Marketing Authorisation under exceptional circumstances for ATMPs

The marketing authorisation granted under exceptional circumstances procedure allows accelerating patient access to new technologies and treatments, especially for rare diseases, if the criteria considered for the approval under exceptional circumstances are met. As with all medicinal products, the benefit-risk balance must be positive despite the limited data due to, for instance to small numbers of patients.

During the assessment and once the authorisation under exceptional circumstances is granted, specific obligations are assigned to the applicant such as additional safety or efficacy studies on the medicinal product. It is required to notify the competent authorities of any incident relating to the medicinal products’ use and the actions to be taken. 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.

Marketing authorisation under exceptional circumstances data are re-assessed annually by the CHMP, as well as the CAT regarding Advanced Therapy Medicinal Products, to continuously evaluate the risk-benefit balance of the product and monitor the completion of the specific obligations required. The authorisation granted will generally not lead to the completion of a full dossier and become a standard marketing authorisation.

The marketing authorisation under exceptional circumstances is a legal tool to foster accelerated patients access to medicinal products, including Advanced Therapy Medicinal Products, for which the comprehensive safety and efficacy data and clinical evidence required for a standard marketing authorisation are never expected to be fully obtained from the applicant.

Nevertheless, the available data must indicate that the benefits of the medicine outweigh its risks (positive benefits-risks balance), and the applicant is continuously required to notify the competent authorities of any incident relating to the medicinal products’ use and the actions to be taken. The authorisation granted under exceptional circumstances is reviewed annually to reassess the benefit-risk balance, in an annual re-assessment procedure conducted by the EMA.

Pursuant to Article 14(8) of Regulation (EC) No 726/2004, the EMA has issued guideline on procedures for the granting of a marketing authorisation under exceptional circumstances to support the applicants. It also provides pre-authorisation guidance to the applicant, and assesses the justifications for exceptional circumstances. More information here (Question 1.9).

The marketing authorisation granted under exceptional circumstances is a legal procedure to facilitate early patient access to medicinal products based on less comprehensive data than normally required.

The general practical steps of a marketing authorisation are described under the ‘Centralised procedure for ATMPs’ and ‘Marketing Authorisation Application file for ATMPs’ EuroGCT .

1. Medicines eligible to marketing authorisation under exceptional circumstances

Medicines (including ATMPs here) to be authorised by the European Union under the centralised procedure whose general steps are described under the ‘Centralised procedure for ATMPs’ entry.

2. Criteria for medicines/ATMPs to enter the procedure of marketing authorisation under exceptional circumstances

The applicant for a marketing authorisation under exceptional circumstances has to show that he is unable to provide comprehensive data on the efficacy and safety under normal conditions of use, for objective, verifiable reasons, and 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.

Annex I Part II-6 of Directive 2001/83/EC (current version with amendments)

3. Specific obligations under marketing authorisation under exceptional circumstances

Specific obligations, and, where appropriate, the timeframe for their completion shall be clearly specified in the conditions to the marketing authorisation. They are made publicly available by the EMA as part of the European Public Assessment Report.

Generally, those specific conditions are specific procedures to be introduced by the applicant, especially regarding the safety of the medicinal product, notification to the competent authorities of any incident relating to its use, and action to be taken.

More specifically, those specific conditions may include the following:

• The applicant shall complete an identified programme of studies within a time period specified by the competent authority, the results of which shall form the basis of a reassessment of the benefit-risk profile,
• The medicinal product in question may be supplied on medical prescription only and may in certain cases be administered only under strict medical supervision, possibly in a hospital and in the case of a radio-pharmaceutical, by an authorised person,
• The package leaflet and any medical information shall draw the attention of the medical practitioner to the fact that the particulars available concerning the medicinal product in question are as yet inadequate in certain specified respects.

Annex I Part II-6 of Directive 2001/83/EC (current version with amendments)

4. Procedure for marketing authorisation under exceptional circumstances

4.1 Early dialogue prior to submission

Early dialogue with the EMA as early as possible during medicinal product development, is strongly recommended by the EMA.

Aim: To discuss with the EMA, especially rapporteurs of the CHMP, PRAC and CAT about the justification for applying for a marketing authorisation under exceptional circumstances, especially on the inability to provide comprehensive data.

How:

• Through CHMP scientific advice or protocol assistance for orphan medicines. (More information on EMA website here on Requesting scientific advice or protocol assistance from EMA).
• Through a pre-submission meeting: after having created an EMA account via theEMA Account Management portal; the ‘MAA pre-submission interactions form’ (available at the bottom of section 2.9 under “references”) shall be filled in electronically and sent to the EMA, by raising a ticket via EMA Service Desk, using the Question option “Pre-Submission Phase Request”, followed by the sub-option “Pre-Submission Interactions”. (More information on the EMA website, here in section 2.9.).

4.2. Submission of an application

When:

• Six to seven months before submission: to notify the EMA of the intention to submit a marketing authorisation application and to include a statement on the appropriateness of the granting of a marketing authorisation under exceptional circumstances.

How:

• To tick the box 1.5.2 of the application form and to include the corresponding justifications on the grounds for a marketing authorisation under exceptional circumstances in module 1 of the dossier, i. e. the claim of inability to provide comprehensive non-clinical or clinical data on the efficacy and safety under normal conditions of use as well as the list of those data, justifications for applying for a marketing authorisation under exceptional circumstances, and Proposals for detailed information on the specific procedures/obligations to be conducted.

4.3 Assessment of an application and granting of a marketing authorisation under exceptional circumstances

The Rapporteur, Co-Rapporteur and the other CHMP and CAT members will assess the justification and the data submitted for a marketing authorisation under exceptional circumstances for an ATMP 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.

The marketing authorisation under exceptional circumstances of an ATMP is granted by the European Commission, based on the scientific assessment led by the CHMP and including the CAT within the EMA.

More information on the procedure for marketing authorisation under exceptional circumstances application in the CHMP Guidelines on procedures for the granting of a marketing authorisation under exceptional circumstances, pursuant to article 14 (8) of Regulation (EC) N° 726/2004, and on EMA website here in section 1.9.  

5. Validity and annual re-assessment of marketing authorisation under exceptional circumstances

The marketing authorisation under exceptional circumstances is granted for a five-year period.

Its continuation is linked to annual re-assessment conducted by the CHMP of the implementation and fulfilment by the applicant of specific conditions and the impact of these conditions’ data on the risk-benefit balance of the medicinal product.

• Submission of the annual re-assessment application:
  • To the EMA,
  • On the anniversary date of the European Commission decision granting the marketing authorisation, within a maximum flexibility of +/- 2 months to synchronise the re-assessment submission with the submission of the specific obligations data,
  • A cover letter, product information and reports on the summary of the specific obligations initially agreed, the data submitted and the status of fulfilment of the obligations and their impact on the overall risk-benefit balance of the medicinal product.
• Evaluation of the annual re-assessment:
  • Joint by the CAT and the PRAC Rapporteur for ATMPs,
  • On the basis that the risk-benefit balance is to be confirmed, regarding the specific obligations contained in the authorisation and the status of their fulfilment and impact on the overall risk-benefit balance of the medicinal product,
  • Final opinion of CHMP to be given within 90 days (if no request for supplementary information) following receipt of a valid annual re-assessment application.
  • Timetable of annual re-assessment for ATMPs is available here.
• Decision on the annual re-assessment: 
  • The CHMP opinion will conclude on whether the marketing authorisation should be maintained, varied or suspended/revoked,
  • Exceptionally, the CHMP may recommend granting a marketing authorisation not subject to specific obligations considering that all specific obligations have been fulfilled and comprehensive data on the efficacy and safety of the medicinal product is available,
  • The European Public Assessment (EPAR) will be revised to reflect the CHMP conclusions in relation to the annual re-assessment procedure, and in case of an unfavourable opinion, a question-and-answer document will be published by the Agency.

More information on the annual re-assessment of marketing authorisation under exceptional circumstances here.

6. Renewal of marketing authorisation under exceptional circumstances

The renewal of the marketing authorisation of a medicinal product under exceptional circumstances follows the same rules as a standard marketing authorisation: after five years the marketing authorisation shall be valid for an unlimited period, unless the Commission decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal. (Article 14 (1-3) of Regulation (EC) N° 726/2004, current version with amendments)

Early contacts with the European Medicines Agency before the submission of the marketing authorisation under exceptional circumstances application

Any issue or question related to the marketing authorisation under exceptional circumstances application can be discussed with the EMA during the pre-submission phase as part of early contacts with regulators. The EMA proposes and encourages close dialogue and advice about the justification for applying for a marketing authorisation under exceptional circumstances. Scientific advice is also encouraged, especially on the inability to provide comprehensive data, and on the limitations imposed by the rarity of the disease, or scientific knowledge to collect comprehensive information on safety and efficacy.

Discussions in advance and pre-submission meetings are organised to provide assistance and guidance to the applicant before finalising the marketing authorisation application. To appreciate the eligibility for an approval under exceptional circumstances, the EMA has issued marketing authorisation pre-authorisation guidance (Question 1.9).

Contacts with the European Medicines Agency during the assessment of the marketing authorisation under exceptional circumstances application

During the validation phase of the application and the whole assessment process, the marketing authorisation under exceptional circumstances applicant will maintain regular contacts and interactions with the EMA to provide any explanations, documentation and data needed, and in particular the verifiable reasons for which comprehensive data on the efficacy and safety under normal conditions of use of the medicinal product cannot be provided.

Contacts with the European Medicines Agency following marketing authorisation under exceptional circumstances

Post-authorisation the applicant has to fulfill specific obligations annually, such as to continue monitoring the safety and efficacy of the medicinal product on an ongoing basis, conduct a programme of new studies, and generate data to the EMA to confirm the medicinal product's benefit-risk balance remains positive. The fulfilment of these specific obligations imposed as part of the marketing authorisation under exceptional circumstances is aimed to provide information on the safe and effective use of the product.

Continuation of the marketing authorisation during the five-year period is subject to the annual re-assessment of these conditions by the CHMP, the Pharmacovigilance Risk Assessment Committee (PRAC), and the involvement of the CAT regarding Advanced Therapy Medicinal Products. The annual re-assessment submission date will be discussed and agreed between the marketing authorisation holder and the EMA.

Published: 17/01/2023

Last updated: 11/03/2024

Authors:

Luc-Sylvain Gilbert, EuroGCT ELSI Legal Information Officer,

and Aurélie Mahalatchimy, EuroGCT WP4 Convenor, UMR 7318 DICE CERIC, Aix-Marseille University, CNRS, Aix-en-Provence- France

Reviewed by:

Under internal review by EuroGCT Commercialisation Working Group.