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Conditional Marketing Authorisation of 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 under the “centralised procedure” following the scientific assessment of the application by the European Medicines Agency. (Article 3(1) and Annex 1a. of the Regulation (EC) No 726/2004

Different options are offered by European Union law for being granted a marketing authorisation through specific regulatory mechanisms to facilitate early patient access to medicinal products, including Advanced Therapy Medicinal Products, while maintaining a high assessment of the quality of these medicines, and of their safety and efficacy regarding the benefit/risk balance. 

When an Advanced Therapy Medicinal Product addresses an unmet medical need of patients, a conditional marketing authorisation may be granted on the basis of less comprehensive data than usually required. In this case, the benefit of immediate availability of the medicine to patients shall outweigh the risk inherent in the fact that additional data are still required. The comprehensive data will be further provided by the applicant within a precise timeframe post authorisation. (Article 14-a of the Regulation (EC) No 726/2004). 

 

Stakeholders

Conditional Marketing Authorisation Applicant: The people or company applying to the European Medicines Agency for a conditional marketing authorisation for medicinal products.  

Conditional Marketing Authorisation holder: The people or company benefiting from a conditional Marketing Authorisation 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 responsible for the scientific assessment of Advanced Therapy Medicinal Products to be marketed within the European Union and the European Economic Area, including in the context of conditional marketing authorisation applications. 

European Commission: The conditional marketing authorisation of Advanced Therapy Medicinal Products is granted or not by the European Commission. The European Commission’s legally binding decision takes into account the scientific assessment conducted by the European Medicines Agency. Notifications of conditional marketing authorisation 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

Conditional Marketing Authorisation: The conditional marketing authorisation is one of the European Union’s legal mechanisms linked to particular criteria, especially that the medicine fulfils an unmet medical need, to facilitate early patient access to medicinal products. The granted conditional marketing authorisation is valid for one year and can be renewed annually (Article 14(7) of Regulation (EC) No 726/2004). (Completed from EMA Glossary of Regulatory terms here).

Unmet medical need: Unmet medical needs mean a condition for which there exists no satisfactory method of diagnosis, prevention or treatment in the Union or, even if such a method exists, in relation to which the medicinal product concerned will be of major therapeutic advantage to those affected (Article 4 § 2 of Regulation (EC) No 507/2006). 

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 European Medicines Agency under the centralised procedure, and will be scientifically assessed by the Committee for Medicinal Products for Human Use (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

Conditional marketing authorisation applications requires the applicant to provide several specific information. 

The conditional marketing authorisation procedure allows the approval of a medicinal product meets several criteria, including that the medicine fulfils an unmet medical need, and supports its availability to patients despite providing less comprehensive data than normally required. Medicinal products for human use are eligible if they are intended for treating, preventing or diagnosing seriously debilitating or life-threatening diseases, including rare diseases. 

Therefore, to be granted a conditional marketing authorisation, the applicant has to demonstrate its ability to provide comprehensive data post-authorisation, that the medicine fulfils an unmet medical need and that the benefit of the medicine's immediate availability to patients is greater than the risk inherent in the fact that additional data are still required, as well as that the benefit-risk balance of the medicine is positive. (Article 4 § 1 of Regulation (EC) No 507/2006

The conditional marketing authorisation granted is valid for one year, renewable annually, and can be converted into a standard marketing authorisation once the conditional marketing authorisation holder has achieved its specific obligations post-authorisation. 

Post-authorisation the applicant has also to fulfil specific obligations, such as to complete ongoing studies or conduct new studies, to confirm the medicine's benefit-risk balance remains positive.  

If the applicant does not fulfil its specific obligations or if new data provided show that the risk-benefit balance is no longer positive, the European Medicines Agency can suspend or revoke the conditional marketing authorisation to protect patients’ health. 

 

Opportunities and incentives

The conditional marketing authorisation is a regulatory tool to foster early patient access to new medicinal products that notably fulfil an unmet medical need despite less complete data provided.  

The European Medicines Agency provides guidance to applicants (more information here), statistics in its annual report, and has issued a report on ten years of experience at the European Medicines Agency to analyse and review its experience on conditional marketing authorisation granted between 2006 and 2016. 

The conditional marketing authorisation has also been used to accelerate the approval of safe and effective COVID-19 treatments and vaccines in the European Union. More information here

 

Practical steps

1/ Medicines eligible to conditional marketing authorisation

  • Medicinal products which aim at the treatment, prevention or medical diagnosis of seriously debilitating or life-threatening diseases.
  •  Medicinal products designated as orphan medicinal products.
  • In emergency situations (e.g. pandemic), “a marketing authorisation for such medicinal products may be granted also where comprehensive pre-clinical or pharmaceutical data have not been supplied”.

(Article 14-a(1) of Regulation (EC) No 726/2004 current version with amendments and Recital 2 of Commission Regulation (EC) N° 507/2006)

2/ Criteria for conditional marketing authorisation to be granted

The following criteria shall be met:

  • The medicine addresses an unmet medical need, i.e. “a condition for which there exists no satisfactory method of diagnosis, prevention or treatment authorised in the Union or, even if such a method exists, in relation to which the medicinal product concerned will be of major therapeutic advantage to those affected”.
  • The risk-benefit balance of the medicinal product is favourable.
  • The applicant is likely to be able to provide comprehensive data.
  • The benefit of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that additional data are still required.

In emergency situations, a conditional marketing authorisation may be granted, subject to the above requirements, also where comprehensive pre-clinical or pharmaceutical data have not been supplied.

(Article 14-a(1) to(3) of Regulation (EC) No 726/2004 current version with amendments and Article 4(1) of Commission Regulation (EC) N° 507/2006)

3/ Specific obligations under conditional marketing authorisation

Conditional marketing authorisation is subject to specific obligations that are reviewed annually by the European Medicines Agency.

 Those specific obligations are especially:

  • to complete ongoing studies, or to conduct new studies, with a view to confirming that the risk-benefit balance is favourable.
  • specific obligations may be imposed in relation to the collection of pharmacovigilance data.

Those 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 European Medicines Agency as part of the European Public Assessment Report.

The summary of product characteristics and the package leaflet shall clearly mention that a conditional marketing authorisation for the medicinal product has been granted subject to specific obligations to be reviewed annually. The summary of product characteristics shall also contain the date on which the conditional authorisation is due for renewal.

 (Article 14-a(4) to(6) of Regulation (EC) No 726/2004 current version with amendments and Article 5 of Commission Regulation (EC) N° 507/2006)

4/ Procedure for conditional marketing authorisation application

4.1/ Early dialogue prior to submission

Early dialogue with the European Medicines Agency and other stakeholders (e.g. health technology assessment bodies) is strongly recommended by EMA.

Aim: To discuss with the EMA, especially rapporteurs of the CHMP, PRAC and CAT, for instance:

  • whether a specific medicinal product being developed for a specific therapeutic indication falls within the category of products intended for the treatment, prevention or medical diagnosis of seriously debilitating or life-threatening diseases, and whether it could meet the unmet medical needs of patients.
  • the development plan and the design of the intended studies (both the pre-authorisation studies and studies to be proposed as specific obligations for collection of remaining data after authorisation).

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 the EMA Account Management portal; the MAA pre-submission interactions form (available here, 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 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 an application and to include a statement on the intention to request a conditional marketing authorisation.
  • At the time of marketing authorisation application: the applicant may present a request for a conditional marketing authorisation.

How:

  • To indicate in the application form the grounds for a conditional marketing authorisation application and to include the corresponding justification in the section 1.5.5 of Module 1 of the dossier.

4.3/ Assessment of an application and granting of a conditional marketing authorisation

The Rapporteur, Co-Rapporteur and the other CHMP and CAT members will assess the justification and the data submitted for a conditional marketing authorisation for an Advanced Therapy Medicinal Product as part of the overall assessment of the application.

The assessment of the justification regarding the scope of conditional marketing authorisation will be reflected in the relevant assessment reports and in the final CHMP assessment report.

A conditional marketing authorisation may be requested by the applicant (before submission of a marketing authorisation application as strongly recommended by EMA, or together with the marketing authorisation application), or proposed by the CHMP (after having consulted with the applicant) during the assessment of the application.

The conditional marketing authorisation of an advanced therapy medicinal product 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 conditional marketing authorisation application in the CHMP guideline on the scientific application and the practical arrangements necessary to implement Commission Regulation (EC) No 507/2006 on the conditional marketing authorisation for medicinal products for human use falling within the scope of Regulation (EC) No 726/2004, and on EMA website here section 1.9.

5/ Validity and renewal of conditional marketing authorisation

Conditional marketing authorisation is valid for one year, on a renewable basis.

(Article 14-a(7) of Regulation (EC) No 726/2004 current version with amendments)

After its period of validity of one year the conditional marketing authorisation may be renewed annually.

More information on the renewal of conditional marketing authorisation in the CHMP guideline on the scientific application and the practical arrangements necessary to implement Commission Regulation (EC) No 507/2006 on the conditional marketing authorisation for medicinal products for human use falling within the scope of Regulation (EC) No 726/2004.

6/ Conversion of conditional marketing authorisation into standard marketing authorisation (not subject to specific obligations)

When the specific obligations of the conditional marketing authorisation have been fulfilled, the European Commission may, following an application by the marketing authorisation holder, and after receiving a favourable opinion from the European Medicines Agency, grant a marketing authorisation not subject to specific obligations (i.e. “standard”), valid for five years and renewable.

More information on the granting of a marketing authorisation not subject to specific obligations in the CHMP guideline on the scientific application and the practical arrangements necessary to implement Commission Regulation (EC) No 507/2006 on the conditional marketing authorisation for medicinal products for human use falling within the scope of Regulation (EC) No 726/2004

 

Interactions with regulators

Early contacts with the European Medicines Agency before the submission of the conditional marketing authorisation application  

Any issues or questions related to the conditional marketing authorisation application can be discussed with the European Medicines Agency during the pre-submission phase as part of early contacts with regulators. Before submitting a marketing authorisation application, the applicant is encouraged to indicate to the EMA its intention to request a conditional marketing authorisation in its notification of intention. Discussions in advance and pre-submission meetings are organised to provide assistance and guidance to the applicant before finalising the conditional marketing authorisation application. 

Pursuant to Article 11 of Regulation (EC) No 507/2006, the EMA has developed and issued guidelines on scientific assessment and practical arrangements necessary to implement conditional marketing authorisation.        

Contacts with the European Medicines Agency during the assessment of the conditional marketing authorisation application  

During the validation phase of the application and the whole assessment process, the conditional marketing authorisation applicant will maintain regular contacts and interactions with the European Medicines Agency, in particular to provide any additional answers or supporting documentation needed. 

Contacts with the European Medicines Agency post-conditional marketing authorisation 

Post-authorisation the applicant has to fulfil specific obligations, such as to complete ongoing studies, conduct new studies, and generate comprehensive data to the European Medicines Agency to confirm the medicinal product's benefit-risk balance remains positive. 

 

European Union Legislation

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

Commission Regulation (EC) No 507/2006 of 29 March 2006 on the conditional marketing authorisation for medicinal products for human use falling within the scope of Regulation (EC) No 726/2004 of the European Parliament and of the Council (Text with EEA relevance), OJ L 92, 30.3.2006, p. 6-9, CELEX number: 32006R0507

 

European Union Guidance

EMA guidelines

 

Relevant literature

  1. Approvals of Drugs with Uncertain Benefit–Risk Profiles in Europe. European Journal of Internal Medicine 26, no 8 (1/10/2015): 572‑584 
  2. Postauthorization Changes to Specific Obligations of Conditionally Authorized Medicines in the European Union: A Retrospective Cohort Study. Clinical Pharmacology & Therapeutics 105, no 2 (02/2019): 426‑435
  3. The European Medicines Agency’s EU Conditional Marketing Authorisations for COVID-19 Vaccines. The Lancet 397, no 10272 (30/01/2021): 355‑357
  4. A Detailed Analysis of Expedited Regulatory Review Time of Marketing Authorization Applications for New Anticancer Drugs in the US and EU. Clinical and Translational Science 15, no 8 (2022): 1959‑1967
  5. Regulatory Affairs 101: Introduction to Expedited Regulatory Pathways. Clinical and Translational Science 13, no 3 (2020): 451‑461 
  6. EU Regulatory Pathways for ATMPs: Standard, Accelerated and Adaptive Pathways to Marketing Authorisation. Molecular Therapy - Methods & Clinical Development 13 (14/06/2019): 205‑232
  7. The Conditional Marketing Authorisation of Covid-19 Vaccines: A Critical Assessment under EU Law. European Journal of Health Law 29, no 1 (4/03/2022): 33‑52
  8. Use of the Conditional Marketing Authorization Pathway for Oncology Medicines in Europe. Clinical Pharmacology & Therapeutics 98, no 5 (11/2015): 534‑541
  9. Characteristics and Follow-up of Postmarketing Studies of Conditionally Authorized Medicines in the EU. British Journal of Clinical Pharmacology 82, no 1 (2016): 213‑226
  10. Comparison of the New Japanese Legislation for Expedited Approval of Regenerative Medicine Products with the Existing Systems in the USA and European Union. Journal of Tissue Engineering and Regenerative Medicine 12, no 2 (2018): e1056‑e1062
  11. Early Market Access of Cancer Drugs in the EU. Annals of Oncology 27, no 1 (1/01/2016): 96‑105
  12. Mégerlin, Francis. « L’AMM conditionnelle issue du règlement communautaire n° 507/2006 et l’urgence de santé publique ». RDSS. Revue de droit sanitaire et social, N° 4, 2006, p. 691
  13. The Iterative Development of Medicines Through the European Medicine Agency’s Adaptive Pathway Approach. Frontiers in Medicine 6, (27/06/2019):1-10
  14. Emergency Use Authorization (EUA), Conditional Marketing Authorization (CMA), and the Precautionary Principle at the Time of COVID-19 Pandemic. Journal of Public Health Policy 42, no 3 (1/09/2021): 518‑521
  15. Approval of Cancer Drugs With Uncertain Therapeutic Value: A Comparison of Regulatory Decisions in Europe and the United States. The Milbank Quarterly 98, no 4 (2020): 1219‑1256. European Pharmaceutical Law Review 4, no 4 (2020): 192‑206
  16. Accelerated Access to Medicinal Products. European Pharmaceutical Law Review 4, no 4 (2020): 192‑206
  17. Adaptive Pathways: Possible Next Steps for Payers in Preparation for Their Potential Implementation.Frontiers in Pharmacology, 8 (23/08/2017): 1-13

 

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Acknowledgements

Published: 17/01/2023

Last updated: 23/01/2024

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

Under internal review by EuroGCT Commercialisation Working Group.