Introduction
There are four procedures for applying for a marketing authorisation for a medicinal product. These are a national procedure, a centralised procedure, the mutual recognition procedure and the decentralised procedure. Under these procedures there are a number of different types of application that can be made. There are also a number of exceptions to the usual routes and legislation/ guidance has recently been published on three exceptions, namely, the conditional marketing authorisation, compassionate use and accelerated assessment.
This article considers the scope of the legislation/ guidance and discusses the impact that these will have on industry.
Background
Under Directive 2001/83/EC (as amended) ("the Medicinal Code") and Regulation (EC) 726/2004 ("the Regulation"), before a medicinal product can be placed on the market it must obtain an MA. This means that that the quality, safety and efficiency has to be demonstrated by submitting the results of extensive pre-clinical and clinical trials and tests.
However, certain categories and types of medicinal products justify the submission of less data in support of the use of the medicinal product, and in certain limited circumstances, the manufacturer may be authorised to place their medicinal product on the market. Further, in certain circumstances it may be appropriate to expedite the entry of a medicinal product onto the market.
In order to harmonise the situation across the EU, the Commission has recently published legislation/ guidance on three such situations.
Scope Of The Legislation/ Guidance
Regulation (EC) 507/2006 on the Conditional Marketing Authorisation
Regulation (EC) 507/2006 is published under Article 14(7)1 of the Regulation. A conditional marketing authorisation ("cMA") will be granted based on an incomplete dossier in respect of the clinical section. The cMA will be granted subject to specific obligations. A cMA is to be used as a way to meet unmet needs of patients and in the interests of public health and is intended to be used for three types of medicinal products:
- those that aim at the treatment, prevention of diagnosis of seriously debilitating or life threatening diseases; or
- those to be used in emergency situations as recognised by the WHO or the EU; or
- orphan medicinal products.
In order to be granted a cMA, four requirements must be met (two positive and two negative). The four requirements are:
- the risk-benefit balance of the medicinal product is positive;
- it is likely that the applicant will be in a position to provide the comprehensive data set;
- unmet clinical needs will be fulfilled2; and
- the benefit to public health by the availability of the medicinal product outweigh the risks caused by the missing data3.
The cMA holder will be required to complete ongoing studies or to conduct new studies in order to confirm that the risk-benefit balance remains positive and to provide the additional data. In addition, obligations in relation to pharmacovigilance data may also be imposed. The status of the cMA must be clearly outlined in the summary of product characteristics and the package leaflet.
A cMA will be granted for a period of one year and can be renewed annually. If the specific obligations are met, the cMA should be converted to a full marketing authorisation.
Further guidelines concerning the application and the practical arrangements for obtaining a cMA are due to be drawn up.
Guideline On Compassionate Use
There are a number of national programmes for compassionate use available in the different Member States, either on a named patient basis (such as in the UK, where "specials" are available, for example, a liquid formulation of an analgesic usually available in tablet form) or for a group of patients. The guideline has been published under Article 83(1)4 of the Regulation so that Member States can request an opinion from the CMHP regarding the conditions for compassionate use of a medicinal product, although it is without prejudice to Member States’ competence on this matter and in fact, Article 83 is intended to be complementary to national legislations.
Under the guideline, a compassionate use programme is intended for EU patients who suffer from a disease for which no satisfactory remedy exists and/ or who cannot enter a clinical trial. The objectives are threefold:
- to improve access for EU patients to compassionate use programmes;
- to follow a common approach for the conditions of use, distribution and types of patients; and
- to increase transparency between the Member States regarding available treatment.
In order to set up a compassionate use programme, there are several requirements that must be met:
- the product must be unauthorised in the EU;
- the patient has a serious/ chronic illness (e.g. cancer/ HIV/ Aids);
- the use of the product will be for a group of patients (i.e. use of a product on a named patient basis is outside the scope of the guidelines);
- the product must be the subject of an application for a centralised marketing authorisation or be undergoing clinical trials.
There are several points that should be noted about a compassionate use programme:
- although safety data may be collected during a compassionate use programme, it is not a substitute for clinical trials;
- the compassionate use programme cannot be used for an authorised product which is used for an unauthorised indication (i.e. off-label use).
Notification of the EMEA is mandatory for products which would have to be authorised via the centralised procedure. For products for which the centralised procedure is optional, the Member States may notify the EMEA, although the CHMP can also decide to give an opinion. The applicant should not contact the EMEA of their own volition, but may inform the EMEA of compassionate use programmes in the Member States.
Guideline On Accelerated Procedure
The guideline has been published under Article 14(9)5 of the Regulation and sets out the procedure for applying for an accelerated assessment for a marketing authorisation whereby the time period of 210 days to give an opinion would be reduced to 150 days.
Applicants requesting an accelerated assessment will be required to justify that the product is expected to be of a major public health interest and innovative in terms of the therapy. The CHMP opinion will be based on the material submitted to justify the request and will not be based on the dossier submitted for the marketing authorisation. At any time during the accelerated assessment procedure, the CHMP may decide that an accelerated assessment is no longer appropriate and revert to the normal procedure.
The applicant is expected to justify on a case-by-case basis that the product is of "a major public health interest" as there is no definition of what this constitutes. It is recommended that to facilitate the accelerated assessment, the applicant pre-notify the EMEA prior to the submission of the request. In any event, the applicant is required to agree the accelerated assessment with the EMEA, prior to the submission of the marketing authorisation dossier. The applicant is also able to request pre-submission guidance from the EMEA.
The request should be a short, comprehensive document, typically 5-10 pages in length. The guidelines also lists the key items that should be addressed in the request:
- the unmet needs and the available methods of prevention, diagnosis or treatment;
- the extent to which the medicinal product is expected to have major impact on medical practice, its major added value, and/or how it addresses the greater unmet needs; and
- a brief outline of the main available evidence (e.g. number of clinical trials, key results) on which the applicant bases its claim of major public health interest.
Impact On Industry
The three situations outlined above will facilitate the entry of medicinal products to the market on an expedited basis. However, for the procedures to be used, there are stringent criteria that must be met.
The cMA Regulation and the compassionate use guidelines are likely to be restricted in the number of products that are able to utilise these procedures, whereas, the accelerated assessment procedure is likely to be of more universal application. In order to use the procedures, forethought is required in the R & D and planning stages for marketing authorisations.
The pharmaceutical industry should carefully consider whether the procedures might be appropriate for a medicinal product, as there are benefits in making such applications. For blockbuster drugs, the accelerated assessment procedure is likely to enable the product to reach the market quicker, which will overall benefit patients.
Footnotes
1. "Following consultation with the applicant, an authorisation may be granted subject to certain specific obligations, to be reviewed annually by the Agency. The list of these obligations shall be made publicly accessible.
By way of derogation from paragraph 1, such authorisation shall be valid for one year, on a renewable basis.
The provisions for granting such authorisation shall be laid down in a Commission Regulation adopted in accordance with the procedure referred to in Article 87(2)."
2. This is defined as "a condition for which there exists no satisfactory method of diagnosis, prevention or treatment authorised in the Community or, even if such a method exists, in relation to which the medicinal product concerned will be of major therapeutic advantage to those affected."
3. It should be noted that in emergency situations a cMA may be granted based on incomplete pre-clinical or pharmaceutical data and that it is not necessary to meet the second and third requirements (outlined above).
4. "By way of exemption from Article 6 of Directive 2001/83/EC Member States may make a medicinal product for human use belonging to the categories referred to in Article 3(1) and (2) of this Regulation available for compassionate use."
5. "When an application is submitted for a marketing authorisation in respect of medicinal products for human use which are of major interest from the point of view of public health and in particular from the viewpoint of therapeutic innovation, the applicant may request an accelerated assessment procedure. The request shall be duly substantiated.
If the Committee for Medicinal Products for Human Use accepts the request, the time-limit laid down in Article 6(3), first subparagraph, shall be reduced to 150 days."
The content of this article is intended to provide a general guideto the subject matter. Specialist advice should be sought about your specific circumstances.
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