/L) regardless of the presence of hypoglycemia symptoms. At this threshold, adrenergic and/or neuroglycopenic symptoms typically begin. However, given that hypoglycemia unawareness is not uncommon, an event of level 2 hypoglycemia does not require adrenergic and/or neuroglycopenic symptoms to be captured. ?
Level 3: (e.g., severe hypoglycemia): Characterized by a severely altered mental and/or physical functioning, which if untreated may result in loss of consciousness, seizures, coma, or ultimately death. Hypoglycemia reversal necessitates the assistance of another person. Glucose measurements may not be available during an event, but neurological recovery attributable to the restoration of blood glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration. ?
Where relevant in the development program, endpoints (rates as well as incidence) to address Level 2 and 3 hypoglycemia can be included. In particular, Level 3 has a propensity to have a degree of subjectivity in the determination of “neuroglycopenic symptoms” and the relief hereof by treatment (glucose ingestion, glucagon or iv. Glucose). Sponsors should consider to either limit Level 3 episodes to those treated by paramedics with glucagon or iv. Glucose, or to apply an independent adjudication of Level 3 hypoglycemia. ?
It is imperative to ensure that the ensuing glycemia (as assessed by a stable 12 weeks of effective drug dose and A1c levels) within the treatment arms, is comparable (as assessed by a non-inferiority margin of 0.3 A1c with a point estimate difference of < 0.1 A1c) to allow for an evaluation of differences in Level 2 and 3 hypoglycemia. ?
Episodes of hypoglycemia always have detrimental effects on patients – in particular when occurring during sleep or when impossible to explain (the incidental skip of a meal, unplanned or avoided exercise, excessive dose taken). A single experience of hypoglycemia can have long lasting effects due to fear and an accompanying apprehension to resume dosing towards the desired glycemic targets. For this reason, the ability to adequately capture data that characterizes the hypoglycemic event is of utmost importance. Patient Reported Outcomes (PRO) have been developed to describe the symptomatology and circumstances of the hypoglycemic episodes. These are typically sponsor developed and proprietary. ?
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FDA emphasizes the use of Continuous Glucose Monitoring (CGM)?
Another important part of the FDA guidance is the inclusion of CGM as a validated medical device to capture insights of the ensuing glycemia, including events of hypoglycemia. CGM devices have evolved tremendously over the past few years both in terms of accuracy and precision, but also as a broadly acceptable form factor and usability. Recent approvals of fully closed loop systems relying on CGM based glycemic measurements for automatic insulin infusion (iLet, Beta Bionic) as well as hybrid (nighttime) closed loops like Medtronic 780G, has led to a broader acceptance of CGM. Furthermore, CMS has in April 2023, updated the CGM coverage to include Type 2 diabetes with problematic hypoglycemia:?
The CGM coverage criteria have been modified to allow coverage of a CGM for beneficiaries with diabetes mellitus who are insulin treated or have a history of problematic hypoglycemia. Problematic hypoglycemia, defined as: ?
With the recent inclusion of CGM based endpoints for studies aimed at developing antidiabetic therapies, the FDA has brought the guidelines in sync with leading scientific treatment guidelines including ADA Standards of Care, Endocrine Society and the joint ADA & EASD 2022 consensus statements. ?
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Practical considerations of the recent FDA guidance when addressing hypoglycemia and using CGMs in developing antidiabetic therapies?
As is evident in the definitions of hypoglycemia, the symptoms experienced by the patient as well as the circumstances around the event, provides crucial information for correctly categorizing the event in Level 2 or Level 3 hypoglycemia and in order to provide suitable treatment guidance. ?
For this reason, it’s imperative to capture patient symptoms in a timely and structured manner related to the event. None of the presently approved commercial CGM applications offer this option and the method for describing symptomatology differs between clinical care and those applied in the development programs of antidiabetic therapy. ?
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Technology Considerations?
It is essential to have a technology that following a CGM (or SMBG for that matter) based hypoglycemic event, automatically prompts the patient to complete protocol-defined PRO questionnaires.?
As the conditions around the event of hypoglycemia is explanatory, having insights into the treatment adherence (potentially through an electronic captured pill box or connected injection device), exercise (e.g. capture by a wearable) and food intake (e.g. via validated structured food diaries), would provide patients, caregivers, sponsors, adjudicators and regulators with the insight needed to make a thorough evaluation of the events. ?
In the guidance, the FDA recommends the use of similar devices in the development program “In general, FDA recommends that a sponsor use a single CGM device model, which is authorized for use in the United States and has acceptable device performance (i.e., accuracy, precision) in the hypoglycemic range, throughout clinical development.” This poses complexity when considering the use of CGMs in a multinational setting where the CGM devices are heterogeneously regulatory approved and commercialized. ?
Having the same device in the entire program is not only scientifically sensible (same methodology, accuracy and precision), but also operationally preferable for sponsors and CROs to handle the logistics and identical data transfer from the sensors to the Clinical Data Management Systems (CDMS). ?
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Use of integrated data sets?
Often, the inclusion of additional data captured in clinical trials is done with limited focus on the usability for both the trial patient and the investigators. In addition, the real-time aspects of CGM offered in standard clinical care to patients, parents of children, and health care providers are lost once CGMs are included in clinical trials.??
This is a key topic in another recent FDA guidance around “Digital Health Technologies (DHT) for Remote Data Acquisition in Clinical Investigations”:?
“Usability studies are a critical component in confirming the suitability of the DHT and/or general-purpose computing platform for the proposed clinical investigation. These studies are considered part of the validation process and should enroll a cohort that is similar to intended trial participants. Usability studies should test the ability of future participants to use the DHT as directed in the trial protocol.??
To this end, it is necessary to consider the integration of these different DHTs in a single user experience - both for clinical trial participants and the investigational staff.??
Similarly, it is from a sponsor / CRO resource effectiveness point of view, wise to pursue an integrated data transfer of DHT generated data in to the CDMS. Having the ability to, in an integrated manner, evaluate the insights from both CGMs, the symptoms of hypoglycemia, or other relevant Patient Reported Outcomes (PROs), insights into potentially explanatory variables such as food diaries and exercise patterns, must become the gold standard for how data capture is conducted in clinical trials.?
Equally and as stated in the above FDA guidance, it is essential to be mindful of the differences in populations when choosing DHTs. A person living with Type 1 diabetes has different needs for insights than for example a person living with Type 2 diabetes on Multiple Daily Injections (MDI), whose needs likely differ from the needs of a person with Type 2 diabetes not treated with insulin. Similarly, considerations must be made for pediatric studies in Type 1 diabetes where parents/school nurses are also intended users of the data presented.?
This is why all applications of DHTs in clinical trials must be tailored to the objective(s) of the study and to the patient populations included.?
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It all depends on the “Why”?
Clinical trial planning and execution is essential in multinational drug development, and antidiabetic drug development is no exception. If the objective of using CGM is to unobtrusively characterize glycemia in non-insulin treated people with Type 2 diabetes or other cardiometabolic diseases (cardiovascular, chronic kidney disease etc.), the effort associated with its deployment should not outweigh the expected benefits. ?
Contrary to this, is the development of a novel meal-time insulin for injection-based therapies where the value of the CGM-obtained data and associated symptoms related to hypoglycemia and associated food diaries and exercise data are much more crucial and justifies safeguarding during the clinical trial planning process. ?
Such planning would require the evaluation of device approval (CGM, dose capture device etc.) in regard to the country selection process. If devices are not approved in countries of interest, the clinical trial protocol can include devices as investigational. Sponsors should be conscious of the Clinical Trial Application process in those countries as some agencies (like Health Canada and BfArM in Germany) handle drugs and devices separately with additional complexities around the approval process and thus timelines. ?
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Conclusion?
The FDA May 26th, 2023 guidance brings the regulatory framework for the development of antidiabetic drugs up to recognized global scientific standards and constitutes a major step forward for drug developers and thus the advancement of therapies to treat diabetes. ? ?
For sponsors, it is critical to have timely and accurate assessments of hypoglycemic events and the related concomitant symptoms experienced as well as succinct information of explanatory elements beyond the investigational therapy. This includes insights to activity levels, dosing adherence and dietary intake. ?
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