EU rethinks regulation
pharmafile | December 2, 2013 | Feature | Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing | EU, Goldacre, Les Rose, MHRA, regulation
What has happened to the science in clinical research? Well, it
is still there, but with the explosion in the regulatory area, it has been swamped by bureaucracy.
Anyone working in late-phase studies spends far more time trying to avoid breaching the rules than doing good science. Not long after the Clinical Trials Directive was implemented in the UK in 2004, and the Good Clinical Practice (GCP) Directive in 2005, the non-commercial trials sector was up in arms.
Smaller pharmaceutical companies also complained about huge administrative overheads, particularly associated with the control of investigational medical products.
There are, as ever, various perspectives on the argument but my view at the time, which I maintain now, was that standards must be common to all trials if patients are to be properly protected, and we are to have any confidence in the data generated.
Astoundingly, a lot of academics wanted weaker regulations for their trials, which perhaps says something about the standards they were following before the directives; my experience as a patient in non-commercial trials is not incongruent with that impression.
Rumblings in the ranks
Such has been the clamour for reform of the directives that the European Commission launched a review of the Clinical Trials Directive in 2009. Here we are, four years later, and the commission has tabled a proposal for reform that is intended to become a regulation.
The difference between that and the existing directive is important. A directive is not enforceable within member states, and has to be transposed into national legislation.
A regulation becomes law in all member states. One of the big problems of running trials across Europe is the variable interpretation of directives. Interestingly, one of the most problematic areas is that of ethics committees, but the commission has steered clear of trying to standardise ethics committee practices – probably because they realise how difficult that would be. So don’t expect that part of your work to get any easier after 2016.
Science is secondary
I don’t pretend to be an expert on regulatory affairs, and have only scanned the vast range of relevant documents, but so far I haven’t found anything which addresses the scientific validity of clinical trials.
I wrote a while back on the need for a new version of GCP, which includes a requirement for good scientific practice, but amazingly the word ‘science’ doesn’t appear (apart from in the occasional organisation name) in any of the documents I have perused.
The word only appears once in the GCP Directive, where it is made subordinate to “the rights, safety and well being of the trial subjects…” The industry, quite rightly in my view, comes under fire for less than optimal handling of data about its products.
Science has developed over the last few centuries not just as a way of acquiring knowledge but, most importantly, as a way of making that knowledge reliable and useful. It is not helpful if data only apply to unrealistically restricted situations, or if they are distorted because of incomplete capture and/or reporting.
It is now well documented that these problems apply to a great many of the medicines that are in wide use. I am not going to give examples here, but I suggest you read Ben Goldacre’s ‘Bad Pharma’ (which I reviewed for Pharmafile last year) if you have not already.
Politicians at the helm
The proposed reforms do not offer anything to address the patchy knowledge base that we have about the medicines we use. They are largely concerned with reducing the administrative burden. While that is to be welcomed, it is what we might expect from a politically-driven process.
One of the major concerns of the commission, expressed in the 2009 consultation document, was the haemorrhage of clinical trials out of the EU. As we know, there are various reasons for the migration eastwards, including lower investigator costs, and access to treatment-naïve patients.
Imposing a heavy bureaucratic overhead on top of those disadvantages could be the death knell for clinical research in Europe, without action. In passing, however, I would observe that my experience with the Far East does not necessarily indicate less onerous regulation there. Drug supply chain logistics can be challenging in India, for example.
Supporting innovation
Perhaps I’m too harsh. The commission also recognises the need to support innovative research within its borders, and there is surely a scientific reason for that. Such research needs to address the needs of its citizens, and it could be argued that populations on the other side of the world do not closely model those of Europe, and not just for genetic reasons.
The downside to that argument is that pharma companies – largely based in the West – will be less willing to address the needs of poorer countries. While that is a valid ethical point, it doesn’t come within the remit of legislation designed to regulate clinical research within the EU.
The EU does support a great deal of Third World development, governed by other provisions, and maybe one day we will see that extended to healthcare. If it is already, do please let me know!
Reducing cycle times for authorisations…
While the need to speed up patient recruitment does drive trials out of Europe, it’s not the only factor. Data on cycle times indicate that study set-up is taking longer, which impacts heavily on costs, not only directly but in terms of delay to market release.
For many years, I have previously cited research by McKinsey & Company which found that delivering a technology project late but on budget was vastly more costly than overspending to deliver on time. As the most common reasons for late completions are late starts, it makes sense to expedite the set-up stages of a study.
The proposal to centralise the authorisation process should be a big help, as long as the mechanisms eventually put in place actually do what they promise to do.
…and reporting
I often think of a study’s final stages as a kind of ‘Cinderella’ phase – as people near the end of the project, they get weary and are more interested in the next one. At present, there is a host of loose ends that need tidying up, such as ensuring that all competent authorities in all countries have all required documents.
Foremost among these is the clinical study report, of which the last one I managed ran to some 12,000 pages. In this networked world, why do we need to send the CSR separately to each regulatory authority and each ethics committee? If the EU centralises reporting, as it proposes to do, we should be able to do this in one action.
One of the major advantages of automated systems is that, while they save labour, they also reduce the risk of error. An enormous amount of cost is attached to checking for errors, particularly omissions, and plugging gaps. I have had clients lose track of which countries have received their CSR, so doing it once and doing it right should save time and effort.
Top-down legislation?
So how do the reforms address the objections of non-commercial investigators and small pharma firms? Last year’s press release from the European Commission was headed “Fostering EU’s attractiveness in clinical research”.
That tells us quite a lot about what lies behind the proposals – they are all about supporting drug development as an economic activity. The relaxed standards demanded by academics probably won’t feature in the eventual legislation, but hopefully they, along with everyone else, will have a bit less work to do.
Removing the need for member state transposition into national law by means of a regulation, not a directive, may help companies running multinational studies, as regulations will be the same in every member state. Let’s not forget, however, that laws still have to be interpreted, and translated into many languages. Don’t expect processes to be the same in Madrid as they are in Riga.
Ethics committees – a law unto themselves?
Despite these good intentions, politicians and civil servants have shied away from trying to standardise ethics committees. They may have tried herding cats before. Yet it is clear that better oversight is required.
I know of a public sector trial which was reviewed by a committee, allowed to proceed, and then the decision was challenged. But by then the committee concerned had been taken over by another one, and the new committee has not responded to requests to repeat the review, despite new data having emerged which could affect patients. The original committee lost the correspondence relating to the request.
The challenge was based on an informed consent issue, yet we are left with a situation in which nobody is being held responsible. Is this something which the European Commission does not want to tackle? Or should it be addressed by GCP Directive reform? We’ll have to wait and see.
Les Rose is a freelance clinical research consultant and medical writer.
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