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Pharmacovigilance: Compassionate Use Program in Europe

31 Aug 2018

The compassionate use programs (CUP) according to the European Regulation (EC) No 726/2004 art 83 lay down Community procedures for the authorization and supervision of medicinal products without a Marketing Authorisation that may be made available for compassionate reasons to a group of patients. This program is meant only for patients who have not responded to treatment with conventional drugs that have a marketing authorization and they cannot be included in any ongoing clinical trials.

The EU regulatory framework describes how medicinal products that are not authorized (or only authorized in different indications), can be provided to patients under certain conditions:

Additional conditions are:

  • The medicinal product is intended for the treatment, prevention or diagnosis of a chronically or seriously debilitating disease or a disease which is considered to be life-threatening
  • The disease cannot be treated satisfactorily by an authorized and available medicinal product
  • Based on the scientific data provided there is a realistic possibility for a therapeutic benefit
  • The medicinal product is either the subject of an application for a centralized marketing authorization in accordance with Article 6 of Regulation 726/2004/EC or is undergoing clinical trials in the European Union and/or elsewhere.
  • A demand to obtain authorization for the indication in question needs to be in process
  • The indication has been authorized but the product is not yet commercially available
  • Clinical trials are ongoing in this indication

The National Competent Authority (NCA) reviews the programs from a patient’s safety point and makes sure the supply is ensured until the need persists. The individual NCA decides whether or not to approve the use of medicinal products without a market authorization. Committee for Medicinal Products for Human Use (CHMP) has an advisory role at the request of a Member State.

Application: The procedure, for obtaining authorization for entry or import of medicinal products without a marketing authorization into member states mandates the applicant (physician or manufacturer’s qualified person-QP) to attach all the supporting documents required in the application form and proof of payment of administrative fees to the NCA.

The application should contain (not limited to):

  • The application form
  • Cover letter
  • A program (similar study protocols for clinical trials)
  • Investigator’s Brochure (IB)
  • Pharmaceutical documentation of the drug (IMPD)
  • Labeling proposals for the CUP drug and patient information
  • List of patients participating


Assessment and approval of compassionate program: Applications must meet the definition of compassionate use and have attached all documentation for procedures to start. Management and assessment of the application for the CUP is normally done within 30-60 days, which may vary depending upon the regulations set by the NCA of each member state.


Pharmacovigilance: Safety Reporting of CUP is regulated by Articles 28.1 and 28.2 of Regulation (EC) 726/2004, together with Articles 107, 107a, 107b and 107c of Directive 2001/83 / EC.

The attending physician shall report all suspected adverse reactions to the CUP permit holder in accordance with their instructions. Suspected serious adverse events (SAR) shall be reported by the license holder to the EudraVigilance database.
The permit holder must also annually, unless otherwise specified in the permit, submit periodic safety reports. The reports must be sent to the NCA electronically and the format should be consistent with ICH guidelines “Development Safety Update Report” (DSUR)

The safety information must be mentioned in the Development Safety Update Report (DSUR) in accordance with ICH E2F guideline on DSUR under Point 3.8.4, which is dedicated to “other therapeutic use of investigational drug” and should include clinically important safety information regarding compassionate use programs.
Nevertheless, if permit holder has already submitted the DSUR for the periodic review of the program and no new version is available at the time of the next periodic evaluation, it is not necessary to provide the same DSUR again.

Line listings should include suspected unexpected serious adverse reactions (SUSARs) that occurred worldwide in clinical trials and compassionate use programs with the medicinal product. If there is no new information in this line listing since the last submission for the periodic review, it is not necessary to provide it again. It is requested to mention that in the cover letter.

The last version of the Investigators Brochure (IB) should accompany this package. Nevertheless, if permit holder has already submitted the IB for a clinical trial application to the NCA and no new version is available at the time of the periodic evaluation, it is not necessary to provide the same IB again.

The submission should be accompanied with a cover letter in which it is expected to mention:


The execution and admission of compassionate use programs with ample safety dimensions promote patient rights and motivation.



1. http://ec.europa.eu/health/files/eudralex/vol-1/reg_2004_726/reg_2004_726_en.pdf
2. http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004481.pdf
3. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/09/WC500097061.pdf
4. http://www.basg.gv.at/en/medicines/prior-to-authorisation/compassionate-use/
5. http://www.fagg-afmps.be/sites/default/files/downloads/guidance%20V1.3%2020160104.pdf
6. http://www.ravimiamet.ee/en/compassionate-use-programs-under-estonian-legislation
7. http://www.ravimiamet.ee/en/compassionate-use-programs-under-estonian-legislation
8. http://www.legemiddelverket.no/Godkjenning_og_regelverk/Klinisk-utproving/Compassionte-use/Sider/default.aspx
9. http://www.jazmp.si/zdravila_za_uporabov_humani_medicini/uvozvnos_zdravil_ki_nimajo_dovoljenja_za_promet_in_riz_zdravil/
10. https://www.aemps.gob.es/medicamentosUsoHumano/medSituacionesEspeciales/instruccTramitacion.htm
11. https://lakemedelsverket.se/malgrupp/Foretag/Lakemedel/Compassionate-Use-Program/
12. http://english.cbg-meb.nl/human/for-marketing-authorisation-holders/contents/prior-to-marketing-authorisation-application/compassionate-use-programme

  • A summary of new safety issues that could have an impact on the safety of patients recruited in the program. The impact on the benefit/risk should be discussed.
  • A summary of the current understanding and management of identified and potential risks.
  • An update on the status of the clinical investigation/development program and study results if applicable.

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