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 (EMEA) 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 EMEA 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 drug 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 scientific secretary will provide the names of the current Steering Committee members needed for preparing confidentiality agreements.
Ideally the first presentation should contain an outline of the microbiological properties of the drug in the light of the clinical indications sought and, thereby, the intended target organisms with full MIC distributions. Other important information that should be provided for the breakpoint setting process include the planned administration forms and dose regimens and the pharmacokinetic data obtained from healthy subjects and patients. Any relevant data from efficacy studies in animal models and any available analyses of the possible relationship between dose regimen, MICs and clinical and microbiological outcomes would be welcomed. If the applicant has already performed Pk/Pd analyses EUCAST would be most interested to see these. EUCAST will not attempt to set 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" and submit it to EUCAST as early as possible in the process (preferably before or at the latest when filing with EMEA). 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.
2.
When the initial assessment of the CHMP has been finalised or the “clock has been stopped” for the CHMP assessment, the EUCAST and EMEA 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 EMEA, 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 EMEA 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 EMEA/CHMP, EUCAST and Industry, EUCAST will consider revising breakpoints as a result of a request from any of the three involved parties (EMEA/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.
