Friday, November 20, 2015

Data, transparency and the new EU regulatory environment

Thursday at the Partnerships in Clinical Trials meeting 2015 saw a panel of experts discussing questions posed by delegates on all manner of topics, such as the concept of "patient centricity" and industry's preparedness for the change, and a very interesting session on the implications of the EU Clinical Trials Regulation.

As I mentioned before, "patient centricity" is at the heart of this year's conference, and it certainly caught a lot of people's attention on Thursday morning. Panellists talked about technology, mobile devices, and new ways of capturing data, and suggested that we have only just begun to scratch the surface here. They painted a future where Google, Apple and the like will be the enablers of such technological advances, with patients monitoring their vital signs at home and conversing with their physicians by video and teleconference, rather than having to visit the clinic. After all, some patients may live a long way from the clinic and find it hard to come in as often as they would like.

But while being a homebird may suit some patients taking part in clinical trials, others will miss the chance to take some time out, the "human touch" of meeting their doctor face to face, the feeling of actually talking to someone properly rather than through an e-medium of some sort.  Probably the end result will be some combination of the two in differing proportions, with technology being seen as an adjunct - if a major one – to the current ways of doing things.

In any case, the patient will take a greater role in clinical trials, whether he or she likes it or not. Patients know best what is going on with themselves, declared Prof Brendan Buckley, CMO at ICON in Ireland. Patients, he said, would act as "data providers, with ownership of the process." "The idea of the patient as sub-investigator will be an important factor in the coming years, allowing us to better handle the very significant increase in data flow that we will have."

But he sounded a note of caution about moving too fast, suggesting that proper partnerships and joined up thinking were a prerequisite for true patient centricity, and this isn't happening now. For example, one CRO gets the data, another one gets the labs, and so on, and this makes it difficult to coordinate the various activities in order to achieve the sought-for patient centricity. What is needed is more partnership between CROs and pharma firms, so that the patient is prioritised. If outsourcing is done piecemeal it will be impossible to pursue this agenda, Buckley noted.

"Don’t get carried away with idealism," he cautioned. "There is a fundamental problem about how outsourcing happens – if the CRO gets the whole deal, and the full service process, there is some chance of advancing that agenda, but mostly outsourcing is technical and goes trial by trial."
It was noted that it's important to ensure that the protocol is well thought out, which apparently does not happen as often as it should. Some sponsors, it was suggested, put far too much into their protocols, and CROs need to make sure they are lean and uncomplicated.

And of course, again, don't forget the patient – or the regulator. The regulator's role is key here: companies are used to working to what regulators require in their guidelines. But in future, the regulators will increasingly want to know this: did you talk to the patients, did you ask them what they really need? And it's not only the regulators that have this in mind - the payers do too. If you have strong patient input, it will make your payer negotiations easier.

Which all goes to show that a joined-up approach to patient involvement, with continuous consultation, collaboration and co-ordination among all the key players, is the  way forward.

One of the afternoon sessions managed to throw some light on the less well-known aspects of the new EU Regulation that will take the European clinical trials scene by storm in a couple of years' time.

The session featured a very interesting presentation by Marine Dehlinger-Kremer of CRO SynteractHCR in Germany, who explained the many far-reaching changes that the Regulation will bring, not least the clinical trials portal and database, a single application to conduct a trial, and a great deal more transparency of trial data. As you may know, the application of the Regulation's provisions has been postponed from a notional mid-2016 to nearer the end of 2017, mainly because of the complexity of testing out the portal and database and undoubtedly a myriad other technical niceties.

Dehlinger-Kremer delved into some of the more technical and procedural changes brought posed by the Regulation, such as greater flexibility of monitoring (light or heavy depending on the nature and aim of trial), and the requirement for the sponsor to evaluate to the extent and nature of monitoring – which she said opens the way to risk based monitoring (RBM).

She also pointed out that failure to abide by the new transparency requirements would incur substantial penalties, although we don’t know yet what kind of sanctions the member states will be able to impose in case of non-compliance.

This was fertile hunting ground for Lawyer Peter Bogaert of Covington and Burling in Brussels, who keeps a very close eye on EU regulatory developments and has been known to represent the odd pharmaceutical company before the Court of Justice of the European Union.

He said that there would be a number of challenges with the implementation of the Regulation. For example, the new concept of a "low intervention trial", which he suggested could inadvertently lead to more off-label use.

A low-intervention trial according to the new legislation is a low-risk trial using an approved drug, for example, and with some administrative simplification with regard to informed consent, monitoring, damages, accountability, and so on. The criteria for such a trial are that you use the drug either in accordance with its approved labelling, or based on published scientific evidence on its safety and efficacy.

But if you apply for low-intervention status, the member state may have to confirm that there is indeed such scientific evidence or some existing treatment protocols that support this use. In this way, it becomes formalised, "which in some way is ratifying off-label use", Bogaert declared.

So, given that some member states are looking at greater off-label use, for example for economic reasons (as is happening in France and Italy with Roche's Avastin in wet AMD), "this will bring another dynamic because you could end up with more off label uses that are considered to be supported by scientific evidence," Bogaert noted. This is a completely separate question from clinical trials, but it could have wide ramifications, he added.

Something that is very germane to clinical trials is the amount of transparency the Regulation will bring to trial data, via the requirement for all studies to be registered and their results reported on the publicly accessible database.

The arguments about the benefits or otherwise of such openness have been well rehearsed. One is the assertion that miscreants might misappropriate the data for their own nefarious ends. The topic surfaced again at the discussion on Thursday, with suggestions that some companies in Latin America had used data released by the EMA to gain approval of their own drugs. Just how this would work is not clear (do you just cross out the originator product's name and insert your own?), but I'm willing to be convinced by some concrete examples.

Another argument leveled against the wider release of trial data is that it could defeat the wider objective of the new Regulation, which is to make the EU more attractive as a site to run clinical trials. Will fear of their data being released wholesale to all and sundry (it won't, or at least there will be safeguards in place to protect truly commercially confidential information) lead companies to flee Europe in droves? That remains to be seen.

What is more likely is that there will be knock-on transparency effects elsewhere. Noting that the EU is the first to ask for this level of transparency, Chiesi Farmaceutici's Antonio Ferrari thought the US and even the emerging markets might soon follow suit. "The US has started with its Sunshine Act, and its next steps will be transparency European style", he declared. Watch this space.

There was at least agreement that the new portal and database could do pharma firms a lot of good, given that it allows a single trial application for the whole of the EU and is also the conduit for inspection reports and trial results; moreover it will have a very nice dedicated workspace where the  member states and applicants can exchange information. 

Bogaert said the Regulation was, generally speaking, an efficient tool for ensuring the EU legislation on clinical trials was as strong as it could be, and that it would address many of the shortcomings of the clinical trials Directive it is replacing.

For those who are interested in the constantly changing EU clinical trial landscape, the hard work of getting the portal and database system up and running is now under way, and user acceptance testing is expected to begin in February 2016. Once that is done the system must be audited to ensure it is fit for purpose, a process that is expected to start around November and last until March 2017. Once the system has been given the all clear, the verdict will be published in the Official Journal, possibly in mid-year, and the whole thing will kick off six months later – ie, around the end of 2017.


It may be two years away, but that's not a long time where a project of this kind is concerned and you'll need to take time to ensure your IT systems and your thinking are up to speed. The advice to pharma companies and CROs? Start getting to know the system now. Many of your competitors already have. 




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