Type 2 Diabetes Mellitus: Evaluating the Safety of New Drugs for Improving Glycemic Control Guidance for Industry

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

32889298dft.docx
02/25/20
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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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

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Draft — Not for Implementation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:	1
Evaluating the Safety of New Drugs	2
for Improving Glycemic Control	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
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I. 	INTRODUCTION	16
17
The purpose of this guidance is to provide the Food and Drug Administration’s (FDA’s) current	18
recommendations regarding the overall evaluation of safety for the development of drugs and	19
biologics2 indicated for improvement of glycemic control in patients with type 2 diabetes	20
mellitus. The recommendations in this guidance reflect discussions at the Endocrinologic and	21
Metabolic Drugs Advisory Committee meeting held October 24–25, 2018,3 that considered	22
FDA’s review of cardiovascular (CV) outcome trials (CVOTs).	23
24
The CVOTs reviewed by the Endocrinologic and Metabolic Drugs Advisory Committee were	25
recommended in the guidance for industry Diabetes Mellitus – Evaluating Cardiovascular Risk	26
in New Antidiabetic Therapies to Treat Type 2 Diabetes (December 2008) (Diabetes Mellitus	27
December 2008 guidance). We are withdrawing the Diabetes Mellitus December 2008 guidance	28
and replacing it with this draft guidance. We are also withdrawing the draft guidance for	29
industry Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and	30
Prevention (February 2008) and replacing it with this draft guidance.	31
32
This guidance provides recommendations on the size and nature of the safety databases needed	33
to support drugs for chronic use to improve glycemic control in patients with type 2 diabetes.	34
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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.

Contains Nonbinding Recommendations
Draft — Not for Implementation
2
This guidance is intended to serve as a focus for continued discussions among the Division of	36
Metabolism and Endocrinology Products, pharmaceutical sponsors, the academic community,	37
and the public.4	
38
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In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	40
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	41
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	42
the word should in Agency guidances means that something is suggested or recommended, but	43
not required.	44
45
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II. 	BACKGROUND	47
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The withdrawn Diabetes Mellitus December 2008 guidance stated that sponsors should	49
demonstrate that new drugs intended to improve glycemic control in patients with type 2 diabetes	50
do not result in an unacceptable increase in CV risk. In response to the 2008 guidance, many	51
CVOTs have been completed. In reviewing those final reports, the Agency has found that	52
inclusion of meaningful numbers of patients with diabetes-associated complications and	53
comorbid conditions in clinical trials is feasible and valuable in assessing the safety profile of	54
new antidiabetic drugs, allowing valid assessment of CV risk. However, none of the CVOTs to	55
date have identified an increased risk of ischemic CV events. Some of the CVOTs have instead	56
demonstrated a reduced risk for CV events.	57
58
In light of these CVOT results, the Agency convened an advisory committee meeting on October	59
24–25, 2018, to discuss the recommendations in the Diabetes Mellitus December 2008 guidance.	60
Committee members were asked to consider the robustness of development program safety	61
databases before 2008, the new information learned since 2008, and whether the	62
recommendations in the Diabetes Mellitus December 2008 guidance were still appropriate.	63
Committee members stressed the need for sufficient safety data submitted before approval to	64
inform decision-making, the continued importance of CV safety data not limited to	65
atherosclerotic events, and the need to base postmarketing requirements on consideration of	66
signals of risk identified in the development program rather than a one-size-fits-all approach.	67
68
Based on these considerations, the Agency recommends a new approach in the evaluation of the	69
safety profile of new drugs to improve glycemic control in patients with type 2 diabetes mellitus	70
detailed in this guidance.	71
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4 In addition to consulting guidances, sponsors are encouraged to contact the Division to discuss specific issues that
arise during development.

Contains Nonbinding Recommendations
Draft — Not for Implementation
3
III. 	EVALUATING SAFETY OF NEW DRUGS TO IMPROVE GLYCEMIC	74
CONTROL FOR PATIENTS WITH TYPE 2 DIABETES MELLITUS	75
76
A. 	Size of the Safety Database	77
78
Patients with type 2 diabetes mellitus require chronic therapy, generally for many years. Given	79
the prevalence of diabetes, substantial patient exposure can be expected. Therefore, drugs	80
approved to improve glycemic control in these patients should have well-characterized safety	81
profiles based on shorter term studies, but some safety concerns may only be identified in longer	82
term studies. For these reasons, the safety database of a new antidiabetic drug for type 2 diabetes	83
mellitus should also include a substantial number of patients exposed to the drug for longer	84
periods to allow for a thorough assessment of the drug’s longer term safety profile. Therefore,	85
the safety database for a marketing application for a new drug for glycemic control should	86
include data from controlled clinical trials and controlled clinical trial extensions with the	87
following exposures:	88
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1) 	At least 4,000 patient-years of exposure to the new drug in phase 3 clinical trials. (This	90
exposure includes all dosage strengths studied in the phase 3 clinical trials.)	91
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2) 	At least 1,500 patients exposed to the new drug for at least 1 year.	93
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3) 	At least 500 patients exposed to the new drug for at least 2 years.	95
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B. 	Patient Characteristics in the Development Program	97
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Patients with type 2 diabetes mellitus often have comorbid conditions and/or diabetes-associated	99
complications (e.g., chronic kidney disease, CV disease). Therefore, it is important to evaluate	100
the safety of new drugs to improve glycemic control in the population of patients who will be	101
using the drugs, including a meaningful number of patients with underlying CV disease, chronic	102
kidney disease, and older patients. When a sponsor submits a marketing application for a new	103
drug for glycemic control, the safety database should include data from patients with relevant	104
age, comorbid conditions, and/or complications in the phase 3 trials as follows:	105
106
1) 	At least 500 patients with stage 3/4 chronic kidney disease exposed to the new drug.	107
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2) 	At least 600 patients with established CV disease (e.g., previous myocardial infarction,	109
documented coronary artery disease, previous stroke, peripheral vascular disease)	110
exposed to the new drug.	111
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3) 	At least 600 patients older than 65 years of age exposed to the new drug.	113
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Recognizing that a given patient could fall into more than one of these three categories, sponsors	115
should aim for at least 1,200 patients with at least one of these conditions.	116
117

Contains Nonbinding Recommendations
Draft — Not for Implementation
4
C. 	Other Considerations	118
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Sponsors should also consider the following concerning the collection of safety data:	120
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• 	Adverse CV outcomes remain an important source of morbidity and mortality for patients	122
with type 2 diabetes mellitus. Therefore, sponsors should use rigorous methods for the	123
collection of adverse CV events and assess them by adjudication.	124
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• 	In some cases, the evaluation of a premarket safety concern may require that a drug	126
development program accrue a minimum number of relevant adverse events to exclude a	127
meaningful degree of risk. Adjudication of these adverse events may also be needed.	128
The Agency expects that situations where the collection of these additional safety data is	129
necessary will be identified and discussed before phase 3 trials are initiated.	130
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• 	Sponsors should include data safety monitoring boards or committees to provide	132
independent oversight of the safety findings from the clinical trials.	133
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