2. Early access

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Course: Regulatory procedures- Marketing-Authorisations and their lifecycle management
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Date: Thursday, 25 July 2024, 3:13 AM

1. Special procedures - recap

(This section is organised in the form of a book, please follow the blue arrows to navigate through the book or by following the navigation panel on the right side of the page.)

There are situations where the early, if not immediate, availability of a specific medicine outside the established (“normal”) regulatory procedures or even without a marketing authorisation (MA) is warranted. This is when the notion of ‘timely access’ might be expanded to include ‘early access’. Several regulatory mechanisms exist in the European Union (EU) pharmaceutical legislation to support patients' early access to (mostly) new and promising medicines, particularly those that target an unmet medical need or are of major public health interest.

They consist of provisions allowing shortening of the timeframe for obtaining marketing authorisations via special authorisation and support procedures, such as:

  • accelerated assessment procedure reducing the timeframe for review of a marketing authorisation application (MAA) from a maximum of 210 days to 150 days,
  • conditional marketing authorisation (MA) on the basis of less complete data than is normally the case, and subject to specific obligations for certain categories of medicines,
  • marketing authorisation under exceptional circumstances where the applicant is unable to provide comprehensive data on the efficacy and safety under normal conditions of use, because the condition to be treated is rare or because collection of full information is not possible or is unethical. This type of marketing authorisation is subject to specific procedures, in particular concerning the safety of the medicine,
  • the PRIME scheme to support development of medicinal products of major public health interest through early and enhanced scientific and regulatory dialogue, including scientific advice/protocol assistance

These special procedures have been dealt with in in lesson 2 (please refer to Lesson 2 for further information).

2. Early access programmes (managed access)

 Early access programmes (managed access [1])

The EU legislative/regulatory framework offers additional possibilities for early access of (innovative) products at national level which can be subsumed under the term ‘Early access programmes’ (EAPs), such as:

  • compassionate use (CU),
  • named-patient basis access (NP),
  • expanded access (EU: options arising from participation in clinical trials).

Early access programmes offer ethical, compliant and controlled mechanisms of access to investigational medicinal products (IMP) outside of the clinical trial space and before marketing for patients with life‑threatening diseases having no treatment options available, who do not match clinical trial entry criteria, have no access to appropriate clinical trials or have completed a clinical trial and would benefit from receiving the investigational medicinal product after the trial before the authorisation is granted. EAPs can also be implemented when the medicine is approved in one country but not in another country where it is needed and requested by seriously ill patients. Different terms are used in various member States (MS) for Early access programmes, and so are different ways of implementing such programmes; there is no ‘one size fits all’. National laws differ from one country to another, and some countries have more significant barriers to EAPs than others. Most countries have named-patient programmes in place, but only a few have programmes based on Compassionate use to allow cohorts of patients rather than individuals, to benefit from early access.

EAPs have great potential in some European countries to benefit all stakeholders involved, from the patient who receives the medicine early, to the pharmaceutical company who provides it. Although EAPs can represent a significant undertaking (e.g., the degree of administrative effort required to initiate the programme, timing required to assess the application), companies who invest in them may see considerable benefit in terms of relationship building with key stakeholders, such as patients, advocacy groups, scientists and regulators, as well as launch preparedness.

A few examples [2]:

France: has the fewest barriers – it is the pioneer in Europe for EAPs, and the only country where systematic review and funding of EAPs exists, through the ‘autorisation d’accès précoce’ (AAP) system, which is social security-funded and covers CU-Programmes and Compassionate access authorisation (autorisation d’accès compassionnel (AAC) covering NP-programmes.

UK has the early access to medicine scheme (EAMS), a three-step process: (1) submission of the available (limited) data to regulators (Medicines and Healthcare products Regulatory Agency (MHRA)) and application for a promising innovative medicine (PIM) designation. 2) Upon receipt of the positive PIM designation, MHRA reviews the data. 3) Following an EAMS positive scientific opinion, commissioning of the medicine in the National Health Service (NHS). Fees are levied at each stage of the application and contrary to other countries such as the US and France, the early access provided by the company through EAMS is free of cost for the health system.

Other countries where early access to medicines is provided free of cost include, for instance, Austria, Germany, and Spain.

Conversely, countries such as Greece and Portugal do not have the infrastructure in place to support EAPs and thus the barriers to implementation are much higher.

Of note: EAPs in US vs EU differ in regulation and implementation but follow similar principles. The acronym EAP in the US, overseen by the FDA, stands for Expanded Access Programs whereas in the EU it signifies Early access programmes (the term ‘Expanded access’ is used differently, see below 2.5). In Europe Compassionate Use Programmes (CUP) and Named patient basis access (NP) differ in certain ways to typical Expanded Access Programs in the US. Compassionate Use is the most similar to the US Expanded Access Program.



[1] The term Managed access programmes (MAP), adopted early on by the pharmaceutical industry, is often used as an umbrella term to cover a variety of early access programmes across countries, e.g. all locally defined pre-approval access mechanisms and programmes such as “Compassionate Use”, “Expanded Access”, “Named Patient access”, “Special Access Schemes/Programs”, “Autorisations temporaires d’utilisation (ATU)” and others.


[2] Source:
- Yazdani Morteza, Boggio Francesca‑initiating early access programs in Europe: Five things to consider: Executive insights.

- Patil S. Early access programs: Benefits, challenges, and key considerations for successful implementation. Perspect Clin Res 2016; 7:4-8.

2.1. Access between regulatory approval and availability and patient access

Some national administrative bodies and/or health care professionals (HCP) may interpret that any action for accessing medicines through other than the usual channels should be considered at least together with any pre-approval programme[1].

According to the Heads of Medicines Agencies (HMA)[2] this should be included under the definition of early access programmes and be designated as “pre-reimbursement access” in order to avoid confusion with pre-approval access. In fact, it concerns authorised medicines that are used under the terms of the marketing authorisation in which the only hurdle for the usual distribution is the reimbursement or price decision.

To illustrate this: Following the marketing authorisation, there may be a considerable gap from the time of authorisation to the time of availability and to patient access. Even for centrally-authorised medicines (authorisation EU-wide) the decision on reimbursement or pricing is taken by individual member states (MS) according to local regulations/legislation.

The European Federation of Pharmaceutical Industries and Associations (EFPIA) regularly publishes a report from a large European study about the availability of innovative medicines,  known as the Patients W.A.I.T. (Waiting to Access Innovative Therapies) Indicator.. The time to availability (previously length of delay) is the days between marketing authorisation and the date of availability to patients in European countries (whether attributable to companies or authorities; for most this is the point at which products gain access to a reimbursement list). It was seen that the average time between market authorisation and patient access can vary by a factor greater than 7 across Europe, from as little as four months to 2.5 years (average time 504 days).

Definition of availability in the report: Inclusion of a centrally-approved medicine on the public reimbursement list in a country. In the report 2021 data from 2016 to 2020 on 34 countries (24 EU, and 10 non-EU) and on 152 innovative medicines are included.



[1] Example France: programme to ensure continued access to the product in AAP conditions after a marketing authorisation is granted, but before the decision on the reimbursement of the authorised product by the public health insurance system (post-marketing authorisation AAP)

[2] The Heads of Medicines Agencies (HMA) is a network of the heads of the National Competent Authorities (NCA) whose organisations are responsible for the regulation of medicinal products for human and veterinary use in the European Economic Area. The HMA co-operates with the European Medicines Agency (EMA) and the European Commission in the operation of the European medicines regulatory network and it is a unique model for cooperation and worksharing on statutory as well as voluntary regulatory activities.

3. Compassionate use

Compassionate use is a treatment option that allows to provide an unauthorised medicine under strict conditions to groups of patients with life-threatening, long-lasting or seriously debilitating illnesses, which cannot be treated satisfactorily with any currently authorised medicine and who cannot enter clinical trials (EMA definition).

3.1. Applicable Medicines

Compassionate use programmes (CUP) allow a patient to receive a promising but not yet fully studied or approved medicine and only applies to medicines that are expected to help patients.  The medicine must be undergoing clinical trials or have entered the marketing-authorisation application process. For medicines in clinical trials, at this stage in the development, generally, toxicology studies will have been completed and analysed, and early studies looking at how the medicine is handled by the body will have been completed. However, its safety profile (which side effects it may cause) and dosage guidelines may not be fully established.  

In terms of efficacy, the assumptions for compassionate use may be based on mature randomised phase III trials (e.g., in case of parallel assessment of compassionate use and application for marketing authorisation). However, acceptable assumptions may also rely on promising early data observed in exploratory trials (e.g phase II trials).

3.2. Initiation and oversight of compassionate use programmes

Compassionate use implementation lies in the competence of a EU member state (MS). Article 83 of Regulation (EC) No 726/2004 on compassionate use (‘Legal basis’ below) is complementary to national legislations but includes an option to MS who wish to receive a CHMP opinion regarding the conditions for compassionate use of a specific medicine which falls within the scope of Article 83. This means that CUPs are co-ordinated and implemented by the MS, according to national rules and legislation. Their authorisation is similar to clinical trials, and patients are followed in the same way as patients in a clinical trial. Not all MS have legislation in place to cover compassionate use programmes, and where it exists, it may differ between MSs, for instance with respect to the required documentation to be submitted with an application for a CUP.

Compassionate use programmes are generally requested by manufacturers and marketing-authorisation applicants providing the medicine in question. This is often triggered by a doctor.

CUPs may continue in certain Member States until the medicine becomes available on the market. Legislation requests that, where a compassionate use programme has been set up, the applicant (company) ensures that patients taking part also have access to the new medicine during the period between authorisation and placing on the market.

The national authority keeps a register of the patients treated with the medicine within the CUP, and systems are in place to record any side effects reported by the patients or their doctors.

3.3. Patient access

In general, medicines that have not been authorised are first made available to patients through clinical trials, and the doctor will first advise the patient on whether there is a suitable clinical trial in their country that they can enter and on how compassionate use programmes work in their country. If an appropriate CUP exists, he can speak to the responsible company and find out whether his patient can be enrolled.

3.4. The role of the European Medicines Agency

On request by a MS the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) can provide recommendations to that MS on how to administer, distribute and use a medicine for compassionate use. It also identifies which patients may benefit from CUPs. It can also do so when it becomes aware that compassionate use programmes with a given medicine are being set up in a number of member states. Recommendations are optional for implementation by a MS, complement national legislation, and do not replace it or create any legal framework in the MSs. Instead, they aim to standardise compassionate use programmes across the European Union and may also help to clarify the conditions of existing compassionate use programmes. The EMA publishes on its website a list of opinions on the compassionate use of medicines that the CHMP has adopted. This registry also includes information on the EMA’s recommendations, such as the patients in whom the medicine can be used, and how it should be used.

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:

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.

4. Named patient basis access

Named-patient basis access is the supply of unauthorised medicines (or authorised medicines from a different country, see below) for individual patients in response to requests by doctors on behalf of specific, or “named”, patients and is limited to the requested named patient or patients only. Unlike CUPs, NPs are entirely initiated by doctors, addressing their request directly to the company to treat an individual patient under the doctor’s direct responsibility.

The Guideline on good pharmacovigilance practices (GVP) – Annex I Definitions (Rev 4) EMA/876333/2011 defines ‘Named patient use’ as: The Supply of a medicinal product which is excluded by a Member State from the provisions of Directive 2001/83/EC, in accordance with legislation in force and to fulfil special needs, in response to a bona fide unsolicited order, formulated in accordance with the specifications of an authorised healthcare professional and for use by an individual patient under his direct personal responsibility [based on DIR 2001/83/EC Art 5(1)].

Article 5(1) of Directive 2001/83/EC:
“A Member State may, in accordance with legislation in force and to fulfil special needs, exclude from the provisions of this Directive medicinal products supplied in response to a bona fide unsolicited order, formulated in accordance with the specifications of an authorised health-care professional and for use by an individual patient under his direct personal responsibility”

and Article 5(2) of Directive 2001/83/EC:  
“A EU member State may temporarily authorise the distribution of an unauthorised medicinal product in response to the suspected or confirmed spread of pathogenic agents, toxins, chemical agents or nuclear radiation, any of which could cause harm”

Some elements are common with CUPs. For example, accordingly with this definition, “special needs” may be considered equivalent to “patient with a chronically or seriously debilitating disease, or a life-threatening disease, and who cannot be treated satisfactorily by an authorised medicine”. However, the need to be “the subject of an application for a centralised marketing authorisation (...) or undergoing clinical trials in the European Union or elsewhere”, would not apply. Thus, this term would cover any access to a non-authorised medicine at any time of its development provided it is not made available under a cohort approach. The decision is made on a case-by-case basis for any case (of NP). This article may also apply to the use of unauthorised medicines but not to off-label use of authorised medicines.

However, Named-patient basis access can also refer to a medicine for a specific patient or patients that is not (yet) authorised and available to them in their own country. Such medicine should or must (depending on legislation) be authorised in at least one country, from which it can be imported into the patient’s country under a Named-patient access programme (NPP).

These may be medicines that are:

  • Authorised but not yet available to be prescribed in the patient’s country
  • Authorised and available in one country but not authorised and available in the patient’s country
  • Discontinued in the patient’s country but not in another country
  • In shortage in the patient’s country but not in another country

An example for how Named-patient use is handled in the EU is given below.

Example NL:

Individual requests are initiated by treating doctors 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 medicine for individual patients or cohorts of patients. In case of 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 medicines in phase 1 clinical trials (for example in case of cancer, where often patients rather than healthy volunteers are included in phase 1 trials)

Legal basis:

Article 5(1), (2) of Directive 2001/83/EC

The Guideline on good pharmacovigilance practices (GVP) – Annex I Definitions (Rev 4)

5. EU Expanded access (programmes) (Clinical trials)

The recommendation of the EMA is for EU countries to include within EAPs patients who have been treated in a clinical trial and who wish to continue the treatment:

“Sometimes patients can enter ‘expanded access programmes’. A company that makes a promising medicine may choose to run one of these programmes to allow early access to their medicine and to widen its use to patients who can benefit from it. For example, patients who have been treated with the medicine during a clinical trial and wish to continue treatment may be able to do so via an expanded access programme. These programmes are often authorised by national authorities in the same way as clinical trials, and patients are followed in the same way as patients in a clinical trial”.

When the company wants to implement extended access with the primary motive of providing continued access and not data collection, EAPs offer an efficient and a cost-effective option.

6. Comparisons

Compassionate use should not be confused with 'named-patient basis' treatments, which see doctors obtain medicines directly from companies before authorisation. This is done on an individual basis under the direct responsibility of the doctor, and the EMA does not need to be informed.

In general, medicines that are not yet authorised are first made available through clinical trials and patients should always be considered for inclusion in clinical trials before being offered compassionate use programmes.

Table 1: High level comparison of early access provision in the US and Europe

Criteria

EAP (US)

CU (EU)

NP (EU)

Applicable legislation

Expanded access prorammes (FDA 1997)

Art. 83 (1) Reg. (EC) No 726/2004

Art. 5 Dir. (EC) 2001/83

Who initiates?

  • Company
  • Physician

Company applies to MS (opinion possible by CHMP)

Doctor requests from company

Criteria to define/select target population by…

  • Company/FDA

Company /CHMP

Company /Doctor

Who benefits?

Limitations in use?

  • Group of patients (treatment INDs & protocols)
  • Named patient (single patients IND)

Group of patients

Only named patients for whom the physician has made a request

Liability

Company

Company

Prescribing doctor

Medicine in clinical trial or under assessment for MA?

Yes

Yes

No

Off-label use permitted?

No

No

Yes

Are doctors paid for participating?

Yes

No

No

Are medicines in programme priced?

No

No

Yes (possible)

Adapted from: Patil S. Early access programs: Benefits, challenges, and key considerations for successful implementation. Perspect Clin Res 2016; 7: 4-8.

Table 2: Exemplary comparison of compassionate use and named-patient access provisions in three countries of the European Union

 

 

Named Patient

Programme

Compassionate Use Programme

Named Patient

Programme

Compassionate Use Programme

Early access to medicines scheme

Type

Individual patient

Groups/ cohorts of patients

Individual patient

Groups/ cohorts of patients

Individual patient

Groups/ cohorts of patients

Responsible Agency

Federal Institute for Drugs and Medical Devices (BfArM)

Paul Ehrlich Institute (PEI)

French National Agency for medicines and Health Products Safety (ANSM)

Medicines and Healthcare products regulatory Agency (MHRA) for benefit/risk scientific opinion;

National Institute for Health and Care Excellence (NICE)

Initiator

Treating physician

Company

Prescribing doctor

Company

Prescribing doctor

Company

Duration

Up to 1 year, renewable, until MA and marketed

1 year, renewable possible (renewal application latest 2 months before expiration)

12 to 18 months with 3-monthly review

Pricing & Reimbursement

Product supplied free of charge

  • Free pricing and full reimbursement possible if there is a valid Cadre de prescription compassionelle (CPC)
  • Difference to price negotiated at launch to be paid back (fines possible if difference is significant)

Product supplied free of charge

Restrictions & Requirements

 

 

  • Rare or serious diseases with no appropriate treatment alternatives available in France
  • Treatment cannot be delayed
  • Product is likely to offer benefit or significant advantage over and above existing options
  • Potential adverse reactions are likely to be outweighed by benefits

Patients should enrol in Clinical Trials where possible

 

- Medicine must be in Clinical Trials in Germany or abroad

- Must be able to show product safety, indicative efficacy, medical need and urgency

- Must involve a severe illness that has a lasting negative impact on an individual’s Quality of life

- No conventional treatment option.

- MAH must give their consent to off-label use

  • Efficacy and safety for patient presumed
  • not the object of a clinical research
  • no appropriate treatment
  • Efficacy and safety for patient presumed
  • presumed innovative
  • must inform patients about noncompliance with the MA, the existence of a CPC and the risks involved and benefits likely to be obtained with the medicine
  • Adverse event reporting mandatory

Although the company will record what is supplied, there is often no central register for treated patients

Applicant is able to supply product in each region of the UK

Germany: Compassionate Use Programs were initiated in Germany in 2010. While the process for the cohort programme is more complex than the named-patient programme, it grants the company a higher degree of control such as limiting the medication to a particular patient subgroup.

France: The Temporary Utilisation Program (ATU) has been in place since 1992; latest revision and renaming 2021: ATU is changed to ‘autorisation d’accès précoce (AAP)’, for NP ‘Compassionate access authorisation (autorisation d’accès compassionnel (AAC)’. Reimbursement opportunities make compassionate use programs in France potentially the most attractive in Europe.

UK: The Early Access to Medicines Scheme programme (EAMS) was launched in 2014 in the UK. The application process for companies requires submission of a dossier with the latest available data, and evidence requirements for both regulatory purposes and NICE appraisal, thus potentially contributing to the data required for MA application and subsequent assessment.

7. References

1. The EMA webpage on Compassionate Use. Available at: Compassionate use | European Medicines Agency (europa.eu)

2. Taken from Questions and answers on the compassionate use of medicines in the European Union. Available at: Microsoft Word - CTS-737459468.doc (europa.eu) 

3. HMA Subgroup on Timely Access. Available at: Mapping of national frameworks for Early Access Programmes

4. New Early Access and Off-Label Use Rules in France, Léna Beley et al., July 6, 2021, Posted in Compassionate Use, European Union, Healthcare system, Medicinal Products, Pharmaceutical companies