Diabetes Mellitus: Efficacy 
Endpoints for Clinical Trials 
Investigating Antidiabetic 
Drugs and Biological Products 
Guidance for Industry 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 90 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact Debra Reid 240-402-9143. 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
May 2023 
Clinical/Medical  
52881887dft.docx 
05/23/23   
Diabetes Mellitus: Efficacy 
Endpoints for Clinical Trials 
Investigating Antidiabetic 
Drugs and Biological Products 
Guidance for Industry 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
May 2023 
Clinical/Medical  
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................2 
III.  EFFICACY ENDPOINTS.....................................................................................3 
A.  A1C ..................................................................................................................................... 3 
B.  Hypoglycemia..................................................................................................................... 5 
1. Hypoglycemia Definitions ................................................................................................... 5 
2. Trial Design Considerations for Hypoglycemia Endpoints ................................................ 6 
3. Hypoglycemia Measurement ............................................................................................... 7 
a.  SMBG test systems ....................................................................................................... 7 
b.  CGM systems ............................................................................................................... 7 
C.  Additional Efficacy Endpoints ......................................................................................... 8 
1. Fasting Plasma Glucose ...................................................................................................... 8 
2. Postprandial Glucose .......................................................................................................... 8 
3. CGM-Based Metrics ............................................................................................................ 8 
IV.  OTHER CONSIDERATIONS ..............................................................................9 
REFERENCES .................................................................................................................10 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Diabetes Mellitus: Efficacy Endpoints for Clinical Trials 
2  Investigating Antidiabetic Drugs and Biological Products 
3  Guidance for Industry1 
4   
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page. 
12   
13   
14   
15  I.  INTRODUCTION 
16   
17  This guidance is intended to help sponsors develop antidiabetic drugs2 for adults and children 
18  with type 1 diabetes mellitus (T1D) and/or type 2 diabetes mellitus (T2D). In this guidance, 
19  antidiabetic drugs refer to drugs intended to improve glycemic control, including drugs intended 
20  to reduce diabetes-related hyperglycemia (i.e., antihyperglycemic drugs) and drugs intended to 
21  mitigate iatrogenic hypoglycemia associated with diabetes management.  
22   
23  This guidance replaces, in part, the draft guidance for industry Diabetes Mellitus: Developing 
24  Drugs and Therapeutic Biologics for Treatment and Prevention, (73 FR 11420) published in 
25  February 2008. In March 2020, FDA withdrew the February 2008 draft guidance for industry 
26  because its recommendations for safety assessment were outdated. At the same time, FDA issued 
27  the draft guidance for industry Type 2 Diabetes Mellitus: Evaluating the Safety of New Drugs for 
28  Improving Glycemic Control3 March 10, 2020 (85 FR 13903). When finalized, this guidance will 
29  address the FDAs current recommendations regarding defining efficacy endpoints for clinical 
30  trials investigating antidiabetic drugs and replace the relevant sections in the withdrawn February 
31  2008 draft guidance for industry. 
32   
33  This guidance does not address the following topics: endpoints related to clinical complications 
34  of diabetes (e.g., cardiovascular risk reduction), endpoints related to the prevention or delay of 
35  T1D, or the use of hypoglycemia efficacy endpoints in trials of conditions other than diabetes 
36  mellitus (e.g., hypoglycemia related to bariatric surgery, congenital hyperinsulinism).  
37   
 
1 This guidance has been prepared by the Division of Diabetes, Lipid Disorders, and Obesity in the Center for Drug 
Evaluation and Research at the Food and Drug Administration.  
 
2 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological 
products unless otherwise specified.  
 
3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
38  In addition, general issues of statistical analysis or clinical trial design are outside the scope of 
39  this guidance and are addressed in the International Council for Harmonisation (ICH) guidances 
40  for industry E9 Statistical Principles for Clinical Trials (September 1998), E9(R1) Statistical 
41  Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials 
42  (May 2021), and E10 Choice of Control Group and Related Issues in Clinical Trials (May 
43  2001).  
44   
45  Recommendations regarding the evaluation of safety for drugs intended for patients with 
46  diabetes mellitus is also outside the scope of this guidance document. Additional information for 
47  trial design considerations related to safety can be found in the ICH guidance for industry E1A 
48  The Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended for Long-Term 
49  Treatment of Non-Life-Threatening Conditions (March 1995) and the draft guidance for industry 
50  Type 2 Diabetes Mellitus: Evaluating the Safety of New Drugs for Improving Glycemic Control 
51  (March 2020).4 
52   
53  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
54  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
55  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
56  the word should in Agency guidances means that something is suggested or recommended, but 
57  not required.   
58   
59   
60  II.  BACKGROUND 
61   
62  Diabetes mellitus, which affects more than 37 million people in the United States (Centers for 
63  Disease Control and Prevention, 2022), is a heterogeneous group of metabolic disorders 
64  characterized by chronic hyperglycemia as a result of defective insulin secretion, increased 
65  insulin resistance, or a combination of both. Most patients with diabetes mellitus have either T1D 
66  or T2D. T1D is characterized by autoimmune-mediated pancreatic beta cell destruction leading 
67  to failure in insulin production, and T2D is characterized by insulin resistance with variability in 
68  insulin secretory deficiency. Diabetes mellitus may also result from other etiologies, including 
69  genetic defects, endocrinopathies, pregnancy, pancreatic diseases, infections, and certain drugs. 
70   
71  Clinical manifestations of uncontrolled diabetes include short-term acute events, such as life-
72  threatening diabetic ketoacidosis (primarily in T1D) or hyperglycemic hyperosmolar nonketotic 
73  coma, and long-term effects, such as microvascular (e.g., retinopathy, nephropathy, neuropathy) 
74  and macrovascular (e.g., coronary artery disease, peripheral vascular disease, stroke) 
75  complications. The Diabetes Control and Complications Trial (DCCT) demonstrated that 
76  intensive glucose lowering measured by change in hemoglobin A1c (A1C) in patients with T1D 
77  significantly reduced the development and progression of microvascular complications (DCCT 
78  Research Group et al. 1993). Data from the United Kingdom Prospective Diabetes Study 
79  (UKPDS) demonstrated the same causal relationship in patients with T2D (UKPDS Group 
80  1998). Consequently, the Agency considers reduction in A1C to be a validated surrogate 
 
4 When final, this guidance will represent the FDAs current thinking on this topic. For the most recent version of a 
guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents.  
2  Contains Nonbinding Recommendations 
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81  endpoint for microvascular disease risk reduction adequate to support traditional drug approval 
82  and has approved drugs to improve glycemic control on the basis of demonstrated reductions in 
83  A1C, without a postmarketing requirement to confirm a clinical benefit associated with the 
84  observed change in A1C. Although there is no clinical requirement to confirm a clinical benefit 
85  associated with A1C reduction, microvascular endpoints (e.g., retinopathy, nephropathy) may be 
86  expected to be collected and analyzed as safety endpoints. 
87   
88  In clinical practice, glycemic goals are individualized and guided by multiple factors, including 
89  patient age, comorbidities, life expectancy, and risk of hypoglycemia. The overall goal of 
90  diabetes management is to achieve individualized glycemic control targets by correcting 
91  hyperglycemia and to avoid hypoglycemic events. Iatrogenic hypoglycemia, or low blood 
92  glucose levels caused by use of antihyperglycemic drugs (e.g., insulin, sulfonylurea), can result 
93  in significant, recurrent, and debilitating morbidity and mortality in patients with diabetes. Fear 
94  of hypoglycemia is often a significant barrier to achieving glycemic goals. For these reasons, 
95  FDA considers drugs that can meaningfully reduce iatrogenic hypoglycemia and maintain 
96  glycemic control beneficial to patients. 
97   
98  Therefore, FDA encourages sponsors to develop antidiabetic drugs that reduce hyperglycemia 
99  with low hypoglycemic risk as well as drugs that may be beneficial as an adjunct to other 
100  antihyperglycemic drugs  particularly insulin  to reduce the risk of iatrogenic hypoglycemia. 
101  Different clinical trial endpoints may be appropriate depending on the clinical goal for the 
102  proposed antidiabetic drug and the regulatory framework for demonstrating substantial evidence 
103  of effectiveness. For antihyperglycemic drugs, FDA continues to recommend showing reduction 
104  in A1C to demonstrate effectiveness. Additionally, FDA considers a reduction in the risk of 
105  hypoglycemia, accompanied by either a reduction or maintenance of an acceptable A1C, a 
106  clinically relevant efficacy endpoint for clinical trials in subjects with diabetes, especially for 
107  subjects using insulin.  
108   
109   
110  III.  EFFICACY ENDPOINTS 
111   
112  A.  A1C 
113   
114  Change from baseline in A1C has been the accepted primary endpoint in clinical trials for 
115  sponsors seeking a glycemic-control indication. As discussed above, A1C is a validated 
116  surrogate endpoint for microvascular disease risk reduction and, therefore, an acceptable 
117  endpoint to support a glycemic-control indication.  
118   
119  To allow for the adequate interpretation of clinical trials utilizing an A1C endpoint, FDA 
120  recommends the following:  
121   
122    Statistically significant reductions from baseline in A1C that are consistent across trials 
123  and relevant subgroups should be demonstrated. The magnitude of reduction may be 
124  weighed against risks. In general, statistically significant but small reductions in A1C 
125  may not overcome serious risks observed with a drug. 
126   
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127    Formal hypothesis testing in a controlled trial with type I error control is expected. 
128  Hypothesis testing for either noninferiority (NI) versus an active comparator (with 
129  adequate justification for the NI margin)5 or superiority versus placebo or active 
130  comparator may be appropriate depending on the trial design.6  
131   
132    A1C should generally be measured in a central laboratory using an assay certified by the 
133  NGSP.7  
134   
135    A1C reflects a weighted average of blood glucose over the preceding 2 to 3 months. To 
136  allow adequate glycemic comparison between treatment arms, A1C should be measured 
137  after at least 12 weeks of stable dosing.  
138   
139    For active comparator trials evaluating titratable drugs, the interpretation of efficacy is 
140  dependent on adequate titration of the trial drug and comparator, so that positive efficacy 
141  findings are not simply a result of insufficient titration of the comparator. Titration 
142  algorithms should ensure similar glycemic targets and allow for commensurate changes 
143  in dose in response to fasting or postprandial blood glucose.  
144   
145    For most development programs, the primary efficacy endpoint should be change from 
146  baseline in A1C after 6 months of randomized treatment, with an additional descriptive 
147  assessment of change from baseline in A1C at 12 months to assess longer term durability 
148  of effect. A controlled trial designed to evaluate change from baseline beyond 6 months 
149  may be necessary for drug development programs in which there is a concern about 
150  durability of effect or in which efficacy is not expected to be evident in a 6-month period 
151  (e.g., the drug requires a long titration period, the drug has a delayed onset of effect on 
152  glycemic control).  
153   
154    Responder analyses for A1C that provide an assessment of the proportion of subjects who 
155  achieve improvements in A1C based on clinically important cut points (e.g., less than 7 
156  percent, less than 6.5 percent) are not recommended as the primary analysis of A1C 
157  because of limited interpretability (Holland 2002). 
158   
159    The dosage of protocol-allowed concomitant glycemic-lowering drugs should be stable 
160  throughout the trial. Changes in dosage or initiation of concomitant glycemic-lowering 
161  drugs (e.g., for glycemic rescue, to prevent hypoglycemia) should be documented as an 
162  intercurrent event and accounted for appropriately in the statistical analysis. 
163   
164    In the phase 3 program, sponsors should enroll a sufficient number of subjects to allow 
165  for the meaningful evaluation of the consistency of effects across subgroups based on 
166  sex, age, race, ethnicity, duration, and severity of diabetes (e.g., based on categories of 
167  A1C at baseline), and other relevant factors. 
 
5 See the guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness (November 2016).  
 
6 See the guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness.  
 
7 NGSP was originally called the National Glycohemoglobin Standardization Program. 
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168   
169  B.  Hypoglycemia 
170   
171  In contrast to the extensive experience with A1C as an efficacy endpoint, hypoglycemia 
172  endpoints have primarily been used to evaluate safety and (at the time of publication of this 
173  guidance) have only rarely been used as endpoints for comparative claims (i.e., efficacy, 
174  comparative safety). Use of hypoglycemia as an endpoint to support a claim has previously been 
175  limited by issues such as lack of consensus definitions of hypoglycemia linked to clinical 
176  outcomes and the lack of availability of fit-for-purpose measurement tools. If a sponsor seeks to 
177  demonstrate an advantage in terms of lower incidence of hypoglycemia versus an active 
178  comparator (i.e., comparative safety claim), such a comparative claim should be based on a level 
179  of evidence similar to when a sponsor uses hypoglycemia as an efficacy endpoint.  
180   
181  The following sections of this guidance discuss endpoint definitions, clinical trial considerations, 
182  and appropriate measurement tools to facilitate evaluation of a hypoglycemia-related drug claim. 
183   
184  1.  Hypoglycemia Definitions 
185   
186  Hypoglycemia is defined and described by the American Diabetes Association (ADA) as follows 
187  (ADA 2023): 
188   
189    Level 1: blood glucose levels less than 70 milligrams/deciliter (mg/dL) (3.9 
190  millimoles/liter (mmol/L)) and greater than or equal to 54 mg/dL (3 mmol/L). This 
191  threshold is an alert value at which patients should take action to avoid continued decline 
192  in blood glucose.   
193   
194    Level 2: blood glucose levels less than 54 mg/dL (3 mmol/L) regardless of the presence 
195  of hypoglycemia symptoms. At this threshold, adrenergic and/or neuroglycopenic 
196  symptoms typically begin. However, given that hypoglycemia unawareness is not 
197  uncommon, an event of level 2 hypoglycemia does not require adrenergic and/or 
198  neuroglycopenic symptoms to be captured. 
199   
200    Level 3 (e.g., severe hypoglycemia): characterized by a severely altered mental and/or 
201  physical functioning, which if untreated may result in loss of consciousness, seizures, 
202  coma, or ultimately death. Hypoglycemia reversal necessitates the assistance of another 
203  person. Glucose measurements may not be available during an event, but neurological 
204  recovery attributable to the restoration of blood glucose to normal is considered sufficient 
205  evidence that the event was induced by a low plasma glucose concentration. 
206   
207  For patients with diabetes mellitus, FDA considers level 3 and level 2 hypoglycemia acceptable 
208  endpoints in support of claims related to improvement in glycemic control and/or iatrogenic 
209  hypoglycemia risk reduction, depending on the trial design. Level 3 hypoglycemia is a direct 
210  measurement of how a subject feels, functions, or survives and is therefore a clinical endpoint. 
211  FDA considers level 2 hypoglycemia to be a surrogate endpoint for neuroglycopenia-related 
212  adverse events (e.g., cognitive impairment, incoordination) acceptable for traditional approval. 
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213  Sponsors should consider the following when seeking a new claim supported by hypoglycemia 
214  data:  
215   
216    The preferred primary endpoint for a hypoglycemia-related claim is a reduction in the 
217  incidence of level 3 hypoglycemia. The rationale for this recommendation is not only 
218  related to the clinical importance of avoiding level 3 hypoglycemia but also because of 
219  the reliability of the endpoint. Level 3 hypoglycemia is less prone to bias from selective 
220  subject reporting. However, the incidence rate of level 3 hypoglycemia is expected to be 
221  low, so either more subjects or a longer trial would be needed to provide statistical power 
222  to detect a treatment difference based solely on level 3 hypoglycemia. Sponsors should 
223  consider enrichment strategies and/or adaptive designs to increase the ability to accrue 
224  events.  
225   
226    In certain circumstances (e.g., when the incidence of severe hypoglycemia is expected to 
227  be very infrequent), the use of a composite primary endpoint of the incidence of level 2 
228  and level 3 hypoglycemia, may be acceptable. However, clinical trials should capture a 
229  reasonable number of level 3 hypoglycemia events to ensure qualitative consistency 
230  between level 2 and level 3 treatment effect (i.e., evidence of reduction in both level 2 
231  and level 3 events).  
232   
233  Sponsors should consult with FDA early in the drug development process to obtain agreement on 
234  proposed endpoints. 
235   
236  2.  Trial Design Considerations for Hypoglycemia Endpoints 
237  For trial designs aiming to demonstrate reduction of hypoglycemia events, FDA recommends the 
238  following for adequate interpretation of the hypoglycemia findings: 
239   
240    Sponsors should use rigorous methods for the collection of level 3 hypoglycemia events 
241  and assess them by adjudication. If glucose measurements during the event are available, 
242  they should be included with the data presentation. As a biomarker endpoint, level 2 
243  hypoglycemia events do not need to be adjudicated but still require rigorous methods for 
244  data collection (see section III. B. 3., Hypoglycemia Measurement). 
245   
246    For all definitions of hypoglycemia, the proportion of subjects experiencing one or more 
247  events (incidence rate) should be used for the primary analysis. Analyses of total number 
248  of events/total patient-years of exposure (event rate) should also be reported. 
249   
250    Because higher average serum glucose concentrations may correlate with fewer 
251  hypoglycemic episodes, similar average glycemic control between trial arms should be 
252  demonstrated. Demonstration of an NI finding in A1C using the commonly used margin 
253  of 0.3 percent is not sufficient by itself to obtain a reduction of risk of hypoglycemia 
254  claim. In addition to excluding the upper 95 percent confidence limit of 0.3 percent, the 
255  point estimate for the difference in change in A1C should be no greater than 0.1 percent.  
256   
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257    The hypoglycemia analysis should include the entire study period, including events that 
258  occurred during both the titration and maintenance periods with titratable drugs such as 
259  insulins. Supportive analyses may examine these time periods separately. 
260   
261    The hypoglycemia analysis should include the entire 24-hour period for each day on 
262  treatment. Confounders, including pharmacodynamic characteristics of a drug (e.g., basal 
263  insulin peak) in relation to the timing of the drug administration, prandial insulin, recent 
264  exercise, and food consumption, may affect the timing of hypoglycemia risk. 
265   
266  3.  Hypoglycemia Measurement 
267   
268  The accurate measurement of endpoints is fundamental to ensure confidence in the results from 
269  clinical trials. Nonsevere hypoglycemia (e.g., level 1 and level 2 hypoglycemia) is typically 
270  measured by medical devices, such as self-monitoring blood glucose (SMBG) test systems or by 
271  continuous glucose monitoring (CGM) systems, each of which has different strengths and 
272  weaknesses in the ability to ascertain hypoglycemic events. In addition, technical characteristics 
273  of specific devices vary. Sponsors should consult with the Agency early in the drug development 
274  program on how best to measure primary endpoints and provide justification for why the selected 
275  device methodology is appropriate for the assessment of the proposed hypoglycemia-based 
276  endpoint(s) within the context of the specific clinical development program. 
277   
278  a.  SMBG test systems 
279   
280  In clinical trials, SMBG test systems have been used extensively to direct insulin dose titration 
281  and detect nonsevere hypoglycemia for safety monitoring. In addition, SMBG device 
282  performance (e.g., accuracy, precision) is generally considered acceptable; however, FDA 
283  encourages sponsors to obtain prior agreement on the acceptability of specific devices to be used 
284  in clinical trials. Limitations to SMBG test systems include the requirement for trial subjects to 
285  actively obtain a blood glucose sample (which may introduce the potential for differences in 
286  endpoint ascertainment across trial arms attributable to subject effort, particularly in an open-
287  label trial), inadequate characterization of nocturnal hypoglycemia, and the potential for missed 
288  events in subjects with hypoglycemia unawareness. Sponsors should address how they intend to 
289  minimize the SMBG test system limitations in the design and analysis of their trials.  
290   
291  b.  CGM systems 
292   
293  CGM systems continuously and passively collect glycemic data and can provide access to near 
294  real-time glucose data and trend information regarding rising or falling glucose levels throughout 
295  the day. There has been increasing use of CGM in clinical practice and, hence, interest in CGM 
296  utilization in clinical trials for the characterization of various aspects of glycemic control. 
297  Historically, there were technical performance concerns that were barriers to CGM adoption in 
298  clinical trials, but technology continues to improve. FDA recognizes that CGM systems have 
299  certain advantages over SMBG test systems for use in clinical trials to assess hypoglycemia as an 
300  efficacy endpoint. For example, CGM systems may be more likely to capture hypoglycemia 
301  events because of the continuous nature of glucose data collection. They also likely limit bias 
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302  due to subject effort in data collection and better capture nocturnal hypoglycemia and 
303  hypoglycemia events in patients with hypoglycemia unawareness.  
304   
305  Given that the use of CGM systems in the regulatory context is evolving and various 
306  uncertainties exist regarding the use of this technology in clinical trials, FDA highly encourages 
307  sponsors to engage with the Agency regarding the use of CGM and CGM-based hypoglycemia 
308  endpoints (e.g., number of occurrences of low glucose values captured by a CGM system in a 
309  defined time period), how data will be analyzed and submitted to the Agency, the intended 
310  population (e.g., pediatric or adult and CGM devices to be used). In general, FDA recommends 
311  that a sponsor use a single CGM device model, which is authorized for use in the United States 
312  and has acceptable device performance (i.e., accuracy, precision) in the hypoglycemic range, 
313  throughout clinical development. 
314   
315  C.  Additional Efficacy Endpoints 
316   
317  There are several additional endpoints that are used supportively in clinical trials for antidiabetic 
318  drugs that may be appropriate for inclusion in drug labeling.  
319   
320  1.  Fasting Plasma Glucose 
321   
322  Fasting plasma glucose is used as an additional indicator of glycemic control, although not 
323  sufficient evidence on its own for a glycemic control indication. The change from baseline in 
324  fasting plasma glucose is typically described in the CLINICAL STUDIES section of labeling. 
325  Fasting plasma glucose data should be measured in a central laboratory using a validated 
326  method. Results should be presented in United States units (mg/dL). 
327   
328  2.  Postprandial Glucose 
329   
330  For certain drugs in which the mechanism of action is primarily due to an effect on postprandial 
331  glucose, assessments of postprandial glucose may be completed in dose-finding, proof-of-
332  principle, short-term, oral glucose challenge studies. Although such demonstrations of 
333  pharmacodynamic activity are not sufficient evidence for a glycemic control indication, they 
334  may provide further understanding of the mechanism of the drug. The sponsor should collect 
335  postprandial glucose data for the entire dosing interval of the drug. 
336   
337  3.  CGM-Based Metrics 
338   
339  Various CGM-based metrics have been proposed as clinical trial endpoints such as time in range 
340  (TIR), defined as the percentage of time spent in a patients target glucose range (e.g., between 
341  70 and 180 mg/dL (3.9 to 10 mmol/L)), time above range (time greater than 180 mg/dL), and 
342  time below range (time less than 70 mg/dL) (Danne et al. 2017). TIR is a biomarker that has not 
343  been established as a surrogate for a clinical outcome, and thus, TIR is not acceptable as the 
344  primary endpoint for a glycemic-control indication. FDA will consider including relevant CGM-
345  based metrics results in the CLINICAL STUDIES section of labeling of drugs approved for a 
346  glycemic-control indication with efficacy demonstrated by change in A1C or an appropriate 
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347  hypoglycemia endpoint, provided that the performance characteristics of CGM devices, data 
348  collection, and analyses are adequate. 
349   
350   
351  IV.  OTHER CONSIDERATIONS 
352   
353  Sponsors can also propose other clinically meaningful endpoints for drugs intended for patients 
354  with diabetes. Examples include the removal of dependency on exogenous insulin or a reduction 
355  in the number of daily insulin injections in subjects with T1D; a reduction in insulin dose alone 
356  is not sufficient.  If a sponsor seeks to demonstrate a clinically meaningful improvement with 
357  respect to a diabetes-related safety issue such as a decrease in diabetic ketoacidosis events versus 
358  an active comparator (i.e., comparative safety claim), such a comparative claim should be based 
359  on a level of evidence similar to that of an efficacy endpoint. Sponsors seeking to pursue a novel 
360  approach should discuss their plans with FDA early in the drugs development program. 
361   
362  Some drugs that were initially approved with a glycemic-control indication in a population with 
363  T2D have been subsequently shown to be effective in other clinically important macrovascular 
364  outcomes (e.g., cardiovascular risk reduction) or microvascular outcomes (e.g., chronic kidney 
365  disease), and FDA has granted new macrovascular- or microvascular-related indications, 
366  respectively. FDA supports the development of drugs seeking to prevent diabetic complications 
367  and comorbidities and encourages sponsors to request further advice from the relevant review 
368  division and consult other existing guidances that may apply. However, A1C continues to be a 
369  valid surrogate endpoint for microvascular risk reduction and an acceptable endpoint for 
370  glycemic-control trials. 
371   
372  There may be other effects of a drug besides its intended effect on glycemic control, such as 
373  changes in blood pressure, serum lipids, and body weight, that may be of clinical relevance to 
374  prescribers when selecting a drug for glycemic control because patients with diabetes often have 
375  comorbid conditions that contribute to excess cardiovascular risk. It may be appropriate to 
376  present these data from adequate and well-controlled trials in the CLINICAL STUDIES section 
377  of labeling upon review of the data.
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378  REFERENCES 
379   
380  American Diabetes Association, 2023, 6. Glycemic Targets: Standards of Care in Diabetes
381  2023, Diabetes Care, 46(Suppl 1):S97S110. 
382   
383  Centers for Disease Control and Prevention, 2022, National Diabetes Statistics Report website, 
384  accessed February 1, 2023, https://www.cdc.gov/diabetes/data/statistics-report/index.html. 
385   
386  Danne T, Nimri R, Battelino T, Bergenstal RM, Close KL, Devries JH, Garg S, Heinemann L, 
387  Hirsch I, Amiel SA et al., 2017, International Consensus on Use of Continuous Glucose 
388  Monitoring, Diabetes Care, 40(12):16311640, doi: 10.2337/dc17-1600. 
389   
390  Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, Lachin J, 
391  Cleary P, Crofford O, Davis M, Rand L, and Siebert C, 1993, The Effect of Intensive Treatment 
392  of Diabetes on the Development and Progression of Long-Term Complications in Insulin-
393  Dependent Diabetes Mellitus, N Engl J Med,;329(14):97786, doi: 
394  10.1056/NEJM199309303291401. 
395   
396  Holland PW, 2002, Two Measures of Change in the Gaps Between the CDFs of Test-Score 
397  Distributions, J Educ and Behav Stat, 27(1):317. 
398   
399  UK Prospective Diabetes Study (UKPDS) Group, 1998, Intensive Blood-Glucose Control With 
400  Sulphonylureas or Insulin Compared With Conventional Treatment and Risk of Complications in 
401  Patients With Type 2 Diabetes (UKPDS 33), Lancet, 352(9131):837853 (Erratum, 1999, 
402  Lancet, 354:602). 
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