Stakeholders want FDA to consider latest advancements in diabetes drug efficacy draft guidance

Stakeholders that commented on the US Food and Drug Administration’s (FDA) draft guidance on establishing efficacy for antidiabetic drugs and biologics have asked the agency to be flexible when considering efficacy endpoints for diabetes mellitus as the field advances.

The draft guidance, which describes established and proposes new clinical efficacy endpoints in diabetes, partly replaces the February 2008 draft guidance for industry on diabetes mellitus due to safety recommendations being outdated.

Reduction of hemoglobin A1C remains an appropriate clinical efficacy endpoint for antihyperglycemic drugs, but the draft guidance also proposed using a reduction in hypoglycemia risk in addition to maintaining an acceptable A1C level are appropriate clinical efficacy endpoints. Other supportive efficacy endpoints mentioned in the draft guidance include fasting plasma glucose, postprandial glucose, and continuous glucose monitoring (CGM) metrics (RELATED: FDA considers new efficacy endpoint for diabetes drugs, Regulatory Focus 31 May 2023).

FDA noted the guidance is not intended to address endpoints associated with the clinical complications of diabetes such as cardiovascular risk reduction, the prevention or delay of type 1 diabetes, or hypoglycemia in non-diabetes mellitus conditions like bariatric surgery and congenital hyperinsulinism. The draft guidance also does not address the design of clinical trials and statistical analysis, nor does it provide recommendations for the efficacy and safety of diabetes drugs, the agency added.

While FDA said it wants sponsors to target the reduction of hyperglycemia and hypoglycemic risk when developing antidiabetic drugs, it acknowledged that various clinical trial endpoints “may be appropriate depending on the clinical goal for the proposed antidiabetic drug and the regulatory framework for demonstrating substantial evidence of effectiveness.”

Comments on FDA’s draft guidance appreciated the update from the 2008 draft guidance, with stakeholders generally asking the agency to keep an open mind when defining future clinical efficacy endpoints as new diabetes mellitus therapeutics are developed.

Missing from guidance

In their comment, AstraZeneca noted the current 2023 draft guidance and the 2020 draft guidance on type 2 diabetes together do not fully replace the previous 2008 draft guidance for industry on diabetes mellitus (RELATED: FDA Revamps Safety Testing for New Type 2 Diabetes Drugs, Regulatory Focus 9 March 2020).

“We ask therefore that the FDA consider including in the new draft guidance reference to where sponsors can find guidance on pharmacokinetic/pharmacodynamic considerations, weight loss, metabolic syndrome, important statistical considerations, randomised withdrawal, and guidance on fixed dose combinations, and other topics not covered,” they wrote.

AstraZeneca also asked FDA to clarify some of the statements made in the current draft guidance with a similar recent guidance released by the European Medicines Agency (EMA) on diabetes mellitus in the areas of pediatrics, patient-reported outcomes, and monotherapy programs that are “covered in the EMA guidance, but not in the current draft FDA guidance.”

The company also questioned why prediabetes and prevention of disease progression were not included in the draft guidance. “Given evolutions in thinking with respect to healthcare strategies and policies to manage global cardiovascular health and wellbeing, which includes earlier intervention, we suggest the agency consider a position on this important topic,” they said.

Hypoglycemia as surrogate endpoint

The American Diabetes Association (ADA) commended the FDA in their comment on their inclusion of updated hypoglycemia levels in the draft guidance that match the ADA’s 2023 Standards of Care document.

In their comment, Zucara Therapeutics said they appreciated FDA’s recognition of level 2 hypoglycemia as a surrogate endpoint. “We believe that a comparison of event rate of level 2 hypoglycemia between treatment and control in a randomized study population provides the most complete assessment of treatment effect, given the high incidence and frequency of these events,” they said, while acknowledging that data on level 3 hypoglycemia requires additional analysis.

Pfizer asked FDA to consider hypoglycemia level 1 as an endpoint for pediatric patients with diabetes. “[H]ypoglycemia prevention is an important element of diabetes management in pediatric patients, particularly in those individuals less than 7 years of age who may not recognize nor express signs and symptoms of low blood glucose, as hypoglycemia negatively impacts neurological and behavioral development in the pediatric population,” they wrote. “Hence, number and severity of hypoglycemia events constitute important endpoints of disease management and the assessment of the efficacy of diabetes treatment options.”

JDRF had several questions in their comment about how to use level 2 and level 3 hypoglycemia as endpoints, and whether using both as a composite endpoint would be appropriate. Specifically, they sought clarity on when/whether a composite endpoint of level 2 and level 3 hypoglycemia was appropriate, how sponsors define ‘a reasonable number’ of events when using them as a composite endpoint, and when use of level 2 or level 3 hypoglycemia alone are appropriate as a primary endpoint.

Limitations of hemoglobin A1C

At the same time, several commenters took the opportunity to highlight the limits of hemoglobin A1C (HbA1C) as an endpoint in all forms of diabetes. “[T]he A1C test is an indirect measure of average glycemia and, as such, is subject to limitations,” the ADA wrote in their comment. Using HbA1C as a sole endpoint can cause problems due to variability in measurement, especially if patients are “close to the threshold that might prompt a change in medication therapy.”

“Most importantly, A1C does not provide a measure of glycemic variability or hypoglycemia,” they added.

The International Society for Pediatric and Adolescent Diabetes (ISPAD) also raised concerns in their comment about the limitations of HbA1C as an efficacy outcome measure.

“Although there is a linear relationship between HbA1c and mean continuous glucose monitor (CGM) sensor glucose, the same HbA1c level has been associated with a wide range of mean glucose concentrations across individuals,” they wrote. “It is unreliable in those with renal failure, hemoglobinopathies, and conditions impacting red blood cell survival, not to mention significant variations among individuals of different races and ethnicities.”

They also explained that FDA should consider different tools when evaluating level 2 hypoglycemia and level 3 hypoglycemia in populations with diabetes. For instance, level 2 hypoglycemia may be appropriate to evaluate all populations; however, level 3 hypoglycemia is not exclusive to young people with diabetes, ISPAD noted.

“Clinical trial endpoints for a disease with a high pediatric prevalence must be applicable to this population,” they wrote. “Limiting the evaluation of Level 2 and 3 hypoglycemia to capillary blood glucose measurements provides a further limitation, considering the population with hypoglycemia unawareness and potential nocturnal glucose variability which are not readily captured with routine self-monitored blood glucose.”

When deciding on efficacy endpoints for diabetes, ISPAD said, the endpoints must match the “rapid pace” of the advancement of new therapeutic options. “While HbA1c values have been the traditional efficacy outcome for diabetes therapeutics, CGM provides insights into intra-individual and inter-individual variability while also providing new metrics that cannot be easily assessed by HbA1c, including glycemic variability, asymptomatic hypoglycemia, and time in range,” they explained.

Other considerations include hypoglycemia differences in children and adults, psychosocial outcomes for populations with diabetes, and clinical and biological surrogate markers in the form of disease progression, clinical outcome measures, and mental health.

Use of CGM, time in range

In their comment, Eli Lilly and Company offered several suggestions to FDA on how the agency could further the use of CGM as a digital health technology (DHT) in clinical research and in the regulatory framework, including expanding guidance on CGM data analysis, using more dynamic approaches like collaboration and public workshops/meetings to standardize sponsors’ use of CGM technology, and creating a regulatory framework for CGM.

“An appropriate regulatory framework for CGMs could provide a model for the use of other DHTs that provide continuous monitoring in clinical trials,” they said.

The ADA said that CGM is “rapidly improving diabetes” management, also pointing to time in range (TIR) as a new standard of care in some clinical settings, which was also advocated for by the Time in Range Coalition in a separate comment. TIR “correlates well with A1C in most studies” and allows providers “to make treatment decisions and evaluate how therapies and treatments are working for their patients,” they said.

“For these reasons, it is critical for FDA to accept and encourage presentation of these data in labels to guide clinicians in making clinical choices for patients who deserve access to the most innovative ways to manage their diabetes,” ADA concluded.

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Stakeholders want FDA to consider latest advancements in diabetes drug efficacy draft guidance

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