Expanded Access Program (Compassionate Use) Frameworks in Europe

For pharmaceutical companies operating in the United States, the U.S. Food and Drug Administration (FDA) regulates the drug approval process and oversees the expanded access pathway for patients with an unmet medical need to access investigational drugs under 21CFR 312 Subpart 1. However, pharma companies seeking access to the European market face dealing with the European Medicines Agency (EMA) for drug approvals, as well as navigating a myriad of country-specific regulations on accessing investigational drugs.

Overall, the experience of working with the EMA is quite different from that of its American counterpart, the FDA. To start with, the terminology is different. Expanded access, as it is known in the US, is called compassionate use in Europe.

When applying for compassionate use in a European country, the key concept to bear in mind is this: EMA can approve pan-European marketing authorizations, but pricing and reimbursement, as well as post- and pre-marketing approvals, are regulated locally, at the level of individual European nations. In addition, a good understanding of the use of potential data collected during these programs is required for pricing negotiations and regulatory agency discussions. Below we discuss some Europe-specific regulations and approaches to compassionate use.

Compassionate use programs in Europe: Article 83 of Regulation (EC) No 726/2004

Compassionate use in Europe 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.

Although there is a pan-European framework for expanded access supervised by EMA, this route is rarely pursued due to various reasons. Over the last 10 years, only six pan-European programs have been approved by EMA, as opposed to hundreds of country-specific programs approved at the level of the member states.

Despite a proposal to put forward new pharmaceutical legislation concerning EMA-wide compassionate use (expanded access), there are, unfortunately, no immediate changes expected anytime soon. Therefore, companies must follow the national framework within each European country. As a result, the wide range of regulations between countries makes navigating the European landscape complex.

Launching several country-specific compassionate use programs (expanded access programs) in Europe simultaneously requires a lot of preparation to craft a sound strategy that can fulfill both the company’s strategic objectives and any regulatory and payor needs down the road.

This article highlights the key considerations and recent trends for France, Germany, Italy, Spain, and the Netherlands within compassionate use programs (expanded access programs). We also discuss the situation in the United Kingdom, even though the country left the EU in 2021.

France: Authorisations Temporaires d’Utilisation (ATU program)

The Authorisations Temporaires d’Utilisation (ATU), or Authorization for Temporary Use, has presented an avenue to obtain early market access since 1994 and is regulated by the French health authority, ANSM. The ATU system is often considered one of the most efficient compassionate use schemes in Europe.

There are two types of ATU programs, the first type is a Nominative ATU, or the “named-patient ATU”, which provides expanded access for patients individually. Treating physicians must request access to a specific drug for a particular patient, and the safety/efficacy of the medication is assessed by ANSM.

The second type is a cohort ATU, which involves a group of patients and is sought by the drug manufacturer for a specific medical condition. Patients under a cohort ATU are treated and monitored following criteria defined in a protocol for therapeutic use (PTU); the PTU specifies requirements for manufacturers to follow and collect specific data during pre-approval access. This pathway requires more clinical data and requirements compared to nominative ATU, while also committing to the market authorization date.

Due to recent efforts to make government spending more efficient, a new scheme will be installed in July 2021. There will be two distinct routes to access investigational drugs: 1) the early access route and 2) the compassionate use route. The former provides early access to drugs in clinical development, which are planned for marketing authorization application. The latter is intended for off-label use of treatments when there is no intent to obtain marketing authorization for this indication.

The inclusion of The French National Authority for Health (HAS) as the decision-maker for the early access route will result in more selective criteria that will reduce the number of treatments eligible for the early access route. This is intended to facilitate access only to highly innovative and promising therapies while keeping real-world data collection in mind.

Germany: Compassionate use

German pharmaceutical legislation allows compassionate use 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). The 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 the program, contact details, and the 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 the Italian Medicines Agency (AIFA) and follows three routes: 1) Compassionate Use, 2) Law 648, and 3) Law 326 (AIFA National Fund). All three pathways apply to drugs that are approved outside of Italy or are still in clinical development.

1. 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).
2. Law 648/1996 provides a pathway for the reimbursement of the investigational drug by the National Health Service. Applications are managed on a cohort basis: after approval, all Italian patients with a given medical condition receive access to an investigational drug.
3. 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.

Both 648 and 326 pathways may be done only with the support of the treating physician and key opinion leaders, and thus not by the pharmaceutical company.

Spain: The Royal Decree 1015/2009

In 2009, the Spanish government issued the Royal Decree 1015/2009, which regulates the 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 for expanded access: 1) individual requests for the named patient program (Leveren op Artsenverklaring), and 2) compassionate use programs. Individual requests are initiated by treating physicians and may be submitted by pharmacists or local wholesalers. These requests are then evaluated by the Dutch Health Inspectorate (IGJ). Cohort-based programs are initiated by pharmaceutical companies and evaluated by the Dutch Medicines Evaluation Board (CBG).

Upon approval, the treating physicians can apply directly to the pharmaceutical companies for the supply of the drug for individual patients or cohorts of patients. In the case of a named patient application, the investigational drug does not need to be registered elsewhere, and there is no strict requirement regarding the phase of development. In exceptional cases, individual requests may get approved for phase 1 clinical trials.

The requirements for compassionate use are clearly defined. To initiate a compassionate use program, the sponsor (a pharmaceutical company) must submit a request to CBG. There are three general rules for application, but on top of that, the pharmaceutical company needs to pursue registration within a specific timeframe. Therefore, these programs are often used late into the clinical development cycle.

United Kingdom: Early Access to Medicines Scheme and Specials

There are two pathways for the compassionate use of medicinal products in the UK. These are the Early Access to Medicines Scheme (EAMS) and specials. For EAMS, a two-step process developed by the MHRA, starts with a company applying for a promising innovative medicine (PIM) Designation, based on 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.

Progressing from an application to a positive scientific opinion usually takes around 75 days. 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 MHRA website, and treating physicians can request the medicine, which the pharmaceutical companies supply free of charge.

The scheme is voluntary and complementary to the routine licensing procedures for medicines and will not replace them. Approvals are issued for a year with the option to renew annually.

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 the 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 to smaller groups of patients.

Conclusion: Compassionate Use Program Frameworks in Europe

With a plethora of approaches and a lack of harmonization across Europe, companies must prepare themselves for a complex path towards the successful execution of a European compassionate use (expanded access) strategy.

There is currently very minimal usage of the EMA framework for expanded access. 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.

No immediate changes in legislation are expected in the near future, despite lobbying efforts and initiatives by large pharmaceutical companies and groups such as the European Organization for Rare Diseases (Eurordis) and the European Federation of Pharmaceutical Industries and Associations (EFPIA), to promote the French ATU system and further amend the EMA guidelines for compassionate use.

Due to the complex patchwork of frameworks, pharmaceutical companies may benefit from partnering with expanded access experts who understand the specifics of European pharmaceutical legislation and regulation and can help create and implement a meaningful, regulatory-driven compassionate use strategy. With COVID-19 impacting the way regulators view the value of health data from patients treated outside of clinical trials, it is key to understand the trends and differences highlighted above.

myTomorrows has successfully developed and run compassionate use programs around the world through our offices in Europe and the United States. Our regulatory and medical teams, who speak 10 languages, have a keen understanding of European medicines agency guidelines, country-specific frameworks, and their respective requirements and complexities. We also have the cultural competence to help connect patients and their physicians with compassionate use programs worldwide.

To learn more about how we can help you navigate the European compassionate use frameworks please visit: http://wordpress.mytomorrows.com/en/biopharma