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14 May 2012 CPMP/EWP/1080/00 Rev. 1 Committee for Medicinal Products for Human Use (CHMP)
Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus
Draft Agreed by CPMP May 2002
Date for coming into effect November 2002
Draft rev.1 Agreed by Efficacy Working Party January 2010
Adoption by CHMP for release for consultation 20 January 2010
End of consultation (deadline for comments) 31 July 2010
Draft rev.1 Agreed by Cardiovascular Working Party 7 July 2011
Adoption by CHMP for 2nd release for consultation 16 September 2011
End of consultation (deadline for comments) 18 November 2011
Agreed by Cardiovascular Working Party 1 February 2012
Adoption by CHMP 14 May 2012
Date for coming into effect 15 November 2012
This guideline replaces the Note for guidance on Clinical Investigation of Medicinal Products in the
Treatment of Diabetes Mellitus CPMP/EWP/1080/00.
Keywords Diabetes, Drug Evaluation, Clinical development, Treatment, Prevention,
Glucose-lowering agents, Insulin
An agency of the European Union
European Medicines Agency, 2012. Reproduction is authorised provided the source is acknowledged.
Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus
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Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus
Table of contents
Executive Summary.................................................................................5
1. ...........................................................5 Introduction (background)
2. ............................................................................................5 Scope
3. ....................................................................................6 Legal basis
4. ...7
Developing and Licensing Glucose Lowering Agents (except insulin products) for the Treatment of Type 2 Diabetes Mellitus
4.1 .......... 7 Specific considerations, strategies and steps in the development.
4.1.1 ................................................................... 7 Pharmacodynamic data
4.1.2 ........................................................................... 7 Pharmacokinetics
4.1.3 .......................................................... 7 Measures of glycaemic control
4.1.3.1 Glycohaemoglobin (Haemoglobin A )1C ............................................... 7
4.1.3.2 .............................................................................. 8 Plasma glucose
4.1.4 ................................................. 8 Other measures of metabolic control
4.1.5 ................................................ 9 Associated cardiovascular risk factors
4.1.6 ......................................... 9 Study population and selection of patients
4.1.7 ............................................................................... 9 Use of placebo
4.2 .................................................. 10 Methodology of the clinical studies
4.2.1 .................................. 10 Therapeutic exploratory studies (dose finding)
4.2.2 .................................................... 10 Therapeutic confirmatory studies
4.2.2.1 Monotherapy studies .................................................................... 11
4.2.2.2 Add-on (or combination) studies .................................................... 12
4.2.2.3 Combinations with insulin.............................................................. 12
4.3 ........................................................ 13 Studies in specific populations
4.3.1 ........................................................................................ 14 Elderly
4.3.2 ............................................................... 14 Children and adolescents
4.4 ............................................................................. 15 Safety aspects
4.4.1 .................................................................. 15 General considerations
Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus
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4.4.2 ............................................................................. 15 Hypoglycaemia
4.4.3 ...................................... 15 Long-term safety and cardiovascular safety
4.4.3.1 Type of studies ............................................................................ 16
4.4.3.2 Study Population.......................................................................... 17
4.4.3.3 Safety outcomes .......................................................................... 17
4.4.3.4 Evaluation of the results ............................................................... 18
4.4.4 ........................................................................... 18 Immunogenicity
5. ............................................19
Developing and licensing insulin preparations for the treatment of type 1 and type 2 diabetes mellitus
5.1 .................................................................. 19 Specific considerations
5.2 .................................................................. 19 Assessment of efficacy
5.3 ................................................................................................. 20 Strategy and steps in the development. Methodology of the clinical
studies
5.3.1 ................................................................. 20 Pharmacodynamic data
5.3.2 ......................................................................... 20 Pharmacokinetics
5.3.3 ....................................................... 20 Methodology of clinical studies
5.3.3.1 ....................................... 20 Study population and selection of patients
5.3.3.2 ..................................................... 21 Therapeutic exploratory studies
5.3.3.3 .................................................... 21 Therapeutic confirmatory studies
5.4 ......................................................... 21 Studies in special populations
5.4.1 ........................................................................................ 21 Elderly
5.4.2 ...................................................................................... 22 Children
5.5 ............................................................................. 22 Safety aspects
5.5.1 ............................................................................. 22 Hypoglycaemia
5.5.2 ................................................................ 22 Local reactions / toxicity
5.5.3 ................................................... 22 Product immunogenicity / affinity
5.5.4 ...................................................................................... 23 Children
6. ................................................................23 Other potential claims
6.1 ...................... 23 Delay in onset / prevention of type 1 diabetes mellitus
6.2 ................................................................................................. 24
Preservation of beta-cell function in patients with type 1 diabetes mellitus
6.3 ........................ 25 Delay in onset/prevention of type 2 diabetes mellitus
Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus
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7. ..................................................................................26 Definitions
7.1 ..................................................................................... 26 Diabetes
7.2 ............................................................................. 27 Hypoglycaemia
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Executive Summary
This guideline intends to address the EU regulatory position on the main topics of the clinical
development of new medicinal products in the treatment or delay in onset / prevention of patients
with diabetes.
1. Introduction (background)
Diabetes mellitus is a metabolic disorder characterised by the presence of hyperglycaemia due to
defective insulin secretion, insulin action or both. The chronic hyperglycaemia of diabetes mellitus
is associated with significant long term sequelae, particularly damage, dysfunction and failure of
various organs especially the kidneys, eyes, nerves, heart and blood vessels.
Type 1 diabetes is the result of pancreatic beta cell destruction and is prone to acute complications,
such as ketoacidosis. In type 1 diabetes the main goal is optimal blood glucose control to be
achieved by optimal insulin replacement therapy, extensive education and disease self
management. Prevention of complications and management of pregnancy are important issues.
Type 2 diabetes is a complex disorder which involves various degrees of decreased beta-cell
function, peripheral insulin resistance and abnormal hepatic glucose metabolism. Glucose control in
type 2 diabetes deteriorates progressively over time, and, after failure of diet and exercise alone,
needs on average a new intervention with gl