Ultimate Guide for European Early & Expanded Access Programs
6 March 2025
Pharmablue
Expanded Access is a treatment option that allows the use of an unauthorized medicine (investigational drugs). Under strict conditions, products in development (with ongoing clinical trial) can be made available to groups of eligible patients who have a disease with no satisfactory authorized therapies and who cannot enter clinical trials.They are commonly called: compassionate use program, early access program or expanded access program (sometimes managed access program).The European Medicines Agency (EMA) provides recommendations through the Committee for Medicinal Products for Human Use (CHMP), but these do not create a legal framework. Expanded access programs are coordinated and implemented by each Member States, which set their own rules and procedures.Established by Article 83 of Regulation (EC) No 726/2004, this tool is designed to facilitate and improve patient access to compassionate use programs in Europe (EU); this is achieved by favoring a common approach regarding the conditions of use, the conditions for distribution and the patients targeted for the compassionate use of investigational drugs; and increase transparency between Member States in terms of treatment availability.Expanded access (EAPs) are only put in place if the medicine is expected to help patients with life-threatening, long-lasting, rare diseases or seriously debilitating illnesses, which cannot be treated satisfactorily with any currently authorized medicine. The medicine must be undergoing clinical trials or have entered the marketing-authorization application process and while early studies will generally have been completed, its safety profile and dosage guidelines may not be fully established.National competent authorities can ask the EMA for an opinion on how to administer, distribute and use certain medicines for compassionate use. The CHMP also identifies which patients would benefit, and each Member States should take note of these recommendations when making decisions.Manufacturers and marketing authorization applicants should not contact EMA to request an opinion, but they may wish to inform the Agency of applications underway at national level. National competent authorities will inform the Agency if they are making a product available to a group of patients for compassionate use.Compassionate use should not be confused with 'named-patient basis' treatments (named patient programs), which see doctors obtain medicines directly from manufacturers before authorization for individual patient. This is done on an individual basis under the direct responsibility of the doctor, and the Agency does not need to be informed. In general, medicines that are not yet authorized are first made available through clinical trials and patients should always be considered for inclusion in trials before being offered compassionate use programs.
From 1st July 2021 the access to new medicines scheme in France became two simplified but linking processes; Early Access Authorisation (“accès précoce”) and Compassionate Access Authorisation (“accès compassionnel”).The Early Access Authorization (EAA) route is for drugs that are in the process of being developed and are to be put on the market for a given indication. The EAA is reserved for unapproved drugs for which the holder has submitted or undertakes to apply for a marketing authorization or an application for reimbursement. However, unlike the previous ATU pathway, early access will only be available for medicines that are presumed to be innovative. EAA will be granted by Haute Autorité de Santé (HAS) and not by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM). The decision of the HAS will result in both the granting of early access and derogatory reimbursement by the health insurance system.The Compassionate Access Authorisation (CAA) route is for off-label drugs that are not being developed for a given indication in France. It replaces the previous nominative ATU pathway, and temporary recommendations for use. The CAA route is intended for drugs that are not necessarily innovative, that are not necessarily intended to obtain marketing authorisation in the indication concerned, but that respond satisfactorily to a therapeutic need. Only drugs that are not subject to research involving the human person for commercial purposes are eligible for compassionate access. It can also be used at a very early stage of clinical development for a patient or patients who are not eligible for a clinical study.Early access programs for innovative treatments are now overseen by HAS, the French Health Technology Assessment (HTA) body, in association with the French national agency for health product safety (ANSM). For pre-MA early access, ANSM is still involved for the assessment of product safety and efficacy, whereas HAS is the only decision-maker for post-MA early access. The ANSM oversees both compassionate access programs. The AAC is requested by the prescribing healthcare professional (“HCP”), and the CPC is requested by the Ministry of Health or set up on the ANSM's own initiative.Learn more about French Early Access Programs 
German pharmaceutical legislation allows early access to investigational drugs via Arzneimittel-Härtefall-Verordnung (AMHV), or Ordinance on Medicinal Products for Compassionate Use, and enables treatment to a group of patients on a cohort basis.The regulation requires the competent federal authority to be notified of the proposed compassionate-use program. For small molecules, this is Germany's Federal Institute for Drugs and Medical Devices (BfArM), and for biologics, it is the Paul Erlich Institute (PEI). The authority provides feedback following an assessment of the application within two weeks (60 days for complex cases). Timeline for the official approval ranges from one to three months. Approval is valid for one year and may be renewed.Information about compassionate use programs in Germany is made publicly available on the health authority websites — BfArM for small molecules and PEI for biologics. This includes the name of program, contact details, and name of the sponsor. This helps increase the general awareness amongst treating physicians and hospitals who may request the investigational drug.
The Italian compassionate use program framework is managed by Italian Medicines Agency Agenzia Italiana del Farmaco (AIFA) and companies follow one of the following routes: 1) Compassionate Use, 2) Law 648/1996, 3) Law 326 (AIFA National Fund) or 4) Non repetitive use for advanced therapies. All four pathways are applicable to drugs that are approved outside of Italy or are still in clinical development.Compassionate use (single patient or group) involves direct delivery of the free-of-charge medicine by the manufacturer when there is no marketing approved drug available. The shipment is dependent on the Ethical committee approval, AIFA notification (in case of no objection) and NOS (Nulla Osta, a request for importation). The medicinal product in question must be the subject of an application for marketing authorization or be undergoing clinical trials.Law 648/1996 provides a pathway for the reimbursement of the investigational drug by the National Health Service (SSN), subject to the opinion of the Technical-Scientific Commission (CTS) of AIFA.The route can be utilized when there is no valid therapeutic alternative, for innovative medicines authorized in other countries, but not in Italy, and for medicinal products not yet authorized, but undergoing clinical trials, for medicinal products to be used for a therapeutic indication other than that authorized In all these cases it is necessary to have completed studies, at least phase II, that demonstrate adequate efficacy with an acceptable risk profile to support the requested indication.AIFA National Fund (Law 326) provides access on a named-patient basis. Through this law AIFA also established a specific fund (Fondo AIFA 5%) for the reimbursement of orphan and lifesaving drugs awaiting market entry. The Fund consists of 50% of the contribution that pharmaceutical companies pay to AIFA on an annual basis. This contribution corresponds to 5% of the annual expenses for promotional activities that pharmaceutical companies allocate to doctors. Both 648 and 326 pathways that may be done only with the support of the treating physician and key opinion leaders, and thus not by the pharmaceutical company.Non-repetitive use of advanced therapies is the scheme whereby access to advanced therapy medicines not yet authorized or not subject to specific clinical trials in progress in Italy is possible subject to AIFA authorization for production and use, in the absence of a valid therapeutic alternative, in cases of urgency and emergency that place the patient in danger of life or serious damage to health.These medicines must meet the definition of "preparation on a non-repetitive basis" understood as the non-routine preparation carried out, even for a cycle of administrations, in accordance with specific quality requirements.
In 2009, the Spanish government issued the Royal Decree 1015/2009, which regulates availability of drugs in special situations, including compassionate use. Specifically, access to compassionate use investigational drugs in clinical development can be granted to patients who are not eligible for clinical trials. Both named patient and cohort routes are available.There is a special route for drugs at the advanced stages of clinical development including those which have completed clinical trials and been submitted for marketing authorization. The Spanish Agency of Medicines and Medical Products (AEMPS) may allow the temporary use of a product, as long as the use of the product by a significant group of patients is foreseen.
In the Netherlands, there are two distinct routes where a medicinal product without a marketing authorisation may be prescribed:
There are two pathways for compassionate use of medicinal products in UK. These are Early Access to Medicines Scheme (EAMS) and ‘specials’. For EAMS, a scientific opinion will be provided after a two-step evaluation process; a company applying for a Promising Innovative Medicine (PIM) Designation, and second the early access to medicines scientific opinions. These will be based on the available clinical and non-clinical data to assess the benefit-risk balance.A successful PIM Designation gives an early indication that a product is suitable for the second step, a request for a scientific opinion. The EAMS is primarily aimed at drugs that have completed Phase 3 trials but may also be applied to drugs that have completed Phase 2 trials in unique circumstances. A positive scientific opinion requires a positive risk-benefit ratio as well as a safety assessment. Once the EAMS approval is granted, it will be published on the Medicines & Healthcare product Regulatory Agency (MHRA) website and treating physicians can request the medicine, which the pharmaceutical companies supply free-of-charge.In principle, an EAMS program may be running until a marketing authorization is granted. For patients who are already receiving the investigational drug, companies are required to ensure access until reimbursement coverage is finalized. This is a potential third step.There is a possibility to use the real-world data generated from EAMS for the technology appraisals of National Institute for Health and Care Excellence (NICE). There is another option with limited data collection possibilities under the “Specials” scheme. This is generally applicable for smaller groups of patients.
Sometimes called “compassionate use”, expanded access is a potential pathway for a patient with an immediately life-threatening condition or serious disease or condition to gain access to an investigational medical product (drug, biologic, or medical device) for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available.FDA's Expanded access program may be appropriate when all the following apply:
Expanded access programs in Europe: Article 83 of Regulation (EC) No 726/2004
Compassionate use in EU is established by Article 83 of Regulation (EC) No 726/2004. These programs are coordinated and implemented by the member states, which set their own rules and procedures.Companies must follow the national framework within each European country and as such, the wide range of regulations between countries makes navigating the European landscape complex.Launching several country-specific compassionate use programs in Europe simultaneously requires a lot of preparation to shape a comprehensive strategy that can fulfil both the company's strategic objectives and the national regulatory requirements.This article highlights the key considerations, local regulations and recent trends for France, Germany, Italy, Spain, and the Netherlands within compassionate use programs. Also discussed is the situation in the United Kingdom, even though the country left the EU in 2021. The methodology for the US and FDA is also briefly mentioned.France: Early Access Authorization (previously ATU)
From 1st July 2021 the access to new medicines scheme in France became two simplified but linking processes; Early Access Authorisation (“accès précoce”) and Compassionate Access Authorisation (“accès compassionnel”).The Early Access Authorization (EAA) route is for drugs that are in the process of being developed and are to be put on the market for a given indication. The EAA is reserved for unapproved drugs for which the holder has submitted or undertakes to apply for a marketing authorization or an application for reimbursement. However, unlike the previous ATU pathway, early access will only be available for medicines that are presumed to be innovative. EAA will be granted by Haute Autorité de Santé (HAS) and not by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM). The decision of the HAS will result in both the granting of early access and derogatory reimbursement by the health insurance system.The Compassionate Access Authorisation (CAA) route is for off-label drugs that are not being developed for a given indication in France. It replaces the previous nominative ATU pathway, and temporary recommendations for use. The CAA route is intended for drugs that are not necessarily innovative, that are not necessarily intended to obtain marketing authorisation in the indication concerned, but that respond satisfactorily to a therapeutic need. Only drugs that are not subject to research involving the human person for commercial purposes are eligible for compassionate access. It can also be used at a very early stage of clinical development for a patient or patients who are not eligible for a clinical study.Early access programs for innovative treatments are now overseen by HAS, the French Health Technology Assessment (HTA) body, in association with the French national agency for health product safety (ANSM). For pre-MA early access, ANSM is still involved for the assessment of product safety and efficacy, whereas HAS is the only decision-maker for post-MA early access. The ANSM oversees both compassionate access programs. The AAC is requested by the prescribing healthcare professional (“HCP”), and the CPC is requested by the Ministry of Health or set up on the ANSM's own initiative.Learn more about French Early Access Programs Germany: Compassionate use
German pharmaceutical legislation allows early access to investigational drugs via Arzneimittel-Härtefall-Verordnung (AMHV), or Ordinance on Medicinal Products for Compassionate Use, and enables treatment to a group of patients on a cohort basis.The regulation requires the competent federal authority to be notified of the proposed compassionate-use program. For small molecules, this is Germany's Federal Institute for Drugs and Medical Devices (BfArM), and for biologics, it is the Paul Erlich Institute (PEI). The authority provides feedback following an assessment of the application within two weeks (60 days for complex cases). Timeline for the official approval ranges from one to three months. Approval is valid for one year and may be renewed.Information about compassionate use programs in Germany is made publicly available on the health authority websites — BfArM for small molecules and PEI for biologics. This includes the name of program, contact details, and name of the sponsor. This helps increase the general awareness amongst treating physicians and hospitals who may request the investigational drug.Italy: Compassionate use, law 648 and law 326
The Italian compassionate use program framework is managed by Italian Medicines Agency Agenzia Italiana del Farmaco (AIFA) and companies follow one of the following routes: 1) Compassionate Use, 2) Law 648/1996, 3) Law 326 (AIFA National Fund) or 4) Non repetitive use for advanced therapies. All four pathways are applicable to drugs that are approved outside of Italy or are still in clinical development.Compassionate use (single patient or group) involves direct delivery of the free-of-charge medicine by the manufacturer when there is no marketing approved drug available. The shipment is dependent on the Ethical committee approval, AIFA notification (in case of no objection) and NOS (Nulla Osta, a request for importation). The medicinal product in question must be the subject of an application for marketing authorization or be undergoing clinical trials.Law 648/1996 provides a pathway for the reimbursement of the investigational drug by the National Health Service (SSN), subject to the opinion of the Technical-Scientific Commission (CTS) of AIFA.The route can be utilized when there is no valid therapeutic alternative, for innovative medicines authorized in other countries, but not in Italy, and for medicinal products not yet authorized, but undergoing clinical trials, for medicinal products to be used for a therapeutic indication other than that authorized In all these cases it is necessary to have completed studies, at least phase II, that demonstrate adequate efficacy with an acceptable risk profile to support the requested indication.AIFA National Fund (Law 326) provides access on a named-patient basis. Through this law AIFA also established a specific fund (Fondo AIFA 5%) for the reimbursement of orphan and lifesaving drugs awaiting market entry. The Fund consists of 50% of the contribution that pharmaceutical companies pay to AIFA on an annual basis. This contribution corresponds to 5% of the annual expenses for promotional activities that pharmaceutical companies allocate to doctors. Both 648 and 326 pathways that may be done only with the support of the treating physician and key opinion leaders, and thus not by the pharmaceutical company.Non-repetitive use of advanced therapies is the scheme whereby access to advanced therapy medicines not yet authorized or not subject to specific clinical trials in progress in Italy is possible subject to AIFA authorization for production and use, in the absence of a valid therapeutic alternative, in cases of urgency and emergency that place the patient in danger of life or serious damage to health.These medicines must meet the definition of "preparation on a non-repetitive basis" understood as the non-routine preparation carried out, even for a cycle of administrations, in accordance with specific quality requirements.Spain: The Royal Decree 1015/2009
In 2009, the Spanish government issued the Royal Decree 1015/2009, which regulates availability of drugs in special situations, including compassionate use. Specifically, access to compassionate use investigational drugs in clinical development can be granted to patients who are not eligible for clinical trials. Both named patient and cohort routes are available.There is a special route for drugs at the advanced stages of clinical development including those which have completed clinical trials and been submitted for marketing authorization. The Spanish Agency of Medicines and Medical Products (AEMPS) may allow the temporary use of a product, as long as the use of the product by a significant group of patients is foreseen.Netherlands: Named Patient Program and Compassionate Use
In the Netherlands, there are two distinct routes where a medicinal product without a marketing authorisation may be prescribed:- individual requests for the named patient program (Leveren op Artsenverklaring) falls under the competence of the Health and Youth Care Inspectorate (IGJ),
- compassionate use programs : Individual requests are initiated by treating physicians and may be submitted by pharmacists or local wholesalers. Cohort-based programs are initiated by pharmaceutical companies and evaluated by the Dutch Medicines Evaluation Board (MEB).
United Kingdom (UK): Early Access to Medicines Scheme and Specials
There are two pathways for compassionate use of medicinal products in UK. These are Early Access to Medicines Scheme (EAMS) and ‘specials’. For EAMS, a scientific opinion will be provided after a two-step evaluation process; a company applying for a Promising Innovative Medicine (PIM) Designation, and second the early access to medicines scientific opinions. These will be based on the available clinical and non-clinical data to assess the benefit-risk balance.A successful PIM Designation gives an early indication that a product is suitable for the second step, a request for a scientific opinion. The EAMS is primarily aimed at drugs that have completed Phase 3 trials but may also be applied to drugs that have completed Phase 2 trials in unique circumstances. A positive scientific opinion requires a positive risk-benefit ratio as well as a safety assessment. Once the EAMS approval is granted, it will be published on the Medicines & Healthcare product Regulatory Agency (MHRA) website and treating physicians can request the medicine, which the pharmaceutical companies supply free-of-charge.In principle, an EAMS program may be running until a marketing authorization is granted. For patients who are already receiving the investigational drug, companies are required to ensure access until reimbursement coverage is finalized. This is a potential third step.There is a possibility to use the real-world data generated from EAMS for the technology appraisals of National Institute for Health and Care Excellence (NICE). There is another option with limited data collection possibilities under the “Specials” scheme. This is generally applicable for smaller groups of patients.United States of America: Expanded Access Process
Sometimes called “compassionate use”, expanded access is a potential pathway for a patient with an immediately life-threatening condition or serious disease or condition to gain access to an investigational medical product (drug, biologic, or medical device) for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available.FDA's Expanded access program may be appropriate when all the following apply:- Patient has a serious disease or condition, or an immediately life threatening disease
- There is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition (no treatment options)
- Patient enrolment in a clinical trial is not possible.
- Potential patient benefit justifies the potential risks of treatment.
Conclusion: Compassionate Use Program Frameworks in Europe
With a plethora of approaches and a lack of harmonization across Europe, companies need to prepare for a complex path towards the successful execution of a European compassionate use (expanded access) strategy.Patient groups and some stakeholders have suggested changes that aim to harmonize guidelines, creating a more level playing field for European compassionate use. Establishing a framework for cohort programs across the member states is critical to allow full operation of Article 83, a pan-European compassionate use framework and favor access to investigational drugs.Due to the complexity of the different frameworks, pharmaceutical companies may benefit from partnering with expanded access experts who understand the specifics of the European pharmaceutical legislation and regulation and can help create and implement a meaningful, regulatory-driven compassionate use strategy. BlueReg has extensive experience with Compassionate Use procedures for medicinal products in Europe, to produce high quality submissions using our multidisciplinary regulatory affairs, scientific writing, and publishing team, and to manage the whole process through to a successful conclusion.As every project and client situation is unique we provide a tailored package of services to meet the specific needs of the application. Our valuable expertise can assist you by anticipating aspects which could be problematic for the different submissions and procedures, so that potential delays are mitigated against.BlueReg expertise and high quality submissions will ensure smooth validation and timely progress and smooth running of the procedures. The complexities of expanded access requests and timelines will be managed, resulting in a close collaboration and development of a strong path to submission and throughout the procedure.List of Abbreviations
AEMPS: Agencia Española de Medicamentos y Productos Sanitarios (Spanish): Agency of Medicines and Medical ProductsAIFA: Agenzia Italiana del Farmaco (Italian): Italian Medicines AgencyAMHV: Arzneimittel-Härtefall-Verordnung (German) Compassionate useANSM: Agence Nationale de Sécurité du Médicament et des Produits de Santé (French): National Security Agency of Medicines and Health ProductsATU: Authorisations Temporaires d’Utilisation (French) Temporary Authorisation of UseBfArM: Bundesinstitut für Arzneimittel und Medizinprodukte (German): Federal Institute for Drugs and Medical DevicesCAA: Compassionate Access AuthorisationCHMP: Committee for Medicinal Products for Human UseCTS: Comitato Tecnico Scientifico (Italian): Technical-Scientific CommissionCUP: Compassionate Use ProgramEAA: Early Access AuthorisationEAMS: Early Access to Medicines SchemeEMA: European Medicines AgencyFDA: Food and Drug AdministrationHAS: Haute Autorité de Santé (French) French Health AuthorityHCP: Healthcare ProfessionalIGJ: Inspectie Gezondheidszorg en Jeugd (Dutch): Health and Youth Care InspectorateMEB: Medicines Evaluation BoardMHRA: Medicines & Healthcare product Regulatory AgencyNICE: National Institute for Health and Care ExcellenceNOS: Nulla Osta - request for importationPEI: Paul Erlich InstitutePIM: Promising Innovative MedicineSSN: Servizio Sanitario Nazionale (Italian): National Health ServiceBibliographic References
Regulation (EC) No 726/2004Regulation (EC) No 726/2004Article 83 of Regulation (EC) No 726/2004Article 83 of Regulation (EC) No 726/2004French HAS Guidance for Authorisation for early access to medicinal products:https://www.has-sante.fr/upload/docs/application/pdf/2021-08/authorisation_for_early_access_to_medicinal_products_has_assessment_doctrine.pdfFrance ANSM Compassionate Use program guidance:https://ansm.sante.fr/actualites/reforme-de-lacces-derogatoire-aux-medicaments-renforcer-lacces-aux-traitements-innovants-pour-les-patients-en-impasse-therapeutiqueFrance Decree No. 2021-869 of June 30, 2021, relating to authorizations for early and compassionate access to certain medicinal products:https://www.legifrance.gouv.fr/jorf/id/JORFTEXT000043728288Germany Ordinance on the placing on the market of unauthorised medicinal products for compassionate use:https://www.bfarm.de/SharedDocs/Downloads/EN/Drugs/licensing/clinicalTrials/compUse/AMHV_en.pdf;jsessionid=C3FB82AE2CA5162FDCADE89268763629.internet281?__blob=publicationFileGermany Guideline for Notification of a Compassionate Use Programme:https://www.bfarm.de/SharedDocs/Downloads/EN/Drugs/licensing/clinicalTrials/compUse/Guideline_for_Notification.pdf?__blob=publicationFileItaly link to compassionate use programs:https://www.aifa.gov.it/en/accesso-precoce-uso-off-label#:~:text=Compassionate%20use%20involves%20direct%20and,clinical%20center%20supports%20the%20costs.Italy Law 648/1996:https://www.normattiva.it/atto/caricaDettaglioAtto?atto.dataPubblicazioneGazzetta=1996-12-23&atto.codiceRedazionale=096G0680&atto.articolo.numero=0&atto.articolo.sottoArticolo=1&atto.articolo.sottoArticolo1=10&qId=f404080a-c37b-4647-b397-d9720be7d04d&tabID=0.8582377604842311&title=lbl.dettaglioAttoItaly Law 326/2003https://www.normattiva.it/uri-res/N2Ls?urn:nir:stato:legge:1996-12-23;648!vig=Italy Law 79/2014https://www.normattiva.it/uri-res/N2Ls?urn:nir:stato:legge:2014-05-16;79!vig=Italy Law 94/98 art.3, paragraph 2 – ex Law Di Bellahttps://www.normattiva.it/atto/caricaDettaglioAtto?atto.dataPubblicazioneGazzetta=2003-11-25&atto.codiceRedazionale=003G0358&atto.articolo.numero=0&atto.articolo.sottoArticolo=1&atto.articolo.sottoArticolo1=10&qId=fee317e4-3c40-4165-9c09-9605dbd50fc9&tabID=0.8582377604842311&title=lbl.dettaglioAttoSpanish Royal Decree 1015/2009https://www.boe.es/eli/es/rd/2009/06/19/1015Spain Compassionate use of IMPshttps://www.aemps.gob.es/en/medicamentosUsoHumano/ofi-innova-conocimiento-med/docs/folleto-oficina-apoyo-innova-conocimiento-med.pdf#page=19Netherlands overview of the compassionate use program:https://english.cbg-meb.nl/topics/mah-compassionate-use-programmeDanish Medicines Act article 40, section 3 (f):https://wetten.overheid.nl/BWBR0021505/2022-01-31#Hoofdstuk4UK Guidance to the early access scheme:https://www.gov.uk/guidance/apply-for-the-early-access-to-medicines-scheme-eamsUK Guidance on applying for Promising Innovative Medicine:https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/375327/PIM_designation_guidance.pdfUK Guidance on applying for Early Access to Medicines Scheme (EAMS)https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/375408/guidance_on_applying_for_a_scientific_opinion__including_the_pre-submission_meeting.pdfUS Guidance on Expanded Access:https://www.fda.gov/news-events/public-health-focus/expanded-accessDid you like this article? Share on social networks:
