Eurordis - Rare Disease Europe

This section explains the role of Compassionate Use Programmes: who are they for, and the conditions for accessing a medicine under compassionate use.

• What is a Compassionate Use Programme?

  

  A medicinal product given on a compassionate basis is first and foremost a treatment. It is a medicinal product not yet fully evaluated, prescribed to treat people with no other therapeutic options.

  Running a Compassionate Use Programme (CUP) consists of making a medicinal product available for compassionate reasons to a group of patients (or sometimes individual patients on a case-by-case basis) with a chronically or seriously debilitating disease or whose disease is considered to be life-threatening, and who cannot be treated satisfactorily by an authorised medicinal product¹.

  • The demand is made by the doctor to the pharmaceutical company that is developing the product, and to national authorities who need to accept the compassionate use.
  • The European legislation (for medicines authorised via the centralised procedure) states that the medicinal product concerned must either be the subject of an application for a marketing authorisation or must be undergoing clinical trials²: in other terms, it is not requested that the medicine in question be already authorised somewhere in the world. If the product has been or is currently being  tested in a clinical trial for the disease you have, then your doctor can request a compassionate use authorisation.
  • Most EU Member States have a special scheme to dispense a medicine on a compassionate basis. Many other European countries have similar processes. These processes are more or less complex and time consuming.

  

  Extract of the EMA Q&A document on compassionate use

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  ¹REGULATION (EC) Nº 726/2004 Title V, article 83.2
   ²Ibidem, article 83.2

• What a Compassionate Use Programme isn’t

  A Compassionate Use Programme is not an experiment or a clinical trial. It is intended  to treat the person

  By definition, a compassionate use is a treatment, yet not fully evaluated, for patients who do not have other options. Other circumstances when a medicine is given should not be confused with compassionate use.

  • Neither a clinical trial nor an experiment: in no case can the medicinal product given on a compassionate use be a placebo, nor a treatment or combination of treatments that the patient has had before, lacking efficacy or poorly tolerated. Even though it is not completely certain whether the treatment the patient receives on a compassionate use basis is useful, if there is no other option and there is the slightest chance that the product will be effective, the patient should benefit from it.
  • A substitute for product development: a Compassionate Use Programme cannot replace clinical trials. Again, a CUP is not an experiment. It cannot conclude whether the product is safe and effective on a group of patients. A CUP can be organised in parallel to clinical trials, but it can only be authorised if clinical trials are already in progress, and recruitment in a CUP should not be an obstacle for the recruitment of patients in clinical trials (for example if patients prefer to receive the medicine on a compassionate basis and not take the risk of receiving a placebo).
  • An off-label use: a medicine used off-label is, by definition, a medicine used in a different way than the authorised one. For example, a medicine can be given for a different disease, or at a different dose than indicated on the label. Thus off-label use only applies to medicines that are already authorised. Compassionate use only applies to medicines that are not yet authorised for any condition.
  • A financial aid programme or a humanitarian programme: financial aid programmes (also called humanitarian programmes) are for medicines that are authorised and placed on the market, but at a cost that the patient cannot afford (for example medicines that are not 100% reimbursed or covered by the health care system). In some cases, the marketing authorisation holder creates a financial assistance programme for patients who do not have enough revenue. This is not compassionate use; it is a marketing tool to open access to a larger group of patients.
  • A way to place a product on the market prior to marketing authorisation: some companies can be tempted to provide a medicine they develop to a large group of patients, prior to its authorisation. This is to make sure the medicine is already largely used, at an early stage, to “capture” a large market share and make it more complex for competitor products to make their own market share. This is why a CUP needs to be properly authorised and monitored by national competent authorities. A CUP cannot be used for investigational purposes or commercial pre-authorisation activities. Promotion of the medicinal product in question, or the CUP itself, is not permitted.
  • A “favour” or a “gift” to clinicians who achieve their objectives in recruiting for clinical trials: completing enrolment of patients in a clinical trial is a key factor of success for a clinical trial, and thus for the product development and evaluation. Clinicians who are also investigators of clinical trials are precious to the trial sponsor, e.g. a pharmaceutical company, as they can ask their own patients to participate in a clinical trial. In a very competitive world, a company can be tempted to gain the favours of clinicians by offering them access to the medicine on a compassionate basis if they manage to enrol high numbers of patients. This practice is not official but does exist, and is not recommended as it creates inequity in accessing the medicine on a compassionate basis.
• Can anyone access medicines on a compassionate basis?

  Before a medicine is authorised and placed on the market, it must be duly evaluated to learn more about its efficacy and safety. The first priority is to conduct clinical trials that will respond to these questions. Only patients who cannot be part of a clinical trial are eligible for a compassionate use.

  Before a medicine is authorised and placed on the market, it must be duly evaluated to learn more about its efficacy and safety. The first priority is to conduct clinical trials that will respond to these questions. Only patients who cannot be part of a clinical trial are eligible for compassionate use.

  Under compassionate use, the treatment that is given to the patient is a medicine, not a placebo. The patient receiving it is expected to benefit from it. In a clinical trial, the medicinal product is tested against a comparative treatment which may be a placebo. People enrolled in clinical trials correspond to specific biomedical criteria, and people who should not be enrolled in a clinical trial are also defined (so-called exclusion criteria).

  A common example involves patients who are too severely ill, with multi-organ impairment, or severe liver or renal deficiency. They are usually excluded from clinical trials. However they can receive the treatment on a compassionate basis. This ensures the optimum care for the more severely ill: they cannot take the risk of receiving a placebo or a treatment that would not help them. Even though it has not been determined whether the treatment patients receive on a compassionate use basis is useful, if there is the slightest chance the treatment may work, patients should benefit from it.

  Regulators, when authorising a compassionate use, can do so on a named patient basis (the doctor makes a request for a given patient), or for a group of patients (a so-called cohort).

  On a named patient basis, authorisation will be on a case-by-case basis. For a cohort compassionate use, regulators will define the patient population eligible for the programme. For example, in a disease for which only two medicines exist, regulators may decide the Compassionate Use Programme is only open for patients who have already been treated with both medicines with no response, or who cannot tolerate either product.

• Are there unlimited supplies of a medicine that can be used for compassionate use?

  A company developing a new product first produces necessary quantities of the product for its clinical trials (a few hundred to a few thousands of patients, pilot production). When the product is authorised, the company needs to manufacture enough product to satisfy the demand in a larger population (commercial batches). Between these two stages, the size of a Compassionate Use Programme may vary.

  A company developing a new treatment first produces necessary quantities of the product for its clinical trials (a few hundred to a few thousands of patients, pilot production). When the product is authorised, the company needs to manufacture enough product to satisfy the demand in a larger population (commercial batches). Between these two stages, the size of a Compassionate Use Programme may vary.

  The manufacturing capacities for a medicinal product vary with time. When the product is first tested in the laboratory or in animals, only small quantities are needed (usually a few grammes to a few kilogrammes).

  When the product is then tested in humans, the first clinical trials are limited in size (typically, a few dozens to a few hundred patients). Thus, quantities of product are still limited. When early results are obtained, the company analyses them and may decide the chances that the medicinal product is safe and effective are high; therefore it elects to  launch larger confirmatory trials and prepare to submit a marketing authorisation application. This is called the Go/No go decision. At this point, the company needs to produce larger quantities of the medicine, as confirmatory clinical trials may enrol thousands of patients.

  As a consequence, there is a phase where larger quantities of product becomes available. Before this, the company may be very limited if the demand for compassionate use is high. After this, production can increase and when authorities grant authorisation for a compassionate use, the company should be able to satisfy the demand. But there is a period beginning with the Go/No go decision where it is not certain all demands can be satisfied, as it takes time to build a manufacturing site and to validate the production quality.

  When the demand is too high In January 1996, people living with HIV knew a new class of anti-HIV medicines was more effective than existing treatments, and by combining different medicines together, survival could then increase, for the first time since the beginning of the epidemic. Patients’ representatives worldwide immediately asked for a Compassionate Use Programme , and tens of thousands of patients expected to receive the so-called Highly Active Anti-Retroviral Treatment in a few weeks. But the manufacturers could not satisfy the demand immediately: in France, for example, there was only enough ritonavir to treat 100 of 18,000 potential patients. It became clear that during the three to six months it would take for the product to arrive in sufficient quantities, many patients would die. The National AIDS Council’s advice was to select patients via a random process. “Since patients will be selected randomly by computer, there will be no conscious or unconscious emotional preference or pressure. Drawing lots will relieve doctors of the responsibility of choice and preserve patients’ trust in their attending physicians. Lots will be drawn each time supplementary drug doses are made available, with the aim of including all eligible patients.”

   

• Main characteristics of CUPs in different EU Member States

  See the main characteristics of Compassionate Use Programmes in 7 different EU Member states

  Timing

  Typically, Compassionate Use Programmes (CUPs) are initiated late in the developmental process of medicinal products, to ‘bridge’ the time between the end of phase III development, regulatory approval and product launch (which may take 1–2 years). However a CUP can start earlier. There are cases of CUP starting at the end of phase I trials.

  Cost: for free, or not for free?

  Some CUPs are free and some have costs. In some countries, the company is prohibited from charging for a medicinal product in a compassionate use setting (on the contrary, the company needs to pay for running the programme, for obtaining approval from ethics committees, etc,. and consequently decides not to propose a CUP). In other countries, it is left at the discretion of the company whether or not to charge.

  Often, when the company does not charge, there can be criticism that the CUP is an attempt to conquer a large market share before obtaining a marketing authorisation, and the company can be accused of using compassionate use as a marketing tactic. On the other hand, when a company does charge,  it is criticised for putting a price on compassion.

  Duration

  Typically a CUP is authorised for one year and can be renewed. But a marketing authorisation application needs to be prepared and submitted sooner or later, as a CUP cannot last for ever. If regulatory authorities are not provided adequate information on the clinical trials and intention to submit a marketing authorisation application, they may reject the demand for a CUP.

  Scope

  To summarise, medicinal products eligible for a CUP aim at treating, preventing or diagnosing a serious or rare disease when there is an unmet medical need (no therapeutic alternative) for some or all patients.

  Efficacy Data and claims on benefit

  There is no consensus on efficacy/benefits data as a prerequisite to authorise a compassionate use. As a CUP is run in parallel to clinical trials, and in particular phase III trials (which aim at demonstrating efficacy), not all data are available when deciding on a CUP. Therefore benefit for the group of patients needs to be plausible, based on earlier trials.

  Consent form

  When receiving a treatment via compassionate use, the patient often needs to read and sign a consent form that explains what is known and not known about the medicine, and which highlights the need to report any responses, both good or bad, that occur when taking the medicine. Responsibility for the prescription remains the healthcare professional’s responsibility.

  Type of CUP, procedure and review times for 7 Member States

   

  Country	CUP type	Regulatory process	Review times
  France	Cohort or named patient	Well defined	Named patient: 24-48h Cohort: 2-4 months
  Denmark	Cohort or named patient	Well defined	Within 3-4 weeks
  Germany	Cohort or named patient	Under change	2-3 months
  Italy	Cohort or named patient	Well defined but complex	Named patient: 1 month Cohort: not defined
  The Netherlands	Cohort or named patient	Well defined	Named patient: 4 weeks Cohort: not defined
  Spain	Cohort or named patient	Need local expertise	Very variable, case by case
  United Kingdom	Named patient	Well defined	4 weeks after receipt of notification of intent to import

  Adapted from Helene Sou, Pharm Med 2010; 24(4):1-7

  How to import, who pays, legal basis for 7 Member States

  Country	Import authorisation	Payer	Legal basis
  France	Nominative ATU authorisation taken as import permit Cohort ATU requires import permit	Hospital or national insurance. 100% covered	Code de la Santé Publique (Art. L.5121-12 and R.5121-68 to 76)
  Denmark	Imported by pharmacy	Hospital/patient co-payment. Reimbursement as for approved products	Lov om laegemidler no. 1180 as amended 17 June 2008
  Germany	Import permit required	Company	14 and 15 ArzneimittelGesetz Novelle
  Italy	Ethics committee written approval required	Hospital or national insurance	Decreto 8 maggio 2003; Legge 648/1996
  The Netherlands	Import permit required	Patient/company Usually not reimbursed	Art. 40.3c Geneesmiddelenwet van 25 Juni 2007. Circular 2002-06-IGZ
  Spain	Need to apply for importation to the national agency	Company	Real Decreto 1015/2009; Ley 29/2006 (Art. 24) and Real Decreto 223/2004 (Art. 28)
  United Kingdom	Import permit required	Reimbursement case by case, price can be set freely	SI 1994 no. 3144

  Adapted from Helene Sou, Pharm Med 2010; 24(4):1-7

• Compassionate Use Glossary

  Terms you may need to understand compassionate use better

  • ATC
  • Biotechnology
  • Centralised Procedure
  • Clinical Trials
  • Committee for Medicinal Products for Human Use – CHMP
  • Compassionate Use
  • Consumer
  • Healthcare professional
  • Informed consent
  • Name of the medicinal product
  • Ultra-compassionate use

  ATC

  Anatomic, therapeutic, chemical. International system for classification of medicines.

  Biotechnology

  Biotechnology is used in two ways: first it describes the traditional biological methods which living organisms use to produce or modify chemical compounds (e.g. antibiotics and vitamins). Secondly, it includes gene technology, which is based on the ability to isolate, replicate, cut and recombine DNA and to transfer DNA from one cell to another. Organisms whose genetic material has been altered in a way that does not occur naturally are called genetically modified organisms (GMOs).

  Centralised Procedure

  Since 1995, medicinal products can be evaluated via the Centralised procedure. Medicinal products that have been approved via this procedure are issued a marketing authorisation that is valid throughout the EU. This marketing authorisation is granted by the European Commission. The use of this procedure is compulsory for medicinal products derived from a biotechnological process, for anticancer treatments, or for medicines to treat diabetes, AIDS/HIV infection, rare diseases, immune diseases, and neurological diseases. For other innovative products, such as products with a new active substance, a company can choose whether to follow this procedure or the Mutual recognition procedure. In the case of the Centralised procedure, a dossier must be submitted to the European Agency for the Evaluation of Medicinal Products (EMA) in London.

  Clinical Trials

  A clinical trial is a research study conducted in human participants to evaluate the safety and efficacy of a medicine to improve patient’s health. Clinical trials conducted on new medicines and sponsored by pharmaceutical companies can only be started after a compound has survived rigorous pre-clinical development work, which involves laboratory testing (chemical/biological/pharmacological/toxicological). It is only when these tests show favourable and promising results that a company can proceed to assess the medicine in humans.

  Committee for Medicinal Products for Human Use – CHMP

  Within the European Medicines Agency (EMA), the Committee for Human Medicinal Products is the scientific committee responsible for preparing the Agency’s opinions on questions relating to the evaluation of medicinal products for human use.

  Compassionate Use

  Refers to situations where a drug is provided to a patient prior to the drug’s receiving regulatory approval.

  Consumer

  A person who is not a healthcare professional such as a patient, lawyer, friend or relative / parent / child of a patient

  Healthcare professional

  For the purposes of reporting suspected adverse reactions, healthcare professionals are defined as medically qualified persons, such as physicians, dentists, pharmacists, nurses and coroners.

  Informed consent

  The concept of informed consent (required to participate in clinical trials and sometimes for compassionate use) is based on the principle that a physician/doctor has the duty to disclose information to the patient (e.g. potential risks, benefits and alternatives) that allows the patient to make reasonable decision regarding his or her treatment on a compassionate basis.

  Name of the medicinal product

  The name which may be either an invented name not liable to confusion with the common name, or a common or scientific name accompanied by a trade mark or the name of the marketing authorisation holder.

  The common name is the international non-proprietary name (INN) recommended by the World Health Organization, or, if one does not exist, the usual common name.

  The complete name of the medicinal product is the name of the medicinal product followed by the strength and pharmaceutical form.

  Ultra-compassionate use

  There are cases when a patient is at the end stage of the disease, suffering, or worsening. Aware that a new product is available, he or she is willing to take the risk, even if very little is known about the product, or even if the toxicity profile is not yet determined. This type of patient may prefer to rake the risk of dying from an adverse drug reaction if the product is finally not safe, because he or she will die soon anyway. And if there is the faintest chance that the treatment benefits him or her, at least he or she will have tried. In such dramatic situations, some regulators take the stand that it is not their role to intervene: it is up to the doctor and the patient to decide. Any regulatory intervention, even in an emergency context, would take time and from their position, regulators do not feel at ease to decide. It is a debate close to the debate on end-of-life  and euthanasia: when legal, the decision belongs to the patient and his/her doctor, there is no need to ask prior authorisation from any authority.