Table 1 Expanded Access Programme: comparison of definition

A case-by-case basis for individual patients, including for emergency use

Under this section, FDA may permit an investigational drug to be used for the treatment of an individual patient by a licensed physician. The following characteristics must be respected:

(1) The physician must determine that the probable risk to the person from the investigational drug is not greater than the probable risk from the disease or condition

(2) FDA must determine that the patient cannot obtain the drug under another Investigational New Drug (IND) application or protocol

(3) Treatment is generally limited to a single course of therapy for a specified duration unless FDA expressly authorises multiple courses or chronic therapy

(4) At the conclusion of treatment, the licensed physician or sponsor must provide FDA with a written summary of the results of the Expanded Access use, including adverse effects

(5) When a significant number of similar individual patient Expanded

Access requests have been submitted, FDA may ask the sponsor to submit

an IND or protocol for the use under an Expanded Access for an intermediate-size patient population or Expanded Access for larger group(s) of patients under a treatment protocol or treatment IND

Moreover, the preamble to the proposed rule stated that to support

Expanded Access for an individual patient when the patient has an immediately life-threatening condition that is not responsive to available therapy, ordinarily completed phase 1 safety testing in humans at doses similar to those to be used in the treatment, together with preliminary evidence suggesting possible effectiveness, would be sufficient to support such use. However, the preamble further stated that in some cases there may be no relevant clinical experience, and the case for the potential benefit may be based on preclinical data or on the mechanism of action

An individual patient (Compassionate Use on a Named Patient basis)

The following characteristics must be respected:

(1) A EU Member State (EuMS) may, in accordance with legislation in force and to fulfil special needs, authorise the use of a medicinal product, otherwise than for the authorised indications or the use of an unauthorised medicinal product, supplied in response to a bona fide unsolicited order, formulated by an authorised health-care professional for use by an individual patient under his direct personal responsibility

(2) A EuMS 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 (3) The doctor responsible for the treatment will contact the manufacturer directly

In Italy, the therapeutic use of drugs undergoing clinical trials outside a clinical trial is permitted when there is no comparable or satisfactory therapeutic alternative for a severe pathology or rare disease or condition that could be life-threatening

The following characteristics must be respected:

(1) The drug is already the subject of ongoing or concluded phase III clinical trials for the same specific therapeutic indication

(2) In specific cases of life-threatening conditions , the drug is the subject of concluded phase II clinical trials.

The drug can be obtained by:

a. physician for an individual patient not treated in a clinical trial;

b. several physicians working in different centres or collaborative multicentre groups;

c. physicians or collaborative groups, for patients who have participated in a clinical trial which has shown effectiveness and tolerability profiles that make it useful, for those who have participate in the trial to exploit the results promptly

Intermediate-size patient population

Under this section, FDA may permit an investigational drug to be used for the treatment of a patient population (smaller than those typical of a treatment IND or treatment protocol: 1–100 patients) with similar treatment needs who otherwise do not qualify to participate in a clinical trial. FDA may ask a sponsor to consolidate Expanded Access under this section when the agency has received a significant number of requests for individual patient Expanded Access to an investigational drug for the same use. The following characteristics must be respected:

(1) There is enough evidence that the drug is safe at the dose and duration proposed for Expanded Access use to justify a clinical trial of the drug in the approximate number of patients expected to receive the drug under

Expanded Access

(2) There is at least enough preliminary clinical evidence of effectiveness

of the drug, or of a plausible pharmacologic effect of the drug, to make Expanded Access use a reasonable therapeutic option in the expected patient population

(3) If the number of patients enrolled increases, FDA may ask the sponsor

to submit an IND or a treatment protocol

Expanded Access under this section may be needed in the following situations:

a) The drug is not being developed: for example, because the disease or condition is so rare that the sponsor is unable to recruit patients for a

clinical trial.b) The drug is being studied in a clinical trial, but patients are unable to participate in the trial because they have a different disease or stage of disease or otherwise do not meet the enrolment criteria; because enrolment in the trial is closed, or because the trial site is not geographically accessible.

c) The drug is an approved product that is no longer marketed for safety reasons or is unavailable on the market due to failure to meet the conditions of the approved application;

d) The drug contains the same active moiety as an approved product that is unavailable on the market due to failure to meet the conditions of the approved application or a drug shortage

Moreover, the Expanded Access submission must state whether the drug is being developed or is not being developed and describe the patient population to be treated.

If the drug is not being actively developed, the sponsor must explain why the drug cannot currently be developed for Expanded Access use and under what circumstances the drug could be developed. If the drug is being studied in a clinical trial, the sponsor must explain why the patients to be treated cannot be enrolled in the clinical trial and under what circumstances the sponsor will conduct a clinical trial in these patients.

Group of patients (Compassionate Use Programmes)

According to Article 83, the aim of this group is:

(1) To facilitate and improve the access of patients in the EU to Compassionate Use Programmes

(2) To favour a common approach regarding the conditions of use, the conditions for distribution and the patients targeted for the compassionate use of unauthorised new medicinal products

(3) To increase transparency between EuMSs in terms of treatment availability

It is applicable to:

a) Unauthorised medicinal products for human use falling within the categories referred to in Articles 3(1) and 3(2) of Regulation (EC) No. 726/2004;

b) ‘'Patients with a chronically or seriously debilitating disease, or a life-threatening disease, and who cannot be treated satisfactorily^a by unauthorised medicinal product’ in the EU, or who cannot enter a clinical trial;

c) Group of patients^b;

d) Medicinal product which 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 EU or elsewhere

It not is applicable to:

a) Use of an unauthorised medicinal product for Compassionate Use on a Named Patient basis (as meant in Article 5 of Directive 2001/83/EC);

b) A medicinal product 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;

c) Medicinal products which are not eligible for the Centralised Procedure. Article 83 on compassionate use is complementary to national legislations and provides an option to MS who wish to receive a CHMP opinion regarding the conditions for compassionate use of a specific medicinal product which falls within the scope of Article 83.

Large populations

Under this section, FDA may FDA may permit an investigational drug to be used for widespread treatment use. The following characteristics must be respected:

(1) The drug is being investigated in a controlled clinical trial under an IND designed to support a marketing application for Expanded Access use, or all clinical trials of the drug have been completed

(2) When the safety and potential effectiveness of drug is known from ongoing or completed clinical trials

(3) The sponsor is actively pursuing marketing approval of the drug for Expanded Access use, with due diligence

(4) When Expanded Access use is for a serious disease or condition, there is sufficient clinical evidence (phase 3 or completed phase 2 studies) of safety and effectiveness to support Expanded Access use

(5) When the Expanded Access use is for an immediately life-threatening disease or condition, the available scientific evidence (phase 3 or completed phase 2 studies, but could be based on more preliminary clinical evidence) provides a reasonable basis to conclude that the investigational drug may be effective and would not expose patients to an unreasonable and significant risk of illness or injury

Expanded Access Programmes (EAPs)

A company that makes a promising medicine may choose to run an EAP 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 EAP. These programmes are often authorised by national authorities in the same way as clinical trials, and patients are followed in the same way as in a clinical trial