2. Early access: Compassionate use versus clinical trials

3. Compassionate use

3.5. Compassionate use versus clinical trials

Article 83 (9) of Regulation (EC) No 726/2004 states that Article 83 “shall be without prejudice to Directive 2001/20/EC” (Directive to be replaced by Regulation (EU) 536/2014 on January 22, 2022). From a methodological point of view, clinical trials are practically the only means of obtaining reliable and interpretable efficacy and safety data for a medicine. Although safety data and real-world data (in some programmes, e.g., in France) may be collected or are mandatory during CUPs, such programmes cannot replace or be a substitute for clinical trials for investigational purposes. Compassionate use should therefore not slow down the implementation or continuation of clinical trials intended to provide essential information pertaining to the benefit/risk balance of a medicine. Patients should always be considered for inclusion in clinical trials before being offered compassionate use programmes.

Legal basis:

Article 83 (1) of Regulation (EC) No 726/2004 introduces the legal framework for the provision of compassionate use in the European Union for medicines that are eligible to be authorised via the Centralised Procedure, stating that “by way of exemption from Article 6 of Directive 2001/83/EC (“No medicinal product may be placed on the market of a Member State unless a marketing authorisation has been issued…”), MS may make a medicinal product for human use belonging to the categories referred to in Article 3(1) and 3(2) of Regulation (EC) No 726/2004 available for compassionate use”.

The term “compassionate use” should be used in line with the definition in Article 83 of Regulation (EC) 726/2004 as:

a) a medicine to be made available to “patients with a chronically or seriously debilitating disease, or a life-threatening disease, and who cannot be treated satisfactorily by an authorised medicinal product” in the European Union
and

b) the medicine is either “the subject of an application for a centralised marketing authorisation in accordance with Article 6 of Regulation (EC) No 726/2004 or is undergoing clinical trials” in the European Union or elsewhere
and

c) the compassionate use programme is intended for a “group of patients”. Thus, the term compassionate use is legally restricted only for cohort approaches. However, in some Member states (MS), the term is used for both, cohorts and individual access. The inclusion of cohorts of patients also implies that, in this case, granting access would most likely occur in the later phases of development when enough knowledge on the product is available. In some MS, early access programmes extend beyond when a marketing authorisation is granted but also to access once a decision on price & reimbursement has been made.

As a consequence, Article 83 is not applicable to:

Medicines which are not eligible for the Centralised Procedures,
Compassionate use on a named patient basis (Article 5 of Directive 2001/83/EC),
A medicine, which has already been authorised via the Centralised Procedure, even if the proposed conditions of use and target population are different from those of the marketing authorisation.

However, the existence of a Community authorisation for a medicine does not affect any national legislation relating to compassionate use.

EMA Guideline on Compassionate Use Of Medicinal Products:

Definitions

“Group of patients”: any set (i.e. more than one) of individual patients that would benefit from a treatment for a specific condition. The terms “cohort”, “collective use”, “patient group prescription” or “special treatment programme” used in some MSs, in accordance with national legislations, may correspond with this concept.
“Chronically or seriously debilitating disease or whose disease is considered to be life threatening”: The severity of the disease according to the wording above needs to be justified, based on objective and quantifiable medical or epidemiologic data. Whereas a life-threatening condition is relatively easily recognisable, definitions of what conditions are chronic and seriously debilitating should consider aspects as regards its association with morbidity that has substantial impact on patients’ day-to-day functioning and will progress if left untreated. Typical examples are cancer, HIV/AIDS, neurodegenerative disorders and auto-immune diseases. Chronic or serious debilitation, or fatal outcome should be a prevalent feature of the target disease.
“Patients who cannot be treated satisfactorily”, as used in Article 83 (2), means patients left without treatment options or patients whose disease does not respond or relapses to available treatments, or for whom the treatments are contraindicated or inadequate. Whether patients can be treated satisfactorily or not, will be assessed by the CHMP.
“company” should be understood as meaning “the manufacturer or the applicant” as referred to in Article 83 (4) of Regulation (EC) No 726/2004 and denotes the person responsible for providing the scientific file to the CHMP for assessment of the compassionate use of a medicine under article 83 of the Regulation. This person is either “a marketing authorisation applicant” if a centralised marketing authorisation is being submitted, or “a manufacturer” if the medicinal product concerned is not the subject of such application.
“Patients targeted” is the restricted population (including age groups), as identified by the CHMP, that would benefit from the treatment for compassionate use.
“Conditions for use” are recommendations for health professionals on how to administer and to use the medicine safely and effectively. These recommendations include relevant information on the clinical, pharmacological, pharmaceutical properties of the medicine and on the conditions for patient monitoring.