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Diabetes Mellitus: Efficacy Endpoints for Clinical Trials Investigating Antidiabetic Drugs and Biological Products

DraftCenter for Drug Evaluation and Research05/25/2023
Adjudication

Description

This guidance is intended to help sponsors develop antidiabetic drugs for adults and children with type 1 diabetes mellitus (T1D) and/or type 2 diabetes mellitus (T2D). In this guidance, antidiabetic drugs refer to drugs intended to improve glycemic control, including drugs intended to reduce diabetes-related hyperglycemia (i.e., antihyperglycemic drugs) and drugs intended to mitigate iatrogenic hypoglycemia associated with diabetes management.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

2
Antidiabetic Drugs

intended to improve glycemic control; Clinical trials investigating antidiabetic drugs and biological products; drugs investigated for glycemic control

Biological Products

Requires analytical comparability per ICH Q5E

Stakeholders

2
Sponsors

Assist sponsors in the nonclinical evaluation

sponsor

responsible for justifying omission of studies

Regulatory Context

Regulatory Activities

1
Traditional Drug Approval

A1C is adequate to support traditional drug approval

Document Types

1
drug labeling

official product information including clinical studies section

Attributes

3
precision

device performance metric for CGM

Non-Inferiority Margin

Commonly used margin of 0.3 percent for A1C

accuracy

Sensor performance characteristic

Technical Details

Substances

3
Insulin

A manufacturer of insulin develops a mobile app intended for use with their insulin product.

Sulfonylurea

Antihyperglycemic drug that can cause iatrogenic hypoglycemia

exogenous insulin

injected insulin for patients with T1D

Testing Methods

4
Fasting Plasma Glucose

additional efficacy endpoint

Postprandial Glucose

additional efficacy endpoint

Responder Analyses

Assessment of the proportion of subjects who achieve improvements in A1C

oral glucose challenge studies

short-term studies to demonstrate pharmacodynamic activity

Clinical Concepts

10
Type 1 Diabetes Mellitus

autoimmune-mediated pancreatic beta cell destruction

Type 2 Diabetes Mellitus

major comorbidities associated with excess adiposity; Common weight-related comorbidity

Hypoglycemia

patients with type 2 diabetes may face unique safety issues such as a risk for hypoglycemia

Hyperglycemia

chronic hyperglycemia as a result of defective insulin secretion

Diabetic Ketoacidosis

life-threatening acute event primarily in T1D; diabetes-related safety issue

A1C

Validated surrogate endpoint for microvascular disease risk reduction; valid surrogate endpoint for microvascular risk reduction

Microvascular Disease

A1C is a surrogate endpoint for microvascular disease risk reduction

Iatrogenic Hypoglycemia

Low blood glucose levels caused by use of antihyperglycemic drugs

Level 3 Hypoglycemia

Characterized by severely altered mental and/or physical functioning

Level 2 Hypoglycemia

Blood glucose levels less than 54 mg/dL

Standards & References

External Standards

1
NGSP

A1C should be measured using an assay certified by the NGSP

Specifications

1
Hemoglobin A1C

validated surrogate endpoint for glycemic control

ICH References (4)

ICH E9

Statistical Principles for Clinical Trials; Discourages deterministic procedures due to high risk of bias; Notes that the use of Bayesian methods in clinical trials may be considered.

ICH E9(R1)

Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials

ICH E10

Choice of Control Group in Clinical Trials.

ICH E1A

The Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended for Long-term Treatment of Non-Life-Threatening Conditions

Related MFDS Guidelines

Korean regulatory guidelines covering similar topics

See Also (8)