Harmonisation challenges in the EU
About the blogger: Dr. Parvinder Punia is a senior regulatory affairs manager at pan-European regulatory affairs organisation ELC Group. With a scientific background, Dr. Punia has nine years of regulatory experience, which includes three years from within two EU health agencies (the National Authority of Medicines and Health Products (INFARMED, I.P.) in Portugal and the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK). She has represented the UK agency at the European Medicines Agency (EMA) level. Her key expertise is in strategy, budgeting, preparation, co-ordination and review of a variety of scientific and regulatory documents for European and experience in non-European countries. Dr. Punia has extensive knowledge of the development cycle and internal knowledge of the EU and other regulated region procedures and has worked in a business development capacity.
The EU directive, as updated in 2005, had many objectives and one of them was to ensure that the agencies harmonised medicines from one county to another. Harmonisation can be seen in several ways but is for the most part divided into two main subject areas: harmonisation of opinion and harmonisation of documentation. Both pose challenges and this is usually rooted in local requirements and culture.
From an opinion perspective, experts are drawing on experience and technical expertise that is limited to their own regulating experts. One regulatory body’s experts may not have the same experience as another. The clinical area is usually the most challenging and smaller agencies rely on external experts to fill these gaps. Furthermore, medical culture also varies significantly. One therapeutic area that has evidently differing opinions is oncology. Cancer treatments differ greatly depending on which physician you ask and what medicines are considered acceptable in first and second line therapy. The difference is so wide that some countries in the EU do not even hold active marketing authorisations (MAs) for some oncological products that may be used as standard in another. Therefore, the generic licensing of such products provides an unharmonised approach.
The challenge then, is to change the medical culture of the territory. It would not be possible to approach an agency with such generic MAs if the doctors are not habitually prescribing it. For a generic to have success, the manufacturer would have to invest heavily in marketing, which is commercially unfeasible as generics
rely on an established market from the innovator. So, in theory, although a generic is licensable in a territory where the originator never was, as part of
the principles of the EU harmonisation recognition, the practice is a lot more complex.
Opinions also vary with regards to quality assessment. There are many examples every month where agencies may differ in opinion on, for example, safe limits of impurities or opinions on safe processes. Although during a decentralised procedure (DCP) the reference member state (RMS) leads and most usually the concerned member states (CMS) will affirm that opinion and may or may not have additional comments, there are some recent examples where one agency would particularly disagree with the opinion of the RMS or vice versa. In one such extreme example, a very opinionated assessor asked the RMS to rethink its ideology of the assessment. The principles now recognise that an agency must share data with another agency but in practice this is not happening. Some of the original data is so old and no longer available. Paper versions are not archived and the original assessments are no longer accessible. This poses a barrier for generics to bridge data where an agency never assessed the originator.
The other area of huge complexity and disharmony is the documentation. The FDA’s International Conference on Harmonisation (ICH) standardised requirements and the electronic common technical document (eCTD) standardised format but content still remains a matter of opinion. In many complex development areas, the guidelines are vague or outdated or even non-existent. This leads to different interpretations of what is a safe, efficacious medicine manufactured to the highest quality.
Lastly, intertwined with the opinion factor are the age-old disagreements on summary of product characteristics (SPCs). The harmonisation group at the EMA has worked laboriously to bridge this gap, but there are still frequent disagreements on approved indications, posology and safety statements. The generic industry suffers immensely through this discord of opinion. Old medicines were licensed nationally and one agency did not know what the other agency was approving, and now the generics suffer the consequences. However, it can also be viewed as a tactically clever ploy by innovators. Differing agency opinions mean that to license a generic using the correct EU approach, the harmonised procedure (i.e. DCP or mutual recognition procedure (MRP)) can be prolonged or even referred to the EMA owing to the discussion of finalising SPC texts.
Does this not lead to the sense that actually, harmonisation does not appear to be happening? The experience of two decades has been gradually catching up with the regulators and the regulated. Harmonisation only began in the 1990s and even then the approach was rather ad-hoc. Nowadays, for a license to go into multiple EU territories, all agencies must work together towards a uniform opinion.