23 June 2016
EMA/317855/2016
Committee for Medicinal Products for Human Use (CHMP)
Concept paper on the need for revision of the guideline
on clinical investigation of medicinal products in the
treatment or prevention of diabetes mellitus
Agreed by Cardiovascular Working Party 11 May 2016
Adopted by the Committee for Medicinal Products for Human Use for
23 June 2016
release for consultation
Start of public consultation 28 July 2016
End of consultation (deadline for comments) 31 October 2016
The proposed guideline will replace 'Guideline on clinical investigation of medicinal products in the
treatment or prevention of diabetes mellitus (CPMP/EWP/1080/00 Rev. 1).
Keywords treatment or prevention of diabetes, prediabetes, cardiovascular
safety, cardiovascular risk, insulin products, definition of
hypoglycaemia, fixed dose combinations, oral treatments for type 1
diabetes
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1. Introduction
This concept paper (CP) refers to the need for revision of the Guideline on clinical investigation of
medicinal products in the treatment or prevention of diabetes mellitus (1).
2. Problem statement
The current guideline was adopted by the CHMP in May 2012 and came into effect 15 November 2012.
The main reason for a revision of the guideline is to update the section on cardiovascular safety to
align it with the recently adopted Reflection paper on assessment of cardiovascular safety profile of
medicinal products (7).
At the same time, some additional changes to the guideline are proposed to be considered based on
recent developments and queries from different stakeholders. These issues include outcome measures
to assess benefit of new products, safety issues associated with higher insulin concentrations,
definitions of hypoglycaemia, guidance with respect to delay in onset/prevention of diabetes and oral
treatments for type 1 diabetes (see further below).
3. Discussion (on the problem statement)
A Reflection paper on assessment of cardiovascular safety profile of medicinal products (7) has
recently been published. Reference to this paper is intended to replace the majority of the text in
section 4.4.3 (long term safety and cardiovascular safety). This section is intended to be consistent
with the corresponding sections of the guidelines on products for weight control, treatment of
hypertension and treatment of lipid disorders. This is the main reason for the update of the guideline.
However, some other areas have been identified that could benefit from revisions.
• Patient groups have expressed concerns that HbA1c may be insufficient to establish benefit of
glucose lowering therapies and that additional measures need to be evaluated to characterize
benefit. Depending on further assessment of this issue, it may be considered to include additional
guidance with respect to potential endpoints others than those directly associated with glycaemic
control, e.g. patient reported outcome measures.
• During the last years, insulins with different concentrations (200 U/ml, 300 U/ml) have been
approved. An addendum to the good practice guide on risk minimisation and prevention of
medication errors reflecting risk minimisation strategy for high-strength and fixed-combination
insulin products has been published in November 2015 (8), and some wording and reference
should be included in the guideline reflecting specific safety issues associated with higher insulin
concentrations.
• Since the last revision of the guideline, no Marketing Authorisation Application has been received
and only limited advice has been given with respect to “delay in onset/prevention of type 2
diabetes”. However, in such a potential scenario, proposed study designs may rather suggest
“treatment of prediabetes” as possible consequential indication. For the claim of “prevention of
type 2 diabetes” preferably a population with no glycaemic abnormalities would need to be
followed for a very long time leading to feasibility issues with such a study design. Therefore some
changes in that section may be proposed to clarify these aspects.
• With respect to definition of hypoglycaemia, the following statement is included in section 7 of the
current guideline: The definitions of hypoglycaemia in individual protocols and across protocols
within the development program should be standardized. One recommended approach for such
Concept paper on the need for revision of the Guideline on clinical investigation of
medicinal products in the treatment or prevention of diabetes mellitus
EMA/317855/2016 Page 2/4
standardization is to use classifications of severity from well-accepted sources, such as the ADA for
adults. Since the EMA has received input from external stakeholders considering the ADA definition
may not be appropriate in all cases, another example for the definition of hypoglycaemia
representing a lower cut off could be added.
• Scientific advices recently given by CHMP on the development of oral treatments for patients with
type 1 diabetes, primarily with the class of SLGT 2 inhibitors, suggest the need for advice on this
topic in the GL. While these products potentially can provide beneficial effects (insulin sparing,
reduced risk of hypoglycaemia), there are also safety concerns, e.g. with respect to risk of atypical
presentation of ketoacidosis which has been reported in patients with type 2 diabetes. This
warrants new text in the guideline as this development is not yet reflected in the current version of
the GL.
4. Recommendation
The CVS Working Party and CHMP recommend revising the Guideline on clinical investigation of
medicinal products in the treatment or prevention of diabetes mellitus (1).
Points that will be addressed are listed in sections 2 and 3 of this CP.
5. Proposed timetable
This CP will be released for 3 months public consultation. Following this it is planned to release the
draft Guideline within 6 months after the completion of the public consultation on the CP. The draft
Guideline will be released for 6 months public consultation and following the receipt of comments it will
be finalised within approximately 6 months.
6. Resource requirements for preparation
The drafting process will be done internally at the CVS WP. Contribution from the Scientific Advice
Working Party, Biostatistics Working Party and Geriatric Experts Group will be requested.
7. Impact assessment (anticipated)
The document is intended to update methodological aspects when performing trials to develop
medicinal products for the treatment or prevention of diabetes. It should also provide a clear basis for
the CHMP when assessing primary safety data and secondary efficacy and safety data of clinical
relevance from studies for medicinal products in this indication and providing advice in this field.
8. Interested parties
The interested parties in the guideline include the Industry, Academia, EASD (European Association for
the Study of Diabetes), ESE (European Society of Endocrinology), European Society of Cardiology
(ESC), European Federation of Internal Medicine (EFIM), ADA (American Diabetes Association) and
clinical trialists in diabetes.
9. References to literature, guidelines, etc.
1. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes
mellitus
Concept paper on the need for revision of the Guideline on clinical investigation of
medicinal products in the treatment or prevention of diabetes mellitus
EMA/317855/2016 Page 3/4
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC50012
9256.pdf
2. Draft reflection paper on the wording of the indication for medicinal products for the treatment of
type-2 diabetes
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/03/WC50016
2192.pdf
3. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a
position statement of the American Diabetes Association and the European Association for the
Study of Diabetes. Inzucchi SE, Bergenstal RM, Buse JB et al. Diabetologia. 2015;58:429-442.
4. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration
with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the
European Society of Cardiology (ESC) and developed in collaboration with the European
Association for the Study of Diabetes (EASD). Authors/Task FM, Rydén L, Grant PJ et al. Eur Heart
J. 2013;34:3035-3087.
5. Use of Glycated Haemoglobin (HbA1c) in the Diagnosis of Diabetes Mellitus. Abbreviated Report of
a WHO Consultation. WHO 2011
http://www.who.int/cardiovascular_diseases/report-hba1c_2011_edited.pdf
6. American Diabetes Association – Standards of care in diabetes – 2016. Diabetes Care, January
2016, Volume 39, Suppl. 1
http://care.diabetesjournals.org/content/suppl/2015/12/21/39.Supplement_1.DC2/2016-
Standards-of-Care.pdf
7. Reflection paper on assessment of cardiovascular safety profile of medicinal products
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/03/WC50020
3804.pdf
8. Risk minimisation strategy for high-strength and fixed combination insulin products (Addendum to
the good practice guide on risk minimisation and prevention of medication errors)
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2
015/11/WC500196980.pdf
Concept paper on the need for revision of the Guideline on clinical investigation of
medicinal products in the treatment or prevention of diabetes mellitus
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