by Michael Pfleiderer
The rules governing vaccines and other medicinal products in the European Union offer multiple pathways to take these products to licensure. Developers can apply for a purely national license, for the Mutual Recognition Procedure (MRP), the Decentralized Procedure (DCP) and, finally, the Centralized Procedure (CP). While MRP and DCP also result in Marketing Authorizations granted nationally the CP results in a Community Marketing Authorization valid in all Member States.
Further to these options for licensure the European pharmaceutical legislation knows another approach for evaluating products according to the same scientific standards and similar regulatory principles as applied for CP products. This option is called the Article 58 procedure and is reserved for products that are not (or not yet) foreseen for EU markets (1).
The principal reasons accounting for why a product is not marketed in the EU is that the corresponding disease doesn’t exist, or standards of care established in EU Member States differ fundamentally from other regions of the world where a medicinal product is urgently needed. Numerous additional reasons might account too.
With regard to vaccines, this restriction means that the EU is not (yet) endemic for a certain pathogen or the vaccine composition cannot be marketed because vaccination recommendations applied in the Member States preclude the use of this particular vaccine.
However, as the world is much bigger than the EU and as numerous products are produced within the EU’s territory just for export, the European Commission in close liaison with WHO, has established a regulatory pathway defined by Article 58 of EU Regulation 726/2004 according to which medicinal products relevant for non-EU territories can be assessed applying the same scientific standards as for products that will be used in the EU. The only difference between an Article 58 and a Centralized Procedure is that at the end of the procedure the European Medicines Agency’s’ (EMA) Committee for Human Medicinal Products (CHMP) will provide a scientific opinion on the product under evaluation rather than a recommendation to the European Commission for granting a Community Marketing Authorization. Although this may at first glance be perceived as a secondary standard approach the only difference between a CHMP scientific opinion and a recommendation for granting a Community Marketing Authorization is a slightly different administrative endpoint.
Most importantly, a favorable Article 58 CHMP scientific opinion facilitates licensure of medicinal products in countries outside the EU. This option is particularly attractive for countries that do not have a strong regulatory system, but which want to ensure that only medicinal products corresponding to highest possible scientific standards will enter their markets.
Furthermore, Article 58 products greatly facilitate WHO’s prequalification (2) of medicinal products as a favorable CHMP opinion only requires some additional regulatory and administrative steps in order to place them on WHO’s list of prequalified products that can be purchased by United Nations Agencies or countries with only moderately functional or non-functional regulatory systems.
Despite these clear advantages only some manufacturers have so far chosen the Article 58 procedure. Consequently, only very few Article 58 products (3) are available slowly entering countries that do not have own capacities to evaluate these products. Some of the Article 58 products are vaccines but also antiparasitic-, antiviral- and blood products have been evaluated via that route.
Because of this unexpected reluctance EMA has reviewed the entire procedure a couple of years ago aimed at strengthening the approach and better promoting it to potential addressees.
In parallel, WHO has reviewed and revised their prequalification procedure resulting in a much stronger linkage of EMA and WHO activities.
The main outcome of these overall revision processes was that third country regulators should more actively be involved in the Article 58 procedure avoiding the perception that EU regulators would not consider all aspects relevant for a non-EU population which is exposed to Article 58 products.
This point is particularly important for vaccines against infectious diseases being endemic in non-EU regions. Most notably, some of these infectious diseases are rapidly spreading from endemic regions formerly located outside the EU towards EU borders and, finally, into the EU causing increasing uncertainty amongst developers whether these vaccines should be regulated via the Article 58 or the Centralized Procedure.
These scenarios create new challenges for both, regulators as well as developers. Recent experience with multiple candidate vaccines against those diseases provides evidence that EU regulators can no longer apply the same tools for determining the benefit-risk-ratio for emergency vaccine for non-EU markets as they routinely do for vaccines used within the EU. Although this approach is appropriate as it primarily aims at avoiding creation of secondary standards there is a high risk that additional aspects relevant to endemic regions are insufficiently considered as they are either unknown to EU regulators or perceived as less important. Ultimately, a mutually agreed understanding needs to be developed between developers and regulators how to optimally apply the tools provided by the Article 58 procedure for vaccines primarily needed in non-EU countries but which in parallel oscillate at the edge of relevance for EU countries.
As already outlined further above, this dilemma can best be overcome by more intensively involving regulators from endemic countries into the Article 58 procedure from the very beginning as they will contribute additional viewpoints to the overall risk-benefit-assessment of an Article 58 vaccine which are of utmost importance for endemic countries. In addition to the individual benefit-risk-ratio of a certain vaccine a wide range of equally important considerations should to be taken into account to evaluate the overall benefit-risk profile. These include epidemiological aspects such as the seasonality of pathogen circulation, peak epidemic activities and various outbreak scenarios. Furthermore, vaccine specific aspects such as safety and efficacy in primed versus unprimed populations, cross-protection against non-vaccine strains or serotypes and overall effectiveness are important parameters that need to be an integral part of the equation calculating the benefit-risk-ratios of vaccines needed in endemic countries. Finally, public health aspects such as cost and availability of therapeutic options for the treatment of infected individuals, hospital resources and, most importantly, swift integration of an Article 58 vaccine into endemic countries’ vaccination programs are relevant points to consider.
In their revised formats both, the EU Article 58 procedure and the WHO prequalification procedure now provide excellent opportunities for vaccine manufacturers developing vaccines primarily for endemic regions outside the EU having a high potential of being needed also within the EU in the future either as a travelers’ vaccine or as a routine vaccine because etiological agents move closer to or even into the EU.
This regulatory option also integrates other tools EMA is offering for faster and more efficient development of medicinal products such as the PRIME program (4). Moreover, a successfully completed Article 58 procedure significantly simplifies a subsequent CP procedure as a full assessment of a product has already been performed by CHMP and only adjustments of the development program for uses in the EU might be required.
If you are developing a vaccine or another medicinal product, medical device or diagnostic tool which is relevant for regions outside the EU but has a growing potential to be needed also within the EU contact us as we have accumulated ample experience in preparing, carrying out and successfully completing the pathway to licensure integrating the requirements set by EMA, WHO and endemic countries’ regulatory agencies.