At EU level, there are essentially two routes to obtaining an authorization from the EMEA to place a product on the market more quickly than through the usual marketing authorization route. The first is an application for a conditional authorization that is available where clinical trials have not been fully completed. This is not a full marketing authorization, but, as its name suggests, has conditions attached. The intention is that once the conditions are fulfilled, the authorization can become a full and unconditional marketing authorization. The other route is through an application to the EMEA for an accelerated or exceptional authorization. For this application, full data is available and a full marketing authorization is obtained, but the decision-making process occurs more quickly. In addition to these EU routes, some individual member states have their own legislation allowing products, subject to controls, to be marketed without a full marketing authorization in specified circumstances. This national legislation is the subject of a harmonizing guideline issued by the EME1, although significant differences still remain in how the member states operate these compassionate-use programmes.
A conditional authorization can be granted by the EMEA under specific legislation where full clinical data is not yet available to support a full marketing authorization. It is designed to provide the public with access to medicines where the speed of access is considered to outweigh the risks involved in the lack of complete clinical data. There are three specified situations in which the conditional authorization might be considered: for products aimed at the treatment, prevention or diagnosis of seriously debilitating diseases or life-threatening diseases; for the use in emergency situations, responding to WHO or community-recognized public health threats; and for orphan products. In emergency situations, defined as those in which public health is threatened, it is even possible to obtain an authorization without complete preclinical or pharmaceutical data.
Applicants for a conditional authorization must provide evidence that: their product has a positive risk-benefit profile; they are likely to (in the future) be able to provide comprehensive clinical data; that the product fulfils unmet medical needs; and that the public benefit of immediate availability outweighs the risk of lack of additional data.
A conditional authorization is seen as the first step toward a full authorization. As such, conditions are imposed regarding the obtaining of full clinical data that would support a full marketing authorization, and a time limit for collection of these data2. Additional requirements might also be imposed on the collection of pharmacovigilance data. Once these data have been supplied and are satisfactory, the EMEA can issue a full marketing authorization.
One disadvantage of a conditional authorization is that it is a requirement that patients are informed that the authorization is a conditional one, and this fact must be included in the summary of product characteristics and on the package leaflet.
The authorization will be valid for one year, and a renewal must be applied for at least six months prior to the end of the period of validity. After the first year, the authorization will be valid until a full marketing authorization is granted.
Accelerated or exceptional authorizations
Where complete clinical data is available, an application might be made to the EMEA for a marketing authorization to be granted more quickly than usual. The product must be of major interest for public health, particularly from the viewpoint of therapeutic innovation. A product of “major interest for public health” is defined in the guidelines3 as a product providing new or improved methods of therapy, thereby significantly addressing unmet needs for improving or maintaining the health of the community.
Advantages for conditional and accelerated authorizations
An added bonus for both the conditional and the accelerated procedures is that the EMEA Committee for Medicinal Products for Human Use (CMPH) is required to give its opinion in 150 days rather than 210 days. In both cases, applicants are encouraged to talk to the EMEA about their intentions in advance of making an application (and a formal notification of this intention should be made four-to-six months in advance for an accelerated authorization).
National compassionate-use programmes
National compassionate-use programmes have existed for many years and have only recently been subject to (albeit minimal) legislation. These programmes therefore continue to operate with their own national idiosyncrasies and have the disadvantage over the EMEA early access procedures that each country has to be approached separately and in accordance with its local legislation. It is possible, however, that access in one country might be the most cost-effective or straightforward initial approach to making sales of a new product in the EU.
The key elements of harmonization are that compassionate use means that the product must be made available to a group of “patients with a chronically or seriously debilitating disease4, or a life threatening disease, and who cannot be treated satisfactorily by an authorized medicinal product5”6, and which is in the category of products that can be authorized centrally (by the EMEA)7. The product must also either be the subject of a centralized application or of ongoing clinical trials.
Member states are required to notify the EMEA if it considers an application for compassionate use for a product that would have to be authorized centrally by the EMEA. The CHMP has the right (but not an obligation) to become involved and to adopt opinions on the conditions for use, distribution and target patients. Member states might indicate whether they would consider that a CHMP opinion would be of interest, but this again creates no obligation on CHMP to offer an opinion. All CHMP opinions given are to be made publicly available on the EMEA website. Where an opinion is adopted, the pharmacovigilance rules and responsibilities applicable to authorized products will apply8.
The guidelines attempt to draw a distinction between compassionate use and use in clinical trials, in that compassionate use is not intended to be a substitute for clinical trials (and hence the requirement that trials either have been or are in the process of being carried out). The compassionate-use programme also cannot be used to authorize an off-label use for an authorized product.
Only one of these three routes is likely to be useful for a particular product at any one time, as they all have different purposes and also different requirements. However, they do all offer real options for innovative and effective products to be brought to market in the EU more quickly than would otherwise be the case.
|Type of authorization/ National/ EU legislation||Eligible Products||Requirements||Information to Provide||Period of Validity/ become a full authorization?|
|Conditional/ EU Regulation 507/2006l||Aimed at treatment, prevention or diagnosis of seriously debilitating diseases or life-threatening diseases
For use in emergency situations, responding to WHO or community-recognized public health threats
|Risk-benefit analysis is positive
Applicant likely (in the future) to be able to provide comprehensive clinical data
Unmet medical needs fulfilled
Public benefit of immediate availability outweighs risk of lack of additional data
|Pre-clinical and pharmaceutical data and available clinical data
In emergency situations, incomplete pre-clinical and pharmaceutical data is acceptable
|Initially valid for one year, application to renew must be made at least six months before expiry
After renewal, valid until a full MA is granted
|Accelerated or Exceptional
EU Regulation 726/2004, Article 14(9)
| A major interest for public health, particularly from the viewpoint of therapeutic innovation
Defined as: new or improved methods of therapy, thereby significantly addressing unmet needs for improving or maintaining health of the community
|CMPH may include criteria for the prescription or use of the particular product||The normal data provided to support an application for a marketing authorization||Valid as a normal marketing authorization|
|National Compassionate Use Programmes||Unauthorized in the EU
Groups of patients with a serious or chronic illness who cannot be treated satisfactorily by an authorized medicinal product in the EU
The subject of an application for a centralized marketing authorization or of ongoing clinical trials
|Patients must have no treatment options or a disease that does not respond or relapses to available treatments, or for whom treatments are contraindicated or inadequate
CHMP might impose conditions in their opinion
|If a CHMP opinion is to be provided, the requirements and conditions need to be justified||There is no limitation on validity of a CHMP opinion, save that once an authorization is obtained, this will prevail and compassionate use will no longer be available|
1 Guideline on compassionate use of medicinal products, pursuant to Article 83 of regulation 726/2004, EMEA/27170/2006
2 Article 5
3 Guideline on the procedure for accelerated assessment pursuant to Article 14(9) of Regulation 726/2004, EMEA 419127/05
4 Examples given in the guidelines of chronic or seriously debilitating diseases are: cancer, HIV/AIDS, neurodegenerative disorders and auto-immune diseases.
5 Patients who cannot be treated satisfactorily means those without treatment options or whose disease does not respond or relapses to available treatments, or for whom the treatments are contraindicated or inadequate.
6 Regulation 726/2004, Article 83
7 Products authorized centrally: Regulation 726/2004, Article 3(1) Regulation (products listed in the Annex), and Article 3(2), containing a new (not authorized in the EU) active substance, or has a significant therapeutic, scientific or technical innovation, or it is in the interests of patients to grant the authorization at Community level.
8 This is as provided in Articles 24(1) and 25 of Regulation 726/2004.