Type 2 Diabetes Mellitus:  
Evaluating the Safety of 
New Drugs for Improving 
Glycemic Control 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Silvana Borges at 301-796-0963.  
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
March 2020 
Clinical/Medical 
32889298dft.docx 
02/25/20   
Type 2 Diabetes Mellitus: 
Evaluating the Safety of 
New Drugs for Improving 
Glycemic Control 
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) 
 
March 2020 
Clinical/Medical 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................2 
III.  EVALUATING SAFETY OF NEW DRUGS TO IMPROVE GLYCEMIC 
CONTROL FOR PATIENTS WITH TYPE 2 DIABETES MELLITUS ........3 
A.  Size of the Safety Database ............................................................................................... 3 
B.  Patient Characteristics in the Development Program .................................................... 3 
C.  Other Considerations ........................................................................................................ 4 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Type 2 Diabetes Mellitus:  
2  Evaluating the Safety of New Drugs  
3  for Improving Glycemic Control 
4  Guidance for Industry1 
5   
6   
7   
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
12  for this guidance as listed on the title page. 
13   
14   
15   
16  I.  INTRODUCTION 
17   
18  The purpose of this guidance is to provide the Food and Drug Administrations (FDAs) current 
19  recommendations regarding the overall evaluation of safety for the development of drugs and 
20  biologics2 indicated for improvement of glycemic control in patients with type 2 diabetes 
21  mellitus.  The recommendations in this guidance reflect discussions at the Endocrinologic and 
22  Metabolic Drugs Advisory Committee meeting held October 2425, 2018,3 that considered 
23  FDAs review of cardiovascular (CV) outcome trials (CVOTs). 
24   
25  The CVOTs reviewed by the Endocrinologic and Metabolic Drugs Advisory Committee were 
26  recommended in the guidance for industry Diabetes Mellitus  Evaluating Cardiovascular Risk 
27  in New Antidiabetic Therapies to Treat Type 2 Diabetes (December 2008) (Diabetes Mellitus 
28  December 2008 guidance).  We are withdrawing the Diabetes Mellitus December 2008 guidance 
29  and replacing it with this draft guidance.  We are also withdrawing the draft guidance for 
30  industry Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and 
31  Prevention (February 2008) and replacing it with this draft guidance. 
32   
33  This guidance provides recommendations on the size and nature of the safety databases needed 
34  to support drugs for chronic use to improve glycemic control in patients with type 2 diabetes. 
35   
                                                 
1 This guidance has been prepared by the Division of Metabolism and Endocrinology Products 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 See the Summary Minutes of the Endocrinologic and Metabolic Drugs Advisory Committee Meeting October 24
25, 2018, available at https://www.fda.gov/media/121265/download. 
 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
36  This guidance is intended to serve as a focus for continued discussions among the Division of 
37  Metabolism and Endocrinology Products, pharmaceutical sponsors, the academic community, 
38  and the public.4   
39   
40  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
41  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
42  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
43  the word should in Agency guidances means that something is suggested or recommended, but 
44  not required. 
45   
46   
47  II.  BACKGROUND 
48   
49  The withdrawn Diabetes Mellitus December 2008 guidance stated that sponsors should 
50  demonstrate that new drugs intended to improve glycemic control in patients with type 2 diabetes 
51  do not result in an unacceptable increase in CV risk.  In response to the 2008 guidance, many 
52  CVOTs have been completed.  In reviewing those final reports, the Agency has found that 
53  inclusion of meaningful numbers of patients with diabetes-associated complications and 
54  comorbid conditions in clinical trials is feasible and valuable in assessing the safety profile of 
55  new antidiabetic drugs, allowing valid assessment of CV risk.  However, none of the CVOTs to 
56  date have identified an increased risk of ischemic CV events.  Some of the CVOTs have instead 
57  demonstrated a reduced risk for CV events.  
58   
59  In light of these CVOT results, the Agency convened an advisory committee meeting on October 
60  2425, 2018, to discuss the recommendations in the Diabetes Mellitus December 2008 guidance.  
61  Committee members were asked to consider the robustness of development program safety 
62  databases before 2008, the new information learned since 2008, and whether the 
63  recommendations in the Diabetes Mellitus December 2008 guidance were still appropriate.  
64  Committee members stressed the need for sufficient safety data submitted before approval to 
65  inform decision-making, the continued importance of CV safety data not limited to 
66  atherosclerotic events, and the need to base postmarketing requirements on consideration of 
67  signals of risk identified in the development program rather than a one-size-fits-all approach.  
68   
69  Based on these considerations, the Agency recommends a new approach in the evaluation of the 
70  safety profile of new drugs to improve glycemic control in patients with type 2 diabetes mellitus 
71  detailed in this guidance. 
72   
73   
                                                 
4 In addition to consulting guidances, sponsors are encouraged to contact the Division to discuss specific issues that 
arise during development.  
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
74  III.  EVALUATING SAFETY OF NEW DRUGS TO IMPROVE GLYCEMIC 
75  CONTROL FOR PATIENTS WITH TYPE 2 DIABETES MELLITUS 
76   
77  A.  Size of the Safety Database 
78   
79  Patients with type 2 diabetes mellitus require chronic therapy, generally for many years.  Given 
80  the prevalence of diabetes, substantial patient exposure can be expected.  Therefore, drugs 
81  approved to improve glycemic control in these patients should have well-characterized safety 
82  profiles based on shorter term studies, but some safety concerns may only be identified in longer 
83  term studies.  For these reasons, the safety database of a new antidiabetic drug for type 2 diabetes 
84  mellitus should also include a substantial number of patients exposed to the drug for longer 
85  periods to allow for a thorough assessment of the drugs longer term safety profile.  Therefore, 
86  the safety database for a marketing application for a new drug for glycemic control should 
87  include data from controlled clinical trials and controlled clinical trial extensions with the 
88  following exposures: 
89   
90  1)  At least 4,000 patient-years of exposure to the new drug in phase 3 clinical trials. (This 
91  exposure includes all dosage strengths studied in the phase 3 clinical trials.) 
92   
93  2)  At least 1,500 patients exposed to the new drug for at least 1 year. 
94   
95  3)  At least 500 patients exposed to the new drug for at least 2 years. 
96   
97  B.  Patient Characteristics in the Development Program 
98   
99  Patients with type 2 diabetes mellitus often have comorbid conditions and/or diabetes-associated 
100  complications (e.g., chronic kidney disease, CV disease).  Therefore, it is important to evaluate 
101  the safety of new drugs to improve glycemic control in the population of patients who will be 
102  using the drugs, including a meaningful number of patients with underlying CV disease, chronic 
103  kidney disease, and older patients.  When a sponsor submits a marketing application for a new 
104  drug for glycemic control, the safety database should include data from patients with relevant 
105  age, comorbid conditions, and/or complications in the phase 3 trials as follows: 
106   
107  1)  At least 500 patients with stage 3/4 chronic kidney disease exposed to the new drug. 
108   
109  2)  At least 600 patients with established CV disease (e.g., previous myocardial infarction, 
110  documented coronary artery disease, previous stroke, peripheral vascular disease) 
111  exposed to the new drug. 
112   
113  3)  At least 600 patients older than 65 years of age exposed to the new drug.  
114   
115  Recognizing that a given patient could fall into more than one of these three categories, sponsors 
116  should aim for at least 1,200 patients with at least one of these conditions. 
117   
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
118  C.  Other Considerations 
119   
120  Sponsors should also consider the following concerning the collection of safety data: 
121   
122    Adverse CV outcomes remain an important source of morbidity and mortality for patients 
123  with type 2 diabetes mellitus.  Therefore, sponsors should use rigorous methods for the 
124  collection of adverse CV events and assess them by adjudication. 
125   
126    In some cases, the evaluation of a premarket safety concern may require that a drug 
127  development program accrue a minimum number of relevant adverse events to exclude a 
128  meaningful degree of risk.  Adjudication of these adverse events may also be needed.  
129  The Agency expects that situations where the collection of these additional safety data is 
130  necessary will be identified and discussed before phase 3 trials are initiated.  
131   
132    Sponsors should include data safety monitoring boards or committees to provide 
133  independent oversight of the safety findings from the clinical trials. 
134   
4