Presubmission guidance: questions 31 to 40

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This page lists questions 31 to 40 of the European Medicines Agency's questions and answers on presubmission guidance.

The page is updated regularly to reflect new developments, to include guidance on further pre-authorisation procedures and to reflect the implementation of new European legislation. Revised topics are marked 'New' or 'Rev.' on publication.

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31. How shall my application be evaluated (timetable)? - Rev. March 2013

Once the application is validated and provided the Rapporteurs have confirmed that they have received the dossier, the EMA starts the procedure at the monthly starting date published on the EMA website. If, within a month from the start of the procedure, any other member of the CHMP has not received the requested parts of the dossier from the applicant, the EMA will stop the clock until confirmation is received that each member of the CHMP has been delivered the requested documentation. It is therefore important that applicants are able to provide a proof of delivery to Rapporteur, Co-Rapporteur and to CHMP members (upon request) to the EMA.

A timetable is prepared by the EMA in consultation with Rapporteur and Co-Rapporteur. This timetable is then proposed to the CHMP for adoption.

In order to allow the CHMP to adopt a timetable at the first CHMP meeting after submission of the valid MAA, applicants are advised to submit the MAA accordingly to the published EMA calendar (See "Dates for CHMP meetings”). 

The submission deadlines and full procedural detailed timetables are now published as a generic calendar on the EMA website (see: "submission deadlines and full procedural timetables").

The published timetables identify the submission, start and finish dates of the procedures as well as other interim dates/milestones that occur during the procedure.

The EMA shall ensure that the opinion of the CHMP is given within 210 days (less any clock-stops for the applicant to provide answers to question from the CHMP) in accordance with the following standard timetable, which can be shortened in exceptional cases (see Request for accelerated assessment).

DAYACTION
1*Start of the procedure
80Receipt of the Assessment Report(s) or critique from Rapporteur and Co-Rapporteur(s) by CHMP members (which includes the peer reviewers) and EMA. EMA sends Rapporteur and Co-Rapporteur Assessment Report/critique to the applicant making it clear that it only sets out their preliminary conclusions and that it is sent for information only and does not yet represent the position of the CHMP.
87PRAC Rapporteur circulates the RMP assessment report and proposed RMP LoQ
100(Co-)Rapporteurs, , other Committee members and EMA receive comments (including peer reviewers).
101-104PRAC adopts PRAC RMP Assessment Overview and Advice for D120 LOQ
115Receipt of draft list of questions (including the CHMP recommendation and scientific discussions), from CHMP (Co-)Rapporteurs , as discussed with the peer reviewers, together with the PRAC RMP Assessment Overview and Advice by CHMP members and EMA
120CHMP adopts the LoQ as well as the overall conclusions and review of the scientific data to be sent to the Applicant by the EMA.
Clock stop.
At the latest by Day 120, adoption by CHMP of request for GMP/GLP/GCP inspection, if necessary (Inspection procedure starts).
121*Submission of the responses, including revised SmPC, labelling and package leaflet texts in English.
Restart of the clock.

* Target dates for the submission of the responses are published on the EMA Website CHMP meeting

After receipt of the responses, the CHMP will adopt a timetable for the evaluation of the responses. In general the following timetable will apply:

DAYACTION
150PRAC Rapporteur circulates the RMP assessment report and proposed LoOI
157Joint Response Assessment Report from CHMP (Co-) Rapporteurs received by CHMP members and the EMA. EMA sends this joint Assessment Report to the applicant making clear that it is sent for information only and does not yet represent the position of the CHMP.
Where applicable inspection to be carried out.
EMA/QRD sub-group meeting for the review of English product Information with participation of the applicant (optional) around day 165.
167PRAC adopts PRAC RMP Assessment Overview and Advice for D180 LoOI
170Deadline for comments from CHMP Members to Rapporteur and Co-Rapporteur, EMA and other CHMP members
180CHMP discussion and decision on the need for adoption of a list of outstanding issues(LoOI) and/or an oral explanation by the Applicant. If an oral explanation is needed, the clock is stopped to allow the Applicant to prepare the oral explanation. Submission of final inspection report to the EMA, Rapporteur and Co-Rapporteur by the inspection team (at the latest by day 180).
181Restart of the clock and oral explanation (if needed).
183PRAC Rapporteur circulates the RMP assessment report
181 to 210Final draft of RMP, English SmPC, labelling and package leaflet sent by Applicant to the Rapporteur, Co-Rapporteur, PRAC Rapporteur, EMA and other CHMP members.
197PRAC adopts the final PRAC RMP Assessment Overview and Advice
By 210Adoption of CHMP Opinion + CHMP Assessment Report. Adoption of a timetable for the provision of product information translations

After adoption of a CHMP opinion, the preparation of the annexes to the Commission Decision is carried out in accordance with the following timetable:

DAYACTION
215 at the latestApplicant provides to the EMA the product information and Annex A in the 20 languages (all EU languages including Norwegian) and the “QRD Form 1” by e-mail* or on CD Rom for review by Member States.
229Member States will send linguistic comments on the product information by e-mail with a copy to the EMA together with QRD Form 1
232 at the latestApplicant provides EMA with final translations of SPC, Annex II, labelling and package leaflet in the 20 languages (+ “QRD Form 2”)
237Transmission of Opinion and Annexes in all EU languages to applicant, Commission, and Members of the Standing Committee, and Norway and Iceland.
239-261Draft Commission Decision
Standing Committee Consultation
By 277Finalisation of EPAR in consultation with Rapporteur, Co-Rapporteur, CHMP and Applicant (the latter for confidentiality aspects)
277Final Commission decision

*By e-mail: qrd@ema.europa.eu or on CD-Rom

References

31a. What are the dates of CHMP meetings? - Rev. Feb 2010
Year201020112012201320142015
MonthDatesDatesDatesDatesDatesDates
January 18, 19, 20, 2117, 18, 19, 2016, 17, 18, 1914, 15, 16, 1720, 21, 22, 2319, 20, 21, 22
February 15, 16, 17, 1814, 15, 16, 1713, 14, 15, 1618, 19, 20, 2117, 18, 19, 2023, 24, 25, 26
March 15, 16, 17, 1814, 15, 16, 1712, 13, 14, 1518, 19, 20, 2117, 18, 19, 2023, 24, 25, 26
April 19, 20, 21, 2211, 12, 13, 1416, 17, 18, 1922, 23, 24, 2522*, 23, 24, 2520, 21, 22, 23
May 17, 18, 19, 2016, 17, 18, 1921, 22, 23, 2427, 28, 29, 3019, 20, 21, 2218, 19, 20, 21
June 21, 22, 23, 2420, 21, 22, 2318, 19, 20, 2124, 25, 26, 2723, 24, 25, 2622, 23, 24, 25
July 19, 20, 21, 2218, 19, 20, 2116, 17, 18, 1922, 23, 24, 2521, 22, 23, 2420, 21, 22, 23
August 16, 17, 18, 1915, 16, 17, 1820, 21, 22, 2319, 20, 21, 2218, 19, 20, 2117, 18, 19, 20
September 20, 21, 22, 2319, 20, 21, 2217, 18, 19, 2016, 17, 18, 1922, 23, 24, 2521, 22, 23, 24
October 18, 19, 20, 2117, 18, 19, 2015,16, 17, 1821, 22, 23, 2420, 21, 22, 2319, 20, 21, 22
November 15, 16, 17, 1814, 15, 16, 1712, 13, 14, 1518, 19, 20, 2117, 18, 19, 2016, 17, 18, 19
December 13, 14, 15, 1612, 13, 14, 1510, 11, 12, 1316, 17, 18, 1915, 16, 17, 1814, 15, 16, 17

*Tuesday
Appointment of (Co) - Rapporteurs will take place at every meeting

Submission dates for applicants/MAHs - For "Full applications", "Full applications" responses to list of questions, Type II variations, Annual re-assessment and Renewal applications.

31b. What are the dates for submission of applications? - Rev. Feb 2010

The appropriate time and planning of submission and the timetable for assessment of applications is important for applicants, MAHs, the European Medicines Agency, CHMP members and experts for a better and efficient working plan. Especially, for full applications, the Agency advises applicants to consider the date of submission very carefully and to notify the Agency, Rapporteur and Co-Rapporteur of a 'real' submission date.

The submission deadlines and full procedural timetables are now published as a generic calendar and are for the information and use of applicants, MAHs, the European Medicines Agency, CHMP members and assessment teams. The published timetables identify the submission, start and finish dates of the procedures as well as other interim dates/milestones that occur during the procedure.  Timetables are classified under different categories depending on the type of procedure (e.g. full application, extensions, variations as well as responses timetables) and individual links are provided in this page.

The submission/start/CHMP dates are generally fixed, other dates may be subject to adjustments until the CHMP Scientific committee proceeds to their adoption for every individual application.

At the start of the procedure, the adopted final timetable will be formally notified in writing to applicants.

The date and time of delivery of the dossier to the European Medicines Agency should be arranged between the applicant and the Agency. The applicant will find the information of scheduled CHMP meetings as well as the deadlines for submission to the Agency in order to be able to identify preferred optimal submission dates on the following web pages.

For detailed information on the assessment procedures please refer to the Pre-submission and Post-Authorisation Guidance.

The address for submission of the application is:

European Medicines Agency
Loading Dock
Ontario Way
Canary Wharf
London E14 4HB
UK

32. How is an EMA Application Number attributed? - Rev. July 2006

On submission of an application, details of the product are entered into SIAMED, the EMA tracking system.

Procedures

The name and the active substance(s) of the product primarily identify applications for the granting of a Community Marketing Authorisation (MA) for a medicinal product. However, for administrative purposes, each application is also given a core number, EMA/H/C/xxxxxx, where H stands for Human and C for Centralised Procedure, with the remainder corresponding to a sequentially allocated and unique number identifying the whole of the application. This core number, which is provided after the submission of the application and communicated to the applicant at the start of the procedure, is retained throughout the life cycle of the product.

In every case of an administrative procedure relating to the product, an additional marker denoting the nature of the procedure is appended to this core number, i.e. for the first application for the granting of the MA, any extension, variation, transfer or renewal of MA. A sequential number is added, too. The markers currently used are as follows:

MarkerProcedureExample
/0000First new applicationEMEA/H/C/000789/0000
N/xxxxNotification Art. 61(3)EMEA/H/C/000789/N/0001
IA/xxxxType IA variationEMEA/H/C/000789/IA/0002
IB/xxxxType IB variationEMEA/H/C/000789/IB/0003
II/xxxxType II variation (regardless of procedural length)EMEA/H/C/000789/II/0004
X/xxxxAnnex II applicationEMEA/H/C/000789/X/0005
S/xxxx
Annual Re-assessmentEMEA/H/C/000789/S/0006
T/xxxxTransfer of MAEMEA/H/C/000789/T/0007
R/xxxxRenewal of MAEMEA/H/C/000789/R/0008
Z/xxxx(Renewal of) Suspension of MAEMEA/H/C/000789/Z/0009

These numbers are used as a reference by the EMA and should be used by the Applicant in all correspondence relating to a certain procedure.

Presentations

In addition, the numbering system covers all presentations (pharmaceutical forms, strengths and pack sizes) of the product. This is mainly relevant during evaluation of the procedure and for the purpose of identifying single presentations in lists such as the Annex A to the opinion. (For correspondence, it is sufficient to indicate the procedural number as above.)

A sequential three-digit number for each presentation is added to the procedural number (core number plus procedural marker). An example is given below for a product consisting of three different presentations, with two ensuing procedures creating new presentations:

ProcedureProcedureNumbers in Annex A
First new applicationEMEA/H/C/000789/0000EMEA/H/C/000789/0000/001
EMEA/H/C/000789/0000/002
EMEA/H/C/000789/0000/003
Type II variation creating three new presentationsEMEA/H/C/000789/II/0004EMEA/H/C/000789/II/0004/004
EMEA/H/C/000789/II/0004/005
EMEA/H/C/000789/II/0004/006
Annex II application creating a further three new presentationsEMEA/H/C/000789/X/0005EMEA/H/C/000789/X/0005/007
EMEA/H/C/000789/X/0005/008
EMEA/H/C/000789/X/0005/009

NB: For all procedures creating new presentations, this numbering system is superseded after MA by the EU numbers, which would from then onwards appear in the Annex A to opinions. The EU number is allocated independently of the EMA number, but retains the principle of identifying each single presentation by ending in a three-digit sequential number.

33. How are the European Union MA numbers assigned for new marketing authorisations? New Feb 2013

The European Commission is responsible for assigning the EU main marketing authorisation number for new marketing authorisation (e.g. EU/1/04/276).

At the time of the adoption of a CHMP opinion for a new marketing authorisation, the Agency will liaise with the European Commission in order to include the EU sub-numbers for each presentation (e.g. EU/1/04/276/01, EU/1/04/276/02, etc.) in the Annex A of the medicinal product, which will be transmitted to the Marketing Authorisation Holder together with the CHMP Opinion and respective annexes.

The Marketing Authorisation Holder should include the assigned EU sub-numbers in all language versions of the Annex A and in all applicable sections of the product information, which are submitted following the CHMP opinion for linguistic review.

The inclusion of the EU sub-numbers in the Annex A transmitted to the Applicant is without presumption as to the outcome of the procedure, which requires the issuance of the Commission decision granting the marketing authorisation.

34. When can I expect a pre-approval GMP inspection and how are they conducted? - Rev. May 2006

Legislative Basis

Directive 2001/83/EC as amended states that Manufacturing Authorisation Holders are obliged to comply with the Good Manufacturing Practice (GMP) for medicinal products and to use as starting materials only active substances that have been manufactured in accordance with the detailed guidelines on Good Manufacturing Practice for starting materials.

The principles and guidelines for GMP for medicinal products for human use are stated in Directive 2003/94/EC. Compliance with these principles and guidelines is mandatory within the European Economic Area (EEA), interpretation of these requirements is provided in part I of the Guide to Good Manufacturing Practice, published in Volume 4 of Eudralex. Part II of this guide provides for the detailed guidelines on Good Manufacturing Practice for active substances used as starting materials.

The guide to Good Manufacturing Practice consists of detailed guidelines (part I and part II) which are supplemented by a series of annexes specific for certain types of product, or for a particular topic.

The ad hoc GMP Inspection Services Group within the EMA is in charge to publish a "compilation of procedure" on behalf of the European Commission to gather all these guidelines, outlining the quality system requirements for National GMP Pharmaceutical inspectorates. The compilation is published on the Inspections page of the EMA website and, according to Directive 2003/94/EC, Member States shall take it into account.

Pre-submission notification

In their notification to submit, Applicants should mention:

  • The name (including contact point), and the address of the proposed manufacturer(s) of the active substance(s) and finished product
  • The name and address of the proposed site(s) in the EEA responsible for batch release of the medicinal product
  • If the medicinal product is imported from a third country, it should also include information on GMP inspections of the site(s) concerned carried out in the last 2-3 years by EEA competent authorities and/or by competent authorities of countries where a Mutual Recognition Agreement (MRA) is in operation, as applicable.
  • Final manufacturing and batch release arrangements will have to be provided when submitting the application
  • A description of the sequence of all different sites involved

    The manufacturing sites mentioned should be in compliance with Good Manufacturing Practice (GMP) and hence be "inspection ready" at the time of submission of the application and throughout the assessment.

    Manufacturing sites in third countries should be aware of European Community GMP requirements as mentioned below.

    Once the application is received, it is normally not permitted to add a new site or to change the steps of manufacture/release described in the dossier during the 210-day assessment procedure. Any additional site should be submitted as a variation after the granting of the marketing authorisation.

    At reception of application, the EMA determines if satisfactory inspections information is available. If not, the EMA with the Rapporteur and co-Rapporteur asks the CHMP to make a request for inspection of the manufacturer of either the active substance or the medicinal product in order to complete the assessment.

    The performance of these inspections by the EEA competent authorities will be co-ordinated by the EMA taking into account:

    • Inspections carried out of the same manufacturers by the EEA Countries
    • Inspections carried out of the same manufacturers by competent authorities of countries where a MRA is in operation, when applicable
    • The advice of the Rapporteur/Co-Rapporteur
    • Specific issues and questions raised during the assessment of the application

Inspection Team

The team required to perform the inspection will be proposed and co-ordinated by the EMA Secretariat. The team will be drawn from the inspection services of the Supervisory and other competent authorities of the EEA. On the advice of the Rapporteur and/or Co-Rapporteur the Inspection Team may include scientific experts and/or a Rapporteur for the Inspection as referred to in the provisions of Article 8 of Regulation (EC) No 726/2004.

Type of inspection

Inspections may be carried out to verify compliance with European Community Good Manufacturing Practice principles and guidelines and/or to cover product or process related issues arising from the assessment of the application. Inspections may cover the following activities:

Manufacture of the Active Substance:
The detailed guidelines on Good Manufacturing Practice adopted by the EEA for the manufacture of the active substance, are contained in part II of the EU Guide to Good Manufacturing Practice (Good Manufacturing Practice for Active Pharmaceutical Ingredients) in "The Rules Governing Medicinal Products in the European Union - Volume 4". Inspectors of the competent authorities in the EEA will inspect against the requirements of this guideline.

Manufacture of the Finished Product:
The GMP principles and guidelines applying to the manufacture of medicinal products for the EEA are laid down in Commission Directive 2003/94/EC, which are restated along with part I of the EU Guide to Good Manufacturing Practice in "The Rules Governing Medicinal Products in the European Union - Volume 4".

Where a manufacturing site is located in the EEA it is normally not necessary to request an inspection to confirm its GMP status as it is required by the above-mentioned Directive to be regularly inspected by the relevant authorities.

An inspection will normally be requested to confirm the GMP compliance status of manufacturing sites in third countries unless satisfactory information is available from an inspection of the same or similar category of product carried out during the last 2-3 years by an EEA competent authority or by the competent authority of a country where a MRA is in operation, as applicable .

In all cases (for sites in the EEA and third countries), an inspection may be requested to cover product or process related issues arising from the assessment of the application. In this case the Rapporteur and/or Co-Rapporteur will provide the Inspection Team with a list of questions/issues, which should be addressed during the inspection.

Importing Site - Site located in the EEA:
Importing sites in the EEA are required by the provisions of title III of Directive 2001/83/EC as amended, to hold a manufacturing authorisation. Inspections of importing sites to confirm their GMP compliance status are not normally requested in connection with applications for marketing authorisations. Inspections may however be requested to cover product or process related issues arising from the assessment of the application. In this case the Rapporteur and/or Co-Rapporteur will provide the Inspection Team with a list of questions/issues, which should be addressed during the inspection.

Timetable for Inspections

Inspection(s) requested in connection with an application for a marketing authorisation must be carried out and the final report(s) sent to the EMA and submitted to the CHMP in accordance with the 210 day time limit for the evaluation of the application by the CHMP.

Once an inspection request is adopted by the CHMP the Inspection Sector of the EMA will write within 5 working days to:

  • the applicant explaining that an inspection(s) will take place, giving details (target date for carrying out the inspection, inspection team, scope of the inspection, contact person in the relevant authority responsible for arranging the inspection)
  • the Rapporteur and Co-Rapporteur for information.

The Inspection Team will contact the Company to agree inspection dates within the agreed target date. Inspections usually take place in parallel with the "clock stop" period and will approximately be conducted within two months from the adoption of the inspection request.

If the manufacture of the product is carried out infrequently or is not scheduled to take place during the period when the assessment of the application is to take place, the Inspection Team and the Rapporteur/Co-Rapporteur may agree to inspect the manufacture of a similar product or process.

Regarding the fees to be paid, details can be found in question "What is the fee for a GMP/GCP inspection?"

Inspection Reports

Inspectors will send the draft Inspection Report to the manufacturer within fifteen days of the Inspection for comments on major factual errors, point of disagreement or remedial actions. Where necessary, the manufacturer should respond within a further fifteen days to provide comments and, if necessary, an action plan with a timetable for implementation. This will be considered during the finalisation of the Inspection Report and, if necessary, attached to it.

The timing of any discussions, further actions and/or the provision of additional information arising from the inspection will be agreed with the Inspectors and communicated by the Inspectors to the Rapporteur, the Co-Rapporteur and the EMA.

Inspectors finalise the report and send to the EMA inspections sector by Day 180 at the latest, which circulate to the Rapporteur, Co-Rapporteur and CHMP. In case of a non-satisfactory inspection report, which cannot lead to a positive opinion, discussions between the EMA, the Rapporteur, the Co-Rapporteur and the applicant should take place.

Documents for inspection

It is helpful to have a site/plant master file for use in preparing and carrying out the inspection. The preferred format is that recommended by the Pharmaceutical Inspection Co-operation Scheme (PIC/PICS). The Applicant should supply this document directly to the Inspection Team as far in advance of the inspection as possible. The site/plant master file is however not required to be submitted to the EMA.

References:

35. When can I expect a pre-approval GCP inspection and how are they conducted? - Rev. May 2006

Clinical trials included in any marketing authorisation application (MAA) in the EU and in any subsequent application to the initial one are required to be conducted in accordance with Good Clinical Practices (GCP). GCP inspections are conducted in accordance with Article 15 of Directive 2001/20/EC. The requirements which apply for the conduct of clinical trials included in a MAA are set out in Recital 16 and Article 6(1) of Regulation (EC) No 726/2004 as well as in Annex I to Directive 2001/83/EC, as amended (Introduction and general principles - sections 4 and 8 - and Part I - Module 5). Requirements for the conduct of clinical trials and GCP inspections are published in Volume 10 of the Rules governing Medicinal Products in the European Community.

The EMA relies for the scientific review of centralised applications for marketing authorisations for medicinal products on the expertise located in the Member States. The same approach exists in the area of inspections, where inspections are conducted by Member States' inspectorates if requested by the CHMP. These inspections are co-ordinated by the EMA if they pertain to centralised applications and in the case of GCP inspections, they are conducted by Member States' inspectorates in accordance with Article 15 of Directive 2001/20/EC . There is a GCP Inspection Services Group, composed of inspectors from the Member States, which meets quarterly at the EMA.

EMA inspection sector reviews all new applications for evidence of GCP compliance and other validation aspects. All new applications are examined to assess the need for GCP inspection(s). The EMA Inspections Sector liaises closely with the Product Team Leader, Rapporteur and Co-Rapporteur during the pre-submission phase and in the period during and after validation to discuss the need to request GCP inspection(s). A need for inspection(s) may be identified at this stage, based on previous relevant experience of the Inspections Sector and the Member States' national inspectorates. In addition, a need for GCP inspection(s) may also be identified during the review by the assessors, in particular during the initial assessment phase up to day 120.

GCP inspection issues are usually addressed in the List of Questions (although the inspection may commence earlier once adopted by CHMP), and therefore are usually adopted at Day 120. The GCP inspection(s) of the concerned site(s) can then take place in parallel with the "clock stop" period. However, GCP inspection(s) may be requested by CHMP at any stage of the assessment.

It should be noted that clinical data submitted as a result of specific obligations/follow-up measures, or within variations, extensions or other information received after the initial authorisation (e.g. in relation to safety updates, risk management plan etc.) may also trigger a GCP inspection request.

The Reporting Inspector appointed is usually from the inspectorate of the Member State of the CHMP Rapporteur or Co-rapporteur unless the site(s) to be inspected are located in a single EEA state (or small number (3 or less) of EEA states), in which case that Inspectorate is usually designated as the Reporting Inspectorate.

In addition to the Reporting Inspector, one Lead Inspector is designated per site to be inspected. The Lead Inspector is usually from the Inspectorate of the Member State where the site to be inspected is located (for inspections in the EEA). The Reporting Inspector may also be the Lead Inspector for one or more sites.

In the case of third country inspections, the Reporting Inspectorate and the inspectors are usually from the Rapporteur/Co-Rapporteur country inspectorates.

The applicant is asked to provide information in the application in order to facilitate the review and where needed the preparation of GCP Inspections. This information should be provided in the Individual Clinical Study Reports and their Appendices (Module 5) in line with the Note for Guidance on the Inclusion of Appendices to Clinical Study Reports in Marketing Authorisation Applications, and the Note for Guidance on Structure and Content of Clinical Study Reports. Some of the key information to be provided for each study, are listed below with the specific references to the section numbers given in the Note for Guidance on Structure and Content of Clinical Study Reports:

  • A clear description of the study administrative structure (clear identification of the sponsor and of the parties who have performed the monitoring, data management, statistics, laboratory assessments, randomization, site(s) of manufacture, site of release in Europe, medical writing, other applicable activities and the location of the trial master file) preferably in a tabular form and indicating name and address of the site where each activity was performed, responsibilities and scope of each activity. These should be identified in the clinical study report of each study, for instance in section 6, or appendix 16.1.4.
  • A list of investigators (name, address, country), preferably in a tabular form, showing the number of patients enrolled by each site, and the total number of sites. In addition a table with the number of patients enrolled per country should be included. These should be identified in the clinical study report of each study, for instance in section 10.1 or appendix 16.1.4.
  • Audit certificates (indicating the sites audited, the dates of audit, the type of audit and the auditor). These should be identified in the clinical study report of each study, for instance in appendix 16.1.8.
  • Signature of the principal or coordinating investigator(s) according to Annex I to Directive 2001/83/EC as amended and in line with the Note for Guidance on Structure and Content of Clinical Study Reports, and not only the signature of the sponsor's responsible medical officer . These should be identified in the clinical study report of each study, for instance in appendix 16.1.5.

A list of inspection(s) conducted or planned by other regulatory authorities, related to the product and trial sites involved, should also be provided, preferably attached to the Application cover letter.

Each clinical study report should contain a statement indicating whether the study was performed in compliance with Good Clinical Practices (GCP), including the archiving of essential documents.

According to the Notice to Applicant, Volume 2B, the clinical overview (Module 2), should assess the quality of the design and performance of the studies and also include a statement regarding GCP compliance.

In addition, in accordance with Article 6(1) of Regulation (EC) No 726/2004, a statement to the effect that clinical trials carried out outside the European Union meet the ethical requirements of Directive 2001/20/EC should be provided, where applicable, in Module 1.9 . This statement should indicate that "clinical trials carried out outside the European Union meet the ethical requirements of Directive 2001/20/EC" together with a listing of all trials (protocol number) and countries (outside the EU) involved.

References:

36. Which tools are used by the EMA to facilitate the streamlining of the European Decision making process / What is the QRD product information? - Rev. Jan 2006

The Quality Review of Documents group (QRD) was established in June 1996 and operates under the mandate adopted by the EMA Management Board on 3 December 1997.

The QRD Group is composed of representatives of the Member State's national authorities with experience in regulatory affairs and product information and representatives of the EMA (which also chairs the Group and provides secretariat facilities). The European Commission as well as observers from candidate EU countries and the Commission "Centre de Traduction" are invited to participate.

The main task of this group is to ensure clarity, consistency and accuracy of the medicinal product information (summary of product characteristics (SPC), labelling and package leaflet) and of its translations, which will be attached to scientific CHMP opinions. The mandate sets out a series of other tasks, namely:

  • Verification of terminology used in translations of Opinions and their consistency with the original version of documents
  • Ensuring linguistic and other formal coherence and consistency between different terminology used in scientific Opinions, and promotion of initiatives towards the standardisation of terminology
  • Review and update of Opinion templates
  • Promotion of legibility of patient information and verification of specimens of sales presentations/mock-ups in all EU official languages
  • Consideration of issues which could lead to delays in the Commission’s decision-making process and possible development, on request, of advice (particularly with a view to contribute to the development of common understanding on the implementation of legislation and guidelines)

The mandate also provides that "the Group shall develop its own working methods" and will consider "how best it may be associated with the different stages of the evaluation and Decision-making process".

In this regard, a New Product Information Linguistic Review Process has been developed and adopted, providing a more streamlined and more efficient review of the Product Information in all EEA languages.

The new process can be summarised as follows:

Pre-opinion:
Before Day 210 two reviews of the English Product Information are performed.

Between Day 80 and 110, a first review is done by the EMA Product Information Quality Group (PIQ) followed by a second review by the QRD group between Day 121 and 165.

The new process also foresees the possibility for one or two Applicant representative(s) to participate to a meeting around Day 165 to discuss the comments and the English Product Information with representatives from the EMA and the QRD.

Post-opinion:
Between Day 215 and 229, a detailed review of all translations of the Product Information is made by the Member States coordinated by the national QRD members concerned.

Between Day 232 and 237, the PIQ reviews the implementation of Member States comments made by the applicants in the final texts.

By Day 237, the final translations are sent to the European Commission to start the external Standing Committee consultation.

As part of a Marketing Authorisation Application, Applicants must submit proposals for SPC, Labelling and Package Leaflet texts in module 1.3.1. using the QRD Product Information Templates.

The Templates:

  • are intended to provide applicants with practical advice on how to draw up the product information, but without prejudice to any final position of the EMA, CHMP and European Institutions as to the contents of the document
  • set out the standard headings and indicate the most commonly used standard phrases and terms in the 20 official EU languages (with addition of Icelandic and Norwegian)
  • define the format and layout for Summary of Product Characteristics (SPC); labelling and Package Leaflet (see also "Convention" to be followed for QRD templates in order to ensure absolute consistency between all language versions)
  • provide useful guidance as to the content of the information to be supplied, in the QRD template with explanatory notes

In addition, QRD Reference Documents provide more detail guidance on various aspects concerning terminology and style.

While the templates and guidance notes aim to provide practical hints to the applicants, in particular in relation to how to address common problem areas, they are by no means a comprehensive guide to the information required to be included in the product literature. Thus applicants must also refer to the current EU legislation, guidelines, CHMP notes for guidance etc, when drawing up their drafts in order to be able to fully comply with the legal requirements in respect to product information.

For more details, please visit the QRD page for all information relating to Product Information and all useful References Documents.

References:

37. How is a MAA pre-submission meeting conducted at the EMA? Rev. Oct 2012

1.  General principle

The pre-submission meetings represent important points in the product development and regulatory approval process, and relate to the preparatory steps in advance of submitting a request for marketing authorisation application (MAA). Successful pre-submission meetings should enable applicants to submit applications, which are in conformity with the legal and regulatory requirements and which can be smoothly evaluated. These meetings will also enable applicants to establish contact with the EMA Product Team Members who will be closely involved in the centralised evaluation procedure of their medicinal product.

1.1.  Purpose/scope of meeting

a.    MAA pre-submission meetings are aimed at providing applicants with information that will assist them in the finalisation of their upcoming marketing authorisation application. Such meetings typically address product-specific legal, regulatory and scientific issues in order to facilitate subsequent validation and assessment of the application. Pre-submission meetings can be especially helpful to SMEs / other companies that may have limited experience of interaction with the EMA or are unfamiliar with the centralised procedure. However, experience has shown the usefulness of pre-submission meetings even for applicants that already have experience with the centralised procedure, to address issues specific to their upcoming application in view of the constantly evolving regulatory framework and its application.

b.    The MAA pre-submission meeting request form provides an overview of the most relevant topics (checklist) that applicants are advised to consider when preparing their upcoming application, and which will be discussed at a MAA pre-submission meeting. For each topic, a reference is included to the corresponding ‘question and answer’ in the EMA Pre-Submission Guidance for Users of the Centralised Procedure (PSG), which is available on the EMA Website. The PSG addresses a number of questions, which users of the centralised procedure may have, together with hyperlinks to relevant legislative documents and procedural guidelines which further complement the advice given in the PSG. The EMA considers that the information provided answers the majority of applicants’ queries. As EMA commits to keeping the pre-submission guidance document updated, there should not be a need to check or confirm the answers given in the PSG document at a pre-submission meeting. A topic should therefore only be proposed for discussion at a pre-submission meeting, in case the applicant’s questions are not fully answered by the PSG or other available guidance documents, due to certain particularities of the upcoming application and/or nature of the product. In that case, applicants are advised to clearly describe the issues in the ‘comments’ box under the topic concerned, and to provide relevant background information. Other topics not listed in the form may be added.

2.  Timing of MAA pre-submission meetings 

Pre-submission meetings for marketing authorisation applications (MAA) usually take place 6-7 months before submission. The MAA pre-submission meeting request form should be sent at least 6 weeks before the proposed meeting date or 3 months in advance if sent together with the Request of Eligibility, so that the meeting can be set-up at a mutually agreed date taking into account availability of EMA participants and meeting rooms. The meeting will start with the applicant’s 20-30’ presentation followed by a discussion on the presentation and the topics ticked in the pre-submission request form. The total meeting duration should not exceed 2 hours.

3.  Who is involved in a MAA pre-submission meeting?

EMA participants at MAA pre-submission meetings are the product Team Members i.e. the Product Team Leader (PTL) together with the Product Team Members (PTM) from the Quality / Safety-Efficacy sector and Regulatory Affairs. Depending on the topics to be discussed, other EMA attendees from the following sectors may attend parts of the meeting: Orphan Drugs, SME, Paediatrics, Inspections, Medical Information, Risk Management, Product and Application Business Support (PA-BUS).

Please note that the PTL will be chairing the meeting and will remain the primary contact point between the applicant and the rapporteurs during the life cycle of your product.

Applicant’s representatives should not exceed 7 to 8 participants. If needed, additional participants can join via teleconference.

4.  Documents to be prepared for a MAA pre-submission meeting

  • The MAA pre-submission meeting request form needs to be filled in electronically and send to PA-BUS at pa-bus@ema.europa.eu. This form includes topics and questions to be addressed at the pre-submission meeting.
  • One of the key-documents to be provided with the MAA pre-submission meeting request form is an overview of the product and its development programme (quality, non-clinical and clinical) together with a draft Table of Contents of the Application, listing the studies performed for each EU-CTD heading and the draft product information.
  • Applicants will need to provide a number of documents in relation to the product and the application with the MAA pre-submission meeting request form.  In addition, depending on the topics to be discussed, the applicant should provide additional topic-specific information (e.g. draft justification for accelerated review).
  • Another important document to be provided is a draft MA Application Form (EU-CTD Module 1.2), which should be completed as far and accurate as possible. The form will provide important information on the product and the type of application (e.g. legal basis, reference product details, manufacturing sites, conditional approval) in relation to the topics to be discussed at the meeting. It will also allow EMA to identify topics, other than those requested by the applicant, for discussion/clarification at the meeting, and thereby preventing issues to be raised at validation. In order to avoid duplication of information, the topics in the pre-submission meeting request form will not require the inclusion of the detailed elements which are already to be provided in the application form (e.g. tick-boxes for legal basis, eligibility for centralised procedure).
  • Following receipt of the pre-submission meeting request form and annexed documents, the EMA Product Team Leader (PTL) will review the topics proposed for discussion. He/she may consider that certain proposed topics would not need to be discussed at the meeting, as they are sufficiently addressed in existing guidance documents or as they could be easily clarified by phone or e-mail, in order to focus the meeting on particular product-specific issues. The applicant will be informed accordingly in advance of the meeting.

Note: Applicants must in all cases comply with all requirements of Community Legislation. Provisions, which extend to EEA countries (i.e. the EU member states, plus Norway, Iceland and Liechtenstein) by virtue of the EEA agreement, are outlined in the relevant sections of the text.

5.  How are MAA pre-submission meetings conducted?

At the start of the meeting, the applicant will be invited to give a 20-30’ presentation on the product development. The applicant’s presentation should include the following topics:

  • Company’s participants and contact points during the evaluation
  • Brief description of the product
  • Brief summary of the dossier content
  • Particular EU guideline deviations

On the basis of the information provided, EMA participants will discuss with the applicant the appropriateness of the chosen legal basis in view of the available data, highlight elements to be specifically addressed in the CTD Overviews (e.g. missing data, deviations from scientific advice), will provide an EMA view on the possibility for requesting approval under exceptional circumstances or conditional approval if applicable, etc. EMA may also draw attention to relevant scientific and regulatory guidelines, in particular the CHMP ‘clock-stop’ rules in case of a potential premature submission, recommend (further) scientific advice and suggest improvements to the product information.

The MAA pre-submission meeting request form will serve as the agenda for the remaining of the meeting. The topics listed in the pre-submission meeting request form are grouped according to the following areas:

  • Quality + GMP
  • Non-clinical + Clinical + GLP + GCP
  • Pharmacovigilance
  • Regulatory + procedural
  • Product information + transparency
  • Administrative

It is envisaged that the issues will be addressed in this order at the pre-submission meeting. This will allow a sequential discussion of all the applicant’s questions on topics related to the same area, with involvement of relevant EMA staff with expertise in the area concerned (e.g. Medical Information Staff members will attend the discussion on the topics dealing with product information and transparency etc).

Note: Applicants wishing to meet with their appointed (Co-) Rapporteur and assessment teams at national level should also inform the EMA PTL who will try to participate to such a meeting via teleconference. In any case, minutes of such meetings should be provided to the EMA PTL.

6.  Follow up of MAA pre-submission meetings

Detailed meeting minutes should be prepared by the applicant and provided to the EMA PTL within 2 weeks after the meeting. EMA Product Team Members will subsequently review the minutes within 2 weeks and agree the final (amended) minutes with the applicant

References:

38. Is my medicinal product eligible for approval under exceptional circumstances? - New Jan 2006

Legal basis and Criteria

The legal basis for the marketing authorisation (MA) under exceptional circumstances is the Article 14 (8) of the Regulation (EC) No 276/2004, and the relevant documentation for applications in exceptional circumstances are laid down in Part II of Annex I of Directive 2001/83/EC, as amended.

Products for which the applicant can demonstrate in this application that he is unable to provide comprehensive data on the efficacy and safety under normal conditions of use, because:

  • the indications for which the product in question is intended are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence, or
  • in the present state of scientific knowledge, comprehensive information cannot be provided, or
  • it would be contrary to generally accepted principles of medical ethics to collect such information,

may be eligible for marketing authorisation under exceptional circumstances.

Consequently, the authorisation under exceptional circumstances is granted subject to a requirement for the applicant to introduce specific procedures, in particular concerning the safety of the medicinal product, notification to the competent authorities of any incident relating to its use, and action to be taken.

Prior to submission

As early as possible during drug development, the applicant is encouraged to seek scientific advice from the EMA about the justification for applying for a marketing authorisation under exceptional circumstances, especially on the inability to provide comprehensive data.

Any further discussion on the appropriateness should preferably occur in the context of the pre-submission meeting.

Timing of the submission and documentation to be supplied

  • First of all, the applicant should submit a statement on the appropriateness of the granting of a marketing authorisation under exceptional circumstances in the notification to the EMA of their intention to submit a marketing authorization application (at least 6 months before submission).
  • Then, if the applicant considers that the grounds for approval under exceptional circumstances should apply, the applicant should tick the box 1.5.2 of the application form and include its justification in module 1, covering the following aspects:

    1) A claim that the applicant can show that he is unable to provide comprehensive non-clinical or clinical data on the efficacy and safety under normal conditions of use

    2) A listing of the non-clinical or clinical efficacy or safety data that cannot be comprehensively provided

    3) Justifications on the grounds for approval under exceptional circumstances

    4) Proposals for detailed information on the specific procedures/obligations to be conducted (Safety procedures, programme of studies, prescription or administration conditions, product information).

The proposals for detailed information on the specific procedures/obligations to be conducted shall also be written in accordance with the Guideline on risk management systems for medicinal products for human use.

Assessment of the justification for exceptional circumstances

The Rapporteur, Co-Rapporteur and the other CHMP members will assess the justification/data submitted for exceptional circumstances as part of the overall assessment of the benefit/risk of the application.

It is up to the CHMP, during the review, to ultimately decide on the type of the marketing authorisation.

Differences between Exceptional circumstances and conditional marketing authorisation

Conditional Marketing AuthorisationMarketing Authorisation under Exceptional Circumstances
Demonstrate positive benefit-risk balance, based on scientific data, pending confirmationComprehensive data cannot be provided (specific reasons foreseen in the legislation)
Authorisation valid for one year, on a renewable basisReviewed annually to reassess the risk-benefit balance, in an annual re-assessment procedure
Once the pending studies are provided, it can become a "normal" marketing authorisationWill normally not lead to the completion of a full dossier and become a "normal" marketing authorisation

A marketing authorisation under exceptional circumstances should not be granted when a conditional marketing authorisation is more appropriate. A conditional marketing authorisation is for example granted in the absence of comprehensive clinical data when it is likely that the applicant will be in the position to provide such data in a short timeframe, whereas the fulfillment of any specific procedures/obligations imposed as part of the marketing authorisation under exceptional circumstances is aimed at the provision of information on the safe and effective use of the product and will normally not lead to the completion of a full dossier.

Particularities of the marketing authorisation under exceptional circumstances

  • It should be noted that designated orphan products are eligible for approval under exceptional circumstances only if the criteria considered for the approval under exceptional circumstances are fulfilled.
  • The summary of product characteristics and package leaflet should mention that a marketing authorisation has been granted subject to certain specific obligations to be reviewed annually.
  • The renewal of the marketing authorisation of a medicinal product under exceptional circumstances follows the same rules as a "normal" marketing authorisation. After 5 years, the marketing authorisation will then be renewed under exceptional circumstances for an unlimited period, unless the competent authority decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal. (See EMA Post-Authorisation Procedural Advice)

References:

39. Do I need to perform User Consultation? / When and how to submit information on User Consultation? - New Jul 2006

Articles 59(3) and 61(1) of Directive 2001/83/EC, as amended, require that the package leaflet reflects the results of consultations with target patient groups ('user consultation') to ensure that it is legible, clear and easy to use and that the results of assessments carried out in cooperation with target patient groups are provided to the competent authority.

A user consultation is always required in the following situations:

  • First authorisation of a medicinal product with a new active substance,
  • Medicinal products which have undergone a change in legal status,
  • Medicinal products with a new presentation,
  • Medicinal products with particular critical safety issues.

However, reference to already approved package leaflets may be acceptable where appropriate, based on a sound justification by the applicant. Examples of when this may be considered acceptable as well as the considerations to be taken into account when choosing the types of ‘reference’ package leaflets are detailed in the Guidance concerning consultations with target patient groups for the package leaflet.

If user consultation has been performed on a package leaflet in the old QRD templates, there is no need to be retested when updating according to the new QRD templates. However, it should be noted that compliance with the QRD templates does not exempt from the obligation to undertake a user test or other form of user consultation. See also question "Which tools are used by the EMA to facilitate the streamlining of the European Decision making process / What is the QRD information?"

The package leaflet should be legible, clear and easy to read in all EEA languages, but it is normally sufficient to undertake user consultation in one EEA language. However, results of user consultation should be presented in English in order to allow assessment.

Methods of user consultation

The legislation does not define a precise method to be used for user consultation.

One of the possible ways of complying with the new legal requirement is by performing a ‘user testing’ of the package leaflet, i.e. to test the readability of a specimen with a group of selected test subjects. It is a development tool which is flexible and aims to identify whether or not the information as presented, conveys the correct messages to those who read it. Testing itself does not improve the quality of the information but it will indicate where there are problem areas which should be rectified.

Other methods than user testing may be acceptable provided that the outcome ensures that the information is legible, clear and easy to use so that patients can locate important information within the package leaflet, understand it and enables the user to act appropriately. Such alternative methodology will have to be justified by the applicant and will be considered on a case-by-case basis.

An example of a method for user testing of a package leaflet is provided in the Annex 2 of Guideline on the Readability of the Label and Package Leaflet of Medicinal Products for Human Use.

Further guidance on one way of user testing is also provided in the EFPIA General Recommendations for Readability User Testing of Package Leaflets for Medicinal Products for Human Use Submitted or Approved under the European Centralised Procedure and its Annexes (www.efpia.eu).

Submission and assessment of information on user consultation

During the pre-submission phase the applicant may discuss how to address 'user consultation' with EMA and (Co-) Rapporteur, if necessary. This discussion may indicate whether new 'user consultation' would be necessary or whether a justification for its absence or 'focused' user testing could be acceptable.

At the time of submission of the application, information regarding the 'user consultation' performed together with a presentation of its results, or a justification for not performing such consultation, is to be included in Module 1 (Section 1.3.4) of the dossier. The presentation of results should be shortened to a summary explaining how the consultation was executed and how the resulting package leaflet accommodated any need for change. The recommended structure of such a summary is provided in the Guidance concerning consultations with target patient groups for the package leaflet.

In their assessment reports, the (Co-) Rapporteur will include the assessment of the results of user consultation or of the justification for its absence as well as a conclusion on the overall readability of the package leaflet. It should be noted that, if not included in the initial submission, the results of user consultation or any further clarification, as requested, will have to be submitted as part of the answers to the list of questions at Day 121.

The user consultation results and the (Co-) Rapporteur’s assessment will also be forwarded to QRD Group, as useful information when reviewing the draft product information.

Further details on the assessment of information on user consultation can be found in the EMA Operational Procedure on Handling of "Consultation with target patient groups" on Package Leaflets (PL) for Centrally Authorised Products for Human Use.

References:

40. Do I need to include Braille on the packaging of my medicinal product? - New Jul 2006

Braille is the internationally widespread reading and writing system for blind and partially sighted people. It consists of arrangements of dots which make up the letters of the alphabet, numbers and punctuation marks.

The revised legislation requires that the name of the medicinal product is expressed in Braille format on the packaging of the medicinal product. In addition, Marketing Authorisation Holders must ensure that the package leaflet is made available on request from patients’ organisations in formats appropriate for the blind and partially sighted.

These new requirements apply to new marketing authorisations with Commission Decisions as of 20 November 2005. Nevertheless, companies are encouraged to apply the provision to all centrally authorised medicinal products as soon as possible.

Packaging requirements

The (invented) name of the medicinal product followed by its strength should be put in Braille on the packaging of the product. The uncontracted Braille system should be used. For medicinal products authorised only in a single strength, it is acceptable that only the invented name in Braille is put on the packaging.

The name in Braille should only appear on the outer/secondary packaging (usually a carton). In case where there is no secondary packaging, it is possible to fix an adhesive Braille label around the bottle. On a volunteer basis, the name in Braille can be expressed on all packaging components.

It is also possible for companies to include, on a voluntary basis, further information in Braille on bigger volume packages (e.g. pharmaceutical form, expiry date, etc).

In case of multilingual packaging, the name in Braille has to be printed in all the different languages concerned.

It should be noted that there is no need to put the name in Braille on the packaging of products which are only intended for administration by health care professionals.

In case of small volume packages (up to 10 ml) with limited space capacity, alternative means of providing Braille information may be considered, e.g. use of contracted Braille system or certain defined abbreviations or addition of a supplementary "tab" label.

At the time of submission of the application, applicants should address in Module 1 - section 1.3.6 of the application dossier the proposed implementation of the Braille requirements on the packaging of the medicinal product. In addition, the information that will appear in Braille on the printed outer packaging should be mentioned, if applicable, as normal text in section 16 of the outer packaging labelling (Module 1 - section 1.3.1 – Annex IIIA) and, where applicable and feasible, should be indicated with dots on the mock-ups - see question: When shall I submit mock-ups and/or specimens? (Module 1 – section 1.3.2).

Package leaflet for blind and partially sighted

On request the package leaflet should be provided for partially sighted people in a suitable print, taking into consideration all aspects determining the readability. For blind people the text has to be provided in an appropriate format, e.g. perceptible by hearing (CD-ROM, audiocassette, etc.) or in Braille. Choice of the appropriate medium should be made by the MAH in consultation with representatives of organisations for the blind and partially sighted.

Further guidance on the implementation of the requirements for Braille and the requirements for the package leaflet for the blind and partially sighted is provided in the European Commission Guidance concerning the Braille requirements for labelling and the package leaflet (Article 56a of Directive 2001/83/EC, as amended). Please note that this guidance will be included in the Commission Guideline on the Readability of the Label and Package Leaflet of Medicinal Products for Human Use, after finalisation of the revision of the guideline.

References: