EU Clinical trial Regulation: Producing plain language summaries
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Producing simplified overviews of clinical studies for the general public isn’t as straightforward a proposition as it might seem. Pooja Phogat & Vidhi Vashisht of Kinapse set out the challenges
From 2019, pharmaceutical organizations will be expected to prepare plain-language summaries (PLSs) for all Phase 1–4 interventional trials, in line with requirements for greater transparency around clinical research under the EU Clinical Trials Regulation 536/2014 (EU CTR Article 37).
These summaries will need to be intelligible to patients and the general public as well as experts. For trial sponsors, this poses a number of challenges. For instance, if the summaries are too simplistic, they could be misleading to some readers - with potentially serious consequences.
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What is the motivation behind PLSs?
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Most firms can sympathize with the motivation behind plain-language summaries. Once de-identified clinical study reports and lay summaries of trial findings are published on the European Medicines Agency’s designated central EU portal, they will be readily available to not only doctors and other researchers, but also subjects who have participated in the trial, any patient affected by the associated medical condition and their care-givers or family members - plus any other member of the general public.
Being more open about clinical research will improve external engagement with the work companies are doing and improve public trust, while simultaneously helping to drive greater efficiencies and faster progress - as other teams are better able to build on what’s gone before. Meanwhile, trial subjects can understand more about the work they have contributed to, and patient advocacy groups can monitor progress with a condition - without having to submit individual requests for firms to respond to.
Given the broad spectrum of potential readers, EMA has proposed that the plain-language roundups of the key findings and conclusions are easily digestible and appeal to the lowest common denominator in terms of readers’ health literacy. Given that they could serve as the only document that many of its readers will look at, clinical trial sponsors must consider carefully what to include and how best to explain it. The documents will need to do justice to the original studies, but achieving this in an abridged document with non-clinical terminology will not be easy. During early attempts at such summaries, study teams have been seen to push back against the proposed wording and choice of what to include, worried that it might give the wrong impression, has altered the emphasis, and could be taken out of context or lead to wrong conclusions being drawn.
Accountability
It is important to be aware that EMA has no expressed plans to vet the summaries being published. This places the onus on companies themselves to ensure that the summary documents do their job effectively, without creating new risks for the organization or to patients. This applies to every market in which the drugs are being sold across the EU too – requiring accurate local-language versions of each document, which again stay true to the original report and do not stray in their emphasis.
The overriding challenge for study teams is not that the EMA’s PLS requirement will create a lot of additional work (although it most certainly will), but rather that the task falls outside of their area of skill and experience. Until now, the output these teams have produced has been almost exclusively for a scientific audience; they are not accustomed to presenting their findings to readers who do not share the same base understanding and points of reference. Therefore, it presents a risk if the summaries become a weak point and reflect badly on their latest, painstakingly completed research – by positioning or promoting a drug inappropriately, for instance.
Sponsors are reacting to the situation in a number of ways. Some are creating summaries to meet the minimum requirements from EMA. They want to avoid being accused of cherry-picking the secondary endpoints they include or skewing the impression the reader takes away from the PLS – compared to the fuller insight a more knowledgeable reader would gain from the comprehensive regulatory and technical disclosure documents. Others instinctively want to add more detail, to cover themselves against potentially being accused of withholding important information. However, this could lead to long and unwieldy summaries, which fail to serve their intended purpose.
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For now, summaries are being produced voluntarily and applied to already-completed clinical studies. Although these scenarios may lack the urgency that will be present when PLSs become a more formal requirement, they do provide a good testing ground. They also present some practical questions, about how these retrospective PLS documents will be distributed to participating subjects, for example.
Other, ongoing logistical challenges include the need to establish standard operating procedures (SOPs) for handling and processing PLSs, and to build templates for forming the content. Designated teams will need to be trained too, so that they more tangibly appreciate how the summaries will be used, the right balance of what to include, and how best to pitch it for a public audience.
To help with this last point EMA has proposed that, early on in the development of a PLS, sponsors engage with patients who can provide early feedback about the documents and their content, and its framing and wording. In the case of local-language versions for other countries, it is advisable here too to test the translations with local audiences. Although translation tools can help with getting the phrasing right in another language, the only safe way to quality-check local versions and ensure individual dialects and cultural meanings are taken fully into account is to perform bi-directional translations, and confirm that nothing has been lost in the process by asking those on the ground in each target country.
If all of this sounds like a lot of preparation, it’s because it is - and sponsors should not underestimate the task in front of them. Certainly, they should not wait until regulation is effective before they start taking action. The transition to producing plain-language summaries of clinical reports as standard will be very intensive and companies will need to be ‘ready to go’ once PLSs become an actual requirement.
Although the demands of EU CTR Article 37 are considerable, with the right help and advice upfront companies can avoid PLS preparation becoming burdensome. Through ongoing work with life sciences companies of different sizes and at varying states of readiness for PLS production, Kinapse has formulated both effective ways of framing discussions including the author and document reviewers to agree appropriate content, and the best approaches to presenting it for a broad, public readership. Basic measures here might include devices to bring the maths to life (e.g. 0.1% expressed as 1 in 1,000 people) supported by simple graphs as illustration.
Finally, it is worth keeping in mind that it is not just the EU that is moving towards greater transparency and public inclusivity. Assuming the US FDA decides to proceed with equivalent measures (the Agency issued a draft document for comment not long ago), companies that do the groundwork now can expect to be able to capitalize on that diligence across other international markets in due course.
Authors: Pooja Phogat is Head of Development Operations at Kinapse, a provider of complete advisory and operational service across all aspects of EU CTR Article 37 preparation and compliance. Vidhi Vashisht is a Senior Manager for Clinical Trial Disclosure.
