Do We Need an EU Vaccine Regulation?

Michael Pfleiderer

by Michael Pfleiderer

Neglected diseases, neglected vaccines. Unprecedented challenges, like the recurrence of known and new infectious diseases pose one of the greatest risks to human health. Environmental factors, such as global warming, may fundamentally change the pattern of pathogens we will be exposed to in future. Responding to those challenges requires flexible and accelerated development programs for vaccines. However, there are serious concerns about the fitness of the legal framework regulating vaccines in EU. Coping with these challenges means that a significant change of scientific and regulatory paradigms is needed that should possibly be addressed by an EU Vaccine Regulation.

Historical overview over the EU regulatory landscape

Historically, evolution of drug laws or pharmaceutical legislations began in the 1950ies as an immediate and necessary reaction to the thalidomide (Contergan) scandal leaving thousands of babies with malformed limbs and other lifelong sequelae.

In the EU, throughout the following decades rules and principles governing medicinal products were turning from a purely national responsibility into numerous Directives and Regulations agreed on by the Member States to be applied in the entire EU. In parallel, regulatory and scientific standards were created ensuring highest possible safety and efficacy of all medicinal products marketed in the EU. This unprecedented level of harmonization was markedly sparked by the foundation of the European Medicines Agency in 1995 providing an excellent platform to take licensure and control of medicinal products into previously inaccessible dimensions.

During the evolution of the EU’s pharmaceutical legislation numerous niches have been opened and populated with a specialized legal framework in response to accumulating necessities imposed by scientific progress and new technologies.

Nowadays, dedicated drug legislation is split into product class specific regulations as represented by the Orphan Drug Regulation (Regulation (EC) No 141/2000) and the Advanced Therapy Medicinal Product (ATMP) Regulation (Regulation (EC) No 1394/2007) providing tailor made legal, regulatory and scientific guidance facilitating development, licensure and marketing of products falling into those product categories (see Figure 1).

In addition to rules related to product classes further legal provisions have been implemented facilitating the development of medicinal products for children as represented by the Pediatric Regulation (Regulation (EC) No 1901/2006) or facilitating the post-marketing control of all medicinal products licensed in the EU regardless of the pathway used for licensure or the licensing status. These latter aspects are represented by a Regulation and a Directive commonly known as the Pharmacovigilance legislation (Directive 2010/84/EU, Regulation (EU) No 1235/2010).

Upcoming evolutionary steps taken by the EU’s system of pharmaceutical legislation foresees the conversion of the former Clinical Trial Directive into a Clinical Trial Regulation (Regulation (EU) No 536/2014) and, similarly, the conversion of three Directives regulating certain implants, medical devices and in vitro diagnostics into Medical Device Regulations (Regulation (EU) No 2017/745, Regulation (EU) No 217/746, see Figure 1).

Converting EU Directives into EU Regulations emerged from a series of evolutionary lessons learned, namely that harmonization of drug legislation installed through an EC Regulation is generally more efficient and successful compared to an EC Directive, the latter one always bearing a risk of implementing regulatory divergence within the Community Member States rather than regulatory convergence.

Looking now from the past into the future of regulating drug development, licensure and control of medicinal products, medical devices and diagnostics indeed presents a unique story of success including the prospects that new products and new techniques providing access to so far unknown therapeutic options will even be faster integrated into the existing set of pharmaceutical legislation as well as scientific and regulatory guidance.

Figure 1: EU dedicated drug legislation is split into product class specific regulations – without covering vaccines so far

EU’s legal and regulatory framework of regulating vaccines requires a fundamental face lift

Beyond this optimistic outlook there is, however, a class of products that seems to be excluded from the rapid development of EU drug legislation: Vaccines.

It is self-evident and commonly acknowledged that vaccines are the most cost-effective medicinal products ever developed. Most vaccine preventable diseases do not pose a risk any longer for populations that do have access to those vaccines and that do accept public recommendations and vaccination programs.

However, the landscape is rapidly changing also for this class of products probably turning success into failure if gears are not shifted in time. Several reasons might account for this prognosis:

First, there is a constantly decreasing number of manufacturers that is experienced in producing vaccines for the EU market. Prodromal symptoms indicating that this tendency might progress into a more serious public health problem are signaled by an increasing number of reports on supply problems or out-of-stock situations persisting over weeks, months or even years.

Second, in parallel to the recurrence of vaccine preventable infectious diseases caused by unsustainable vaccine procurement, numerous novel infectious diseases caused by emerging and re-emerging pathogens might potentially cause massive future health threats also for the EU population.

Third, accelerated and increasing emergence of multi- and pan-resistant microbial pathogens might cause unsurmountable health risks for the EU population in case new effective antibiotics cannot be developed and made available as a therapeutic option. Preventive vaccines compensating for this loss of options are unlikely to become available in time as nobody is willing and able to invest in their development.

Diagnosing the reasons driving these unfortunate tendencies reveals that vaccine development apparently has become too costly and too lengthy. While it goes without saying that vaccines are given as prophylactic medicinal products to an otherwise healthy population, as such requiring strict adherence to highest safety standards, the question arises whether vaccine safety always needs to be evidenced by studies comprising thousands or even ten thousand of study participants.

Vaccine development based on novel and generic, yet reliable and proven scientific principles might accelerate and facilitate vaccine development and might invite more developers to invest into new vaccines (see related article in this Newsletter from Ilona Baraniak-Lang on vaccine biomarkers and previous contributions from BE on simplifying vaccine development). However, there is a significant lack of readiness and guidance signaling to developers that there is room for innovative approaches regarding the pharmaceutical and clinical development of new vaccines. EMA’s guideline (including its revision) on the clinical development of new vaccines is quite vague in offering compromises, in essence, preferring conservative rather than innovative approaches when alluding to sample sizes needed to demonstrate vaccine safety and efficacy.

Furthermore, experience gained with vaccines granted eligibility for EMA’s PRIME program reveals that it is a very lengthy and cumbersome process to identify commonly acceptable alternative pathways that significantly reduce timelines for vaccine development.

All these aspects have recently been discussed during an EU Vaccine Industry Roundtable meeting . Conclusions made during this meeting unequivocally demand that the legal and regulatory structure governing vaccines in the EU should change soon and drastically in order to ensure protection of the EU population from existing and newly emerging pathogens.

Most notably, the last time that legal provisions specific for vaccines have been implemented into EU pharmaceutical legislation was around the year 2003, related to the concept of a Vaccine Antigen Master File (VAMF). This concept, however, turned out to be inappropriately complex and costly and was in fact never applied in practice.

A more promising example indicating that abbreviation of development programs can indeed result in very safe and effective vaccines is the EU’s unique system of pandemic influenza mock-up vaccines that has revolutionized and massively accelerated the development of suitable pandemic influenza vaccines. This approach has ever since been adopted by numerous regulatory systems around the globe as well as by WHO.

Concluding on what has been outlined above points to the necessity that the EU’s legal and regulatory framework of regulating vaccines requires a fundamental face lift.

As the new Commission of the European Union has recently been inaugurated, together with a newly elected European Parliament, it seems prudent to reflect about the development of a “Vaccine Regulation” that paves the way for responding to the unprecedented challenges posed by infectious diseases the EU population might likely to be exposed to in the near future.

Apparently, the aforementioned Roundtable Meeting only marks the beginning of such an initiative. Attendees clearly identified that reshaping the EU’s legal framework for regulating vaccines is overdue and unavoidable.

If you are interested in learning more about this debate or if you want to take advantage from our ample experience in handling vaccines together with regulatory agencies around the world in this complex environment, contact us – we are happy to provide you with our professional assistance.

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