Diabetes Mellitus — Evaluating Cardiovascular Risk in New
Antidiabetic Therapies to
Treat Type 2 Diabetes
U.S. Department of Health and Human Services
Food and Drug Administrationchinasmack
Center for Drug Evaluation and Rearch (CDER)
December 2008
Clinical/Medical
Diabetes Mellitus — Evaluating Cardiovascular Risk in New
Antidiabetic Therapies to
Treat Type 2 Diabetes
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v/cder/guidance/index.htm
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U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Rearch (CDER)
December 2008
Clinical/Medical
cierre
TABLE OF CONTENTS
I.INTRODUCTION (1)更新英文
II.BACKGROUND (2)
III.RECOMMENDATIONS (3)
Guidance for Industry1payroll
Diabetes Mellitus — Evaluating Cardiovascular Risk in
常用英语培训
New Antidiabetic Therapies to Treat Type 2 Diabetes
This guidance reprents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can u an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.
I. INTRODUCTION
This guidance provides recommendations for the development of drugs and therapeutic biologics regulated within the Center for Drug Evaluation and Rearch at the Food and Drug Administration (FDA) for the treatment of diabetes mellitus.2 Specifically, this guidance makes recommendations about how to demonstrate that a new antidiabetic therapy to treat type 2 diabetes is not associated with an unacceptable increa in cardiovascular risk.
In March 2008, the FDA issued the draft guidance for industry Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and Prevention.3 Concerns related to cardiovascular risk w
ill be addresd in the final version of that guidance. In the meantime, we are issuing this final guidance for immediate implementation to ensure that relevant issues related to minimizing cardiovascular risk are considered in ongoing drug development programs. We will address cardiovascular risk asssment for currently marketed antidiabetic therapies in a parate guidance.
FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are
1 This guidance has been prepared by the Division of Metabolism and Endocrinology Products in the Center for Drug Evaluation and Rearch (CDER) at the Food and Drug Administration.
2 For discussion of general issues of clinical trial design or statistical analysis, e the ICH guidances for industry E8 General Considerations for Clinical Trials and E9Statistical Principles for Clinical Trials. We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER guidance Web page at v/cder/guidance/index.htm.
3 When final, this guidance will reprent the FDA’s current thinking on this topic. For the most recent version of a guidance, check the CDER guidance Web page at v/cder/guida
nce/index.htm.
cited. The u of the word should in Agency guidances means that something is suggested or recommended, but not required.
II. BACKGROUND欧洲艺术生留学
Diabetes mellitus has reached epidemic proportions in the United States and more recently worldwide. The morbidity and mortality associated with diabetes is anticipated to account for a substantial proportion of health care expenditures. Although veral drug treatments currently are available, we recognize the need for new agents for the prevention and treatment of diabetes (e.g., development of drugs and therapeutic biologics).
Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia caud by defective insulin cretion, resistance to insulin action, or a combination of both. Alterations of lipid and protein metabolism also are important manifestations of the defects in insulin cretion or action.
Most patients with diabetes mellitus have either type 1 diabetes (which is immune-mediated or idiop
athic) or type 2 diabetes (with a complex pathophysiology that combines progressive insulin resistance and beta-cell failure). Both type 1 and type 2 diabetes have a heritable basis. Diabetes also can be related to the gestational hormonal environment, genetic defects, other endocrinopathies, infections, and certain drugs.
The treatment goals for patients with diabetes have evolved significantly over the last 80 years, from preventing imminent mortality, to alleviating symptoms, to the now recognized objective of normalization or near normalization of gluco levels with the intent of forestalling diabetic complications. The Diabetes Control and Complications Trial has conclusively demonstrated that tight gluco control in patients with type 1 diabetes significantly reduces the development and progression of chronic diabetic complications, such as retinopathy, nephropathy, and neuropathy.4 Long-term follow-up of the patients demonstrated beneficial effects on macrovascular outcomes in the Epidemiology of Diabetes Interventions and Complications study.5
There are also compelling data in patients with type 2 diabetes supporting a reduced risk of microvascular complications with improved long-term glycemic control. Glycemic control in the studies has been bad on changes in HbA1c. This endpoint reflects a beneficial effect on the immediate clinical conquences of diabetes (hyperglycemia and its associated symptoms) and low
ering of HbA1c is reasonably expected to reduce the long-term risk of microvascular complications. Therefore, reliance on HbA1c remains an acceptable primary efficacy endpoint for approval of drugs eking an indication to treat hyperglycemia condary to diabetes mellitus. However, diabetes mellitus is associated with an elevated risk of cardiovascular dia, which is the leading cau of morbidity and mortality in this patient population. Although this excess cardiovascular risk is prent in both type 1 and type 2 diabetes, the
4 See N Engl J Med, 1993, 329:977-986.
5 See Diabetes, 2006, 55:3556-3565.
absolute deficiency of insulin in patients with type 1 diabetes dictates the need for insulin therapy as an immediate lifesaving treatment for which evaluation of long-term cardiovascular risk may not be practical. For type 2 diabetes, the wider range of therapies available before insulin therapy is considered for controlling hyperglycemia allows for an opportunity to evaluate the effect of the therapies on cardiovascular risk, enabling a more informed decision on the management of type 2 diabetes.
On July 1 and 2, 2008, the Endocrinologic and Metabolic Drugs Advisory Committee met to discuss t
he role of cardiovascular asssment in the premarketing and postmarketing ttings. After considering the discussion at this meeting as well as other available data and information,6 we have determined that concerns about cardiovascular risk should be more thoroughly addresd during drug development.
III. RECOMMENDATIONS
To establish the safety of a new antidiabetic therapy to treat type 2 diabetes, sponsors should demonstrate that the therapy will not result in an unacceptable increa in cardiovascular risk. To ensure that a new therapy does not increa cardiovascular risk to an unacceptable extent, the development program for a new type 2 antidiabetic therapy should include the following.
For new clinical studies in the planning stage:shelf的复数
•Sponsors should establish an independent cardiovascular endpoints committee to prospectively adjudicate, in a blinded fashion, cardiovascular events during all pha 2
and pha 3 trials. The events should include cardiovascular mortality, myocardial
infarction, and stroke, and can include hospitalization for acute coronary syndrome,
urgent revascularization procedures, and possibly other endpoints.
•Sponsors should ensure that pha 2 and pha 3 clinical trials are appropriately designed and conducted so that a meta-analysis can be performed at the time of completion of
the studies that appropriately accounts for important study design features and patient or study level covariates. To obtain sufficient endpoints to allow a meaningful estimate of risk, the pha 2 and pha 3 programs should include patients at higher risk of
cardiovascular events, such as patients with relatively advanced dia, elderly patients, and patients with some degree of renal impairment. Becau the types of patients are
likely to be treated with the antidiabetic agent, if approved, this population is more
appropriate than a younger and healthier population for asssment of other aspects of the test drug’s safety.
•Sponsors also should provide a protocol describing the statistical methods for the propod meta-analysis, including the endpoints that will be assd. At this time, we
believe it would be reasonable to include in a meta-analysis all placebo-controlled trials, add-on trials (i.e., drug versus placebo, each added to standard therapy), and active-
6 See Lancet, 1998, 352:837-853 and 854-865.
