Information for industry

Information for pharmaceutical companies intending to bring new antimicrobial drugs to EUCAST for breakpoints

As part of the Centralised Procedure for the assessment and approval of new drugs in the European Union, a Standard Operating Procedure (SOP/H/3043) regarding the setting of antimicrobial susceptibility testing breakpoints has been drawn up between the European Medicines Agency (EMA) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST). The SOP sets out the conditions under which applicant company, the Rapporteurs appointed by the Committee for Medicinal Products for Human Use (CHMP), the EMA and EUCAST will work together in confidence. Please refer to the SOP for details.

Download SOP

Subject to the agreement of the applicant to share data from the application dossier with EUCAST, EUCAST will review data relevant to the setting of appropriate susceptibility testing breakpoints before a final opinion regarding approval is reached by CHMP. Subject to the agreement of the CHMP for each product, the EUCAST breakpoints will be included in section 5.1 of the Summary of Product Characteristics (SPC).

The EUCAST process for setting new breakpoints will adhere to the agreed timetable drawn up by the aforementioned bodies for each Centralised Procedure. The EUCAST Steering Committee plays a key role in the process and meets at least four times per year, usually in January, the day before the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) in March-April, in September and in November. If needed, extra meetings or telecom conferences may be organized.  

This document has been developed by EUCAST to provide practical advice and information for companies regarding the breakpoint-setting process.

1.

EUCAST encourages pharmaceutical companies to be prepared to give a first presentation of the agent to the EUCAST Steering Committee before the Centralised Procedure commences. In order to initiate this process, the EUCAST Chairman and Scientific Secretary should be contacted through the official EUCAST website (http://www.eucast.org).

The EUCAST Scientific Secretary will provide the contact details of the current Steering Committee members if this is needed for confidentiality agreements. Prior to the meeting the company should inform the EUCAST Scientific Secretary of the names and roles of the persons who will represent the company at the meeting.

The total time for the first meeting will be 60 minutes. A 30 minute presentation allows time for comment and discussion. The process is most productive if the presenter allows EUCAST members to ask questions and make comments during the presentation. Ideally, the first presentation should contain:

• Brief structure, mode of action, resistance mechanisms/selection of resistance
• Clinical indications and expected benefits over existing agents
• Microbiological activity (full species-related MIC distributions, not MIC50/90).
   - submit MIC-distributions using the available MIC templates
   - submit zone diameter distributions using available Zone templates
• Administration forms and dosages
• Pharmacokinetic data in healthy volunteers and patients
• Activity in animal models
• Pharmacodynamic studies, Monte Carlo simulations
• Clinical studies
• Relationships between dose, MICs and clinical and microbiological outcomes
• Company proposal for breakpoints
• Planned timescale for studies, regulatory approval
• Anything else that the company considers important/useful

It is very helpful if a copy of the presentation can be sent to EUCAST at least a week before the meeting. The company does not need to produce a "Company Rationale Document" at this early stage but companies have found it useful to bring their data together in this format before the formal process through EMA. No "dossier" is needed but if the company wishes to provide additional information it may do so.

EUCAST will not propose breakpoints at this stage.

EUCAST Rationale Documents list data (dosing, indications, target micro-organisms, MIC distributions, existing breakpoints, pharmacokinetics, pharmacodynamics, clinical evaluation) used by EUCAST in the breakpoint setting process. We suggest that companies prepare a document in the style of the "EUCAST rationale document" (download template) and submit it to EUCAST as early as possible in the process (preferably before or at the latest when filing with EMA). The "Company Rationale Document" will be one of many of EUCAST´s sources of information in the breakpoint setting process. It will be treated with the same confidentiality as all other material which is part of the process. It will be available only to the Company, EUCAST and the Rapporteur. However, the existence of a Company Rationale Document will help highlight differences between the Company and EUCAST with respect to data and interpretation. The Company Rationale Document can be amended by the Company at any time during the process whereby the changed (added or deleted) section must be highlighted and a copy sent to EUCAST and the Rapporteur.  A template rationale document and an example of a EUCAST rationale document can be downloaded.

Document updated 2010-06-21

2.

When the initial assessment of the CHMP has been finalised or the “clock has been stopped” for the CHMP assessment, the EUCAST and EMA secretariats will schedule a meeting between the EUCAST Steering Committee and the CHMP appointed Rapporteurs together with their relevant assessors. At this meeting the company will have the opportunity to present and discuss the drug.

3.

Following this meeting EUCAST will suggest epidemiological cut off values and preliminary clinical breakpoints and prepare a rationale document listing the data supporting the EUCAST breakpoint proposal. The rationale document will list:

  • Dosages and administration forms, the intended clinical indications and the target organisms;
  • Wild type MIC distributions and epidemiological cut off values – EUCAST requests tabulated non-aggregated MIC distributions for each target species including, when possible, isolates with and without resistance mechanisms;
  • Breakpoints already set by other organizations (breakpoint committees, medicines agencies);
  • Pharmacokinetics;
  • Pharmacodynamics;
  • Monte Carlo simulations of population pharmacokinetics in relation to pharmacodynamic properties of the drug;
  • Clinical data;
  • References.

4.

The proposed breakpoints and the rationale document are sent by EUCAST to the EMA, the assessors of the Rapporteurs, National Breakpoint Committees (whose Chairholders constitute most of the EUCAST Steering Committee) and the company for comments and questions. Comments should be given in writing. However, should either party request a meeting with EUCAST to clarify or discuss the proposal, a date for such a discussion will be set, preferably at the following EUCAST Steering Committee meeting. Such meetings should occur prior to day 150 of the Centralised Procedure.

5.

When there are no more questions on the EUCAST proposed breakpoints they will be finalised and transmitted to the EMA for consideration by the CHMP. This will normally occur within the 150-day period of the approval process. Following the registration of the drug, EUCAST will publish the breakpoints for the drug on the EUCAST website, either as part of an existing table for existing classes of drugs, or as a separate table for a new class. From the breakpoint table the rationale document can be accessed. The rationale document will also be published as a EUCAST Technical Note (ETN) in Clinical Microbiology and Infection.

6.

In the post-approval period companies may choose to bring new data to EUCAST to request a revision of the breakpoints. New data may support the setting of breakpoints for species or indications which were not given breakpoints during the approval process. New data may also support a different breakpoint than given originally. Please note that EUCAST will only consider setting breakpoints for species relevant to the already approved clinical indications. However, although there is no formal process set up by EMA/CHMP, EUCAST and Industry, EUCAST will consider revising breakpoints as a result of a request from any of the three involved parties (EMA/CHMP, EUCAST or Industry). In case EUCAST and companies agree to add or to change breakpoints relevant for the pharmacodynamic information in the SPC for centrally approved medicinal products, a variation to the marketing authorisation of that product would be expected.

7.

Questions on any of these steps in the process can be addressed to EUCAST secretariat (emails available on www.eucast.org).