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Early access route

Innovative drugs can benefit substantially from compassionate use programmes, as long as the demand for them has not been solicited by the manufacturer

Sun rising over train tracksAs the European Union (EU) is a highly regulated environment for medicinal products, in the vast majority of cases, supplying patients requires a Marketing Authorisation (MA), granted either by the respective national competent authority or by the European Medicines Agency.

Exceptions are possible in the following cases:

  • If a drug has not yet reached the point where a MA could be granted, but evidence already exists for the drug's efficacy in the treatment of specific conditions for which there is currently no satisfactory and authorised alternative therapy. Although results on the drug's toxicology and pharmacokinetics would already have been obtained at this stage, full details on its safety profile may not yet be available and even an optimal dose for administration or a comprehensive list of adverse events may not have been established

  • If the manufacturer of a product of proven efficacy and safety has chosen not to market a product in a particular member state and no satisfactory alternative exists in that country.

EU and, to various degrees, national, legislation exists for these cases that regulates the provision of such unlicensed products. As rules and regulations differ from country to country, the EU regulatory environment for unlicensed products is quite complex. Thus, before initiating any supply programmes for them, it is advisable that pharmaceutical companies fully explore the options and possibilities in order to respond to relevant demand from patients and healthcare professionals or, alternatively, to develop early access programmes actively for their investigational drugs. As detailed below, such activities have the potential to yield substantial benefits for the company involved.

Compassionate use
Article 83 of Regulation (EC) No 726/2004 forms the basis of so-called 'compassionate use' programmes on the European level, i.e. for centrally authorised products. It allows member states to introduce compassionate use programmes for products that fall within the remit of the centralised authorisation procedure. In addition, several countries have implemented similar legislation for products that are authorised on a national basis (see below). The main characteristics of these programmes are that:

  • They are intended for patients suffering from chronically or seriously debilitating or life-threatening diseases and who cannot be treated satisfactorily by an authorised medicinal product

  • They are intended to cover groups of patients

  • The product in question must at least be undergoing clinical trials at the time of application.

All compassionate use programmes have to be authorised by the respective national competent authorities. However, the national authorities may ask for an opinion to be issued by the Committee for Medicinal Products for Human Use (CHMP) on the conditions for use, the conditions for distribution and the patients targeted. Compassionate use programmes are not available in all member states and the details of the scope and requirements of such programmes differ from country to country. Notable countries that have implemented compassionate use legislation are France (autorisation temporaire d'utilisation de cohorte), Germany (Arzneimittel-Haertefallprogramme) and Spain (uso compasivo de medicamentos en investigación), while the UK currently has no comparable legal framework.

Single user supply
Article 5 of Directive (EC) 83/2001 allows member states to authorise the provision of an unlicensed drug to individual patients, provided that the demand has not been solicited by the supplier. Again, it has been up to legislation enacted on the level of each member state to implement this option.

Before initiating any supply programmes … fully explore the options and possibilities in order to respond to demand

It is important to stress that the manufacturer of the medicinal product is not the instigator in supplying its product to the individual user, as it is solely responding to an unsolicited request by a healthcare professional, who will administer the medicinal product under his or her direct personal responsibility. Nevertheless, depending on the specifics of the national legislation, the manufacturer may be involved in obtaining the required authorisation in order to be allowed to fulfil the demand for its unlicensed product.

Besides the two exceptions presented so far, it is also possible to supply patients with investigational drugs using clinical trials legislation. In this way, companies may choose to make their product available to patients that did not qualify for inclusion in the main trials, or to patients who have participated in previous trials and who wish to continue treatment with the investigational product. Such schemes are sometimes referred to as 'expanded access programmes', though they should not be confused with similarly named schemes in the US that have a comparable scope. Patients and their reactions are followed under the same rules that apply for clinical trials.

Benefits and drawbacks
The main beneficiaries of making unlicensed products available to patients in need are, and should always be, the patients themselves. However, supplying unlicensed products can also have benefits for the manufacturer. In the case of providing early access to an investigational drug, the added experience that can be gained during its use in a larger population can be regarded as beneficial. This widened experience can also be a reason for concern to the innovator company, as any adverse events arising in this expanded population of patients, many of whom will not have met the inclusion criteria for the clinical trials, may impact on the final risk/benefit assessment of the product during the MA process.

Instrumental to success
On the other hand, early access to the investigational drug may be instrumental in the successful commercialisation of the product, especially in cases where an alternative treatment may become available in the near future. Of course, companies must be careful not to run foul of Europe's strict rules on permitted promotional activities and should also make sure that expanded access/compassionate use programmes do not interfere with clinical trial patient recruitment or introduce any bias into the clinical trials needed for a proper evaluation of the risk/benefit analysis.

It is important to stress that the manufacturer …is not the instigator in supplying its product to the individual user

The cost issue must also be taken into account. Supplying single users with medicines that are unlicensed in their respective countries may provide additional revenue. Compassionate use programmes have the potential to be even more lucrative. However, some countries prohibit companies from charging for their product supplied in such programmes (e.g. Germany), which has to be taken into account in any final cost/benefit analysis, financial or otherwise.

Liability issues should also be carefully considered. However, at least part of the responsibility rests with the prescriber, especially in the case of supplying single patients with unlicensed products. Finally, manufacturers should also be aware of the possibility of a member state intervening to prevent imports and supply of the unlicensed product where there are possible safety concerns. For example, this was the case in the UK, when the Medicines and Healthcare products Regulatory Agency (MHRA) objected to the import of unlicensed cisapride-containing products because of potential cardiotoxicity issues.

While the European medicines market is a highly regulated environment, many opportunities exist to supply products outside the strict legal confines of the MA process. Companies should consider their options carefully at the start of the regulatory process, as compassionate use and other expanded access programmes open possibilities for the early exposure of the investigational product to wider patient groups. This can advance visibility of the product, which is likely to result in a faster market uptake once the MA has been granted and the product is officially launched.

Karen JamesThe Author
Karen James, managing director at Cambridge Regulatory Services, wrote this article with assistance from Dr Andre Moeller, regulatory affairs project executive at Cambridge Regulatory Services.

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12th October 2011


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