Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

First experiences with Conditional Marketing Authorisations in the EU: requirements, obligations, initial experiences and perspectives ***

Dr. Ursula Protin (Abschlußjahr: 2007)

Language: English

For patients suffering from serious or life-threatening diseases efficient treatment can not come too soon. With the intention to make much needed and innovative medicinal products faster available to all patients in the EU, new tools were implemented into the European pharmaceutical legislation. One of them is the concept of conditional marketing authorisation (CMA), the legal provision of which was introduced by Article 14(7) of Regulation 726/2004 into the framework of the Centralised Procedure. Regulation 507/2006 lays down details on CMA, and a supporting Draft Guideline was developed to give advice on the scientific application and practical arrangements to implement this Regulation.

Accordingly, medicinal products are eligible for CMA in cases where comprehensive clinical data on safety and efficacy are less than complete at the date of application but are considered reasonably likely to be completed and presented to the CHMP in due time after approval. Usually, all necessary pre-clinical and pharmaceutical data should be available at the time of application for CMA.

To qualify for CMA, a medicinal product must belong at least to one of the following categories:
medicinal product intended for treatment, prevention or diagnosis of seriously debilitating or life-threatening diseases

• designation as orphan medicinal product by the EU Commission in accordance with Article 3 of Regulation 141/ 2000
• medicinal product intended to be used in emergency situations, responding to European Community- or WHO-recognised health threats. Only in this case it is possible to obtain CMA without complete non-clinical or pharmaceutical data, subject to completion through the specific obligations process.

As precondition for granting CMA, fulfillment of unmet medical needs and a positive risk/benefit balance must be demonstrated by comprehensive scientific evidence. The risks inherent in the fact that additional data on efficacy and safety of the medicinal product still need to be provided must be outweighed by the benefits to public health through patients early access to the product.

The CMA is valid for one year on a renewable basis. At the occasion of annual reassessment the marketing authorisation holder is obliged to present the status of fulfillment of the imposed specific obligations. These may contain ongoing studies to be completed or new studies to be conducted in order to demonstrate a positive risk/benefit balance.

Until early September 2007, CMA was already granted for three medicinal products which were developed for the treatment of different serious and life-threatening diseases: cancer, HIV and severe myoclonic epilepsy in infancy (SMEI). Two of these medicinal products were previously granted orphan designation. The data provided in the CMA application dossier were at divergent stages of completion, reflecting the different phases of progress of the clinical trials on the respective medicinal product. This was due to very varying study designs, restricted availability of patients for recruitment for the clinical trials in the orphan indications, especially in SMEI, and to considerable differences of basic knowledge about the respective diseases background.
Sutent®, the medicinal product for the treatment of cancer, has meanwhile already obtained “full” marketing authorisation. The relevant clinical trials have shown the greatest progress at the time of application, compared to the two other products: only one already ongoing study in the indication metastatic renal cell carcinoma (MRCC) had to be finalised in order to present the comprehensive data on safety and efficacy required for “full” marketing authorisation.
Prezista® (for treatment of HIV) and Diacomit® (for treatment of SMEI) are still subject to specific obligations; it is expected that the marketing authorisation holders can fulfill them in due course within the scheduled timeframes.

Because of the very different history and circumstances which may be associated with medicinal products intended for CMA as the three examples already indicate - great flexibility will have to be proven in the future. Regulatory Authorities will need to adapt to the different situations in order to perform an adequate estimation on whether preconditions for CMAs are fulfilled.

Patient organisations raise their voice to get involved into the regulatory review process of CMAs as the ultimately concerned stakeholders of the drug development process. Patients often have a different point of view than regulators regarding the risks they are prepared to take when weighed against the potential benefits of a new medicinal product. Therefore, initiatives to participate patients in the regulatory risk/benefit assessment of new drugs for serious or lifethreatening diseases are already in the phase of creation. Such initiatives need to be combined with appropriate financial support to patient organisations, transparency of information on the new medicinal products and safety surveillance after CMA has been granted for the medicinal product.

For the pharmaceutical industry, application for a CMA includes the possibility of earlier market access as competitors and the prospect of a good reputation and financial profits. However, the main motivations to apply for a CMA should include a strong focus on the pharmaceutical enterprises responsibility versus the public out of ethical considerations. Opposed to the mentioned advantages, also certain disadvantages exists in connection with a CMA for a pharmaceutical company. They include extra workload when the annual renewal is due, large numbers of variation applications to be submitted, and possible additional risk management requirements to be fulfilled. Furthermore, a certain danger can not be excluded that the company may not be able to present the comprehensive data agreed upon as specific obligations by granting of CMA. This includes possible serious negative financial consequences and a negative reputation.

The clinical development of medicinal products for serious and life-threatening diseases, especially in orphan indications, requires innovative methodological approaches. It is important to recognise that new biomarkers may have the potential to speed up the availability of medicinal products if they are not only used for development decisions in companies, but also for regulatory decision making. In order to be used as the clinical basis for CMA they should be sufficiently widely accepted for trials with the same intention.

An important issue for CMA at a relatively early stage in clinical development for innovative new medicines is the generation of an adequate safety profile. Improvements in risk management processes, including pharmacovigilance measures, could contribute to encourage applicants to envisage more readily the approach of CMA.

In Part I of this Masterthesis an overview is presented over the legal provisions for CMAs which are clarified with the help of the explanations of the Draft Guideline. Part II deals with first experiences with CMAs in the EU, mainly regarding the clinical development and evaluation of the available data based on which CMA for the first three medicinal products was granted.
Impact and perspectives in the context of CMAs are subsequently discussed in Part III.

Pages: 71, Annexes 2, pages 5