Marketing Authorisation under exceptional circumstances for ATMPs
Introduction
Any company wishing to market Advanced Therapy Medicinal Products (ATMPs) within the European Union must hold a marketing authorisation issued by the European Commission.
Different options are offered by the European Union for being granted a marketing authorisation through specific regulatory mechanisms to facilitate early patient access to medicinal products, including ATMPs, while maintaining a high assessment of the quality of these medicines, and of their safety and efficacy regarding the benefit-risk balance.
A marketing authorisation under exceptional circumstances for medicinal products may be granted when the applicant is unable to provide comprehensive data on the efficacy and safety under normal conditions of use, because the indication to be treated is too rare, the present state of scientific knowledge is insufficient to provide comprehensive information, or it would be unethical to collect this information. (Article 14(8) of Regulation (EC) No 726/2004, current version with amendments) and (Annex I Part II 6 of Directive 2001/83/EC, current version with amendments)
This procedure is particularly relevant for orphan medicinal products and rare diseases if the criteria considered for the approval under exceptional circumstances are fulfilled.
On 1st February 2024, 3 ATMPs were granted a marketing authorisation under exceptional circumstances in the European Union: Glybera®, Upstaza®, and Ebvallo®.
Stakeholders
Marketing Authorisation under Exceptional Circumstances Applicant:The people or company applying to the European Medicines Agency for a marketing authorisation under exceptional circumstances.
Marketing Authorisation under Exceptional Circumstances holder: The people or company benefiting from a Marketing Authorisation under Exceptional Circumstances submitted through the "Centralised procedure" to commercialise a medicinal product in the European Union.
European Medicines Agency: The European Medicines Agency (EMA) is an agency of the European Union whose goal is to protect and promote human and animal health. The agency is notably responsible for the scientific assessment of medicinal products to be marketed within the European Union and the European Economic Area, including in the context of marketing authorisation under exceptional circumstances applications.
European Commission: The marketing authorisation under exceptional circumstances of ATMPs is granted or not by the European Commission. The European Commission’s legally binding decision takes into account the scientific assessment conducted by the EMA. Notifications of marketing authorisation under exceptional circumstances from the European Commission are published in the Official Journal of the European Union.
All information concerning current or active marketing authorisations, refused, withdrawn, suspended, expired or not renewed for medicinal products subject to the centralised procedure is available on the European Union Register of Medicinal Products.
Definitions
Marketing Authorisation under Exceptional Circumstances: The marketing authorisation under exceptional circumstances is one of the European Union’s regulatory mechanisms to facilitate early patient access to medicinal products that cannot be approved under a standard authorisation. This authorisation may be granted when the applicant is unable to provide comprehensive safety and efficacy data of the medicinal product under normal conditions of use required for a standard marketing authorisation, for objective and verifiable reasons. (Article 14(8) of Regulation (EC) No 726/2004, current version with amendments). This occurs when the condition to be treated is rare or because collection of full information is not possible or is unethical. (Annex I Part II 6 of Directive 2001/83/EC, as amended). (Definition completed from EMA Glossary of Regulatory terms here).
The marketing authorisation under exceptional circumstances is granted for a five-year period and its continuation is linked to annual re-assessment of the risk-benefit profile conducted by the Committee for Medicinal Products for Human Use (CHMP).
Marketing authorisation: All medicinal products must have been granted a marketing authorisation prior to be placed legally on the market within the European Union and the European Economic Area. The purpose of the marketing authorisation is to ensure safety, efficacy and high quality as well as a positive benefit-risk balance of the medicinal products. For Advanced Therapy Medicinal Products, a single application is submitted to the EMA under the centralised procedure, and will be scientifically assessed by the CHMP as well as other relevant Committees, especially the Committee for Advanced Therapies (CAT). The marketing authorisation issued by the European Commission is valid in the European Union Member States, Iceland, Norway and Liechtenstein for a five-year period.
Challenges
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.
Opportunities and incentives
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.
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.
Practical steps
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.
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.
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.
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.
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)
European Union Legislation
Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, OJ L 311, 28.11.2001, p. 67–128, CELEX number: 32001L0083.
Original text (available in the 24 official languages of the EU)
Document summary (available in the 24 official languages of the EU)
Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (Text with EEA relevance), OJ L 136, 30.4.2004, p. 1-33, CELEX number: 32004R0726
Original text (available in the 24 official languages of the EU)
Legal basis & types of approvals (europa.eu), Regulatory considerations for human medicines development: Legal basis for marketing authorisation applications & conditional marketing authorisations and authorisations under exceptional circumstances SME info day on 26 October 2018
Acknowledgements
Published: 17/01/2023
Last updated: 11/03/2024
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
Under internal review by EuroGCT Commercialisation Working Group.