Pooja Phogat

	From 2019, to comply with requirements for greater transparency around clinical research as part of the EU Clinical Trials Regulation 536/2014 (EU CTR Article 37), life sciences firms will be expected to prepare plain-language summaries (PLSs) for all Phase I through IV interventional trials, which can be understood by patients, the general public, and experts. For trial sponsors, this is a significant undertaking. Its perceived magnitude is reflected in the concerns now being raised by study teams and those who will be responsible for delivering the PLSs. These include the fear that, if the summaries are too simplistic in what is included and how it is worded, they could be misleading to some readers-with potentially serious consequences for the organizations responsible.

	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, as well as 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. The main reports are inherently very long, detailed and technically complex-i.e. hard to decipher for someone without an industry background and/or prior knowledge of the particular field of study. So the PLS must fill that gap--potentially as the only document that many of its readers will look at to understand the research and its outcomes.

	In this context, firms must decide what makes for an optimal summary: what should be included and how best to explain it, as well as what should be left out in order not to lose the least knowledgeable reader. Sponsors are understandably keen to ensure that these documents do justice to the original studies, getting across everything that’s important and retaining the original emphasis. Achieving this in an abridged document that uses simpler, non-clinical terminology will be no easy task. During early attempts at these 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. As an example, groups of patients may wrongly infer that the given drug is appropriate and safe for their particular circumstances based on the results of a single study without considering key information or broader contextual insight which the researchers and the health authorities conclude from multiple studies.

	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 risk 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.

	Laying the foundations for public transparency

	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. So 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 the 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. But this could lead to long and unwieldy summaries, which fail to serve their intended purpose.

	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 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 

 not long ago, open for comments), companies that do the groundwork now can expect to be able to capitalize on that diligence across substantial international markets in due course.

Pooja Phogat is Head of Development Operations at Kinapse, and Vidhi Vashisht is a Senior Manager for Clinical Trial Disclosure.

Articles

From 2019, to comply with requirements for greater transparency around clinical research as part of the EU Clinical Trials Regulation 536/2014, life sciences firms will be expected to prepare plain-language summaries for all Phase I through IV interventional trials, which can be understood by patients, the general public, and experts.

EMA’s Demands for Plain-Language Summaries for Clinical Trial Results that can be Understood by Anyone Could Create new Challenges for Sponsors

	When the European Medicines Agency (EMA) first introduced plans to create a public database of clinical research findings

, it had a two-fold aim-to enable secondary analysis by other researches, and to increase public trust by allowing them unprecedented access to the clinical trial data. Policy 0070 was established to provide guidelines and processes for this, with a strong focus on how life sciences companies should protect the privacy of trial participants.

	Now, with the EU’s new General Data Protection Regulation (GDPR) coming into force in May this year

, the impetus for life sciences firms to cement their data management strategies has increased. A further driver for finding optimal approaches to publicly available information is initiatives by other regions, such as North America,

 to adopt similar requirements for external publication of clinical findings.

	Early attempts by companies to fulfil EMA Policy 0070 requirements have left a lot to be desired. For perceived ease and economy, firms have commonly defaulted to redacting public-facing content so that any clues to people’s identities are simply blocked out.

	Although it has served the basic purpose, this rudimentary approach to preparing anonymized clinical reports is less than ideal. For the supposed beneficiaries, the value of a heavily redacted clinical study report (CSR) is questionable. In the main, redaction is a laborious and largely manual process too.

	With other anonymization methods, several priorities can be addressed simultaneously-the delivery of higher-value output with greater utility yet still with strong measures to protect patient privacy (information is simply hidden in plain sight); risk is easier to measure; and processes are potentially easier to automate.

	It is for all of these reasons that EMA is encouraging companies to move away from document redaction towards other data anonymization approaches-those using rules-based formula that disguise detailed references sufficiently to de-identify participants’ identities, while preserving the quality of the output.

	One of the keys to achieving a good balance of these two priorities is the ability to measure and manage risk-which will vary depending on the nature of the clinical study, its population and trial sites. EMA has published hard metrics to define the level of acceptable risk of patient re-identification (set at 0.09)

. Yet, with redaction, it is difficult to arrive at a quantitative measure of risk. With more sophisticated anonymization methods, by contrast, it is possible both to calculate risk and also to adjust the actions taken according to the scope for participant exposure.

	Based on its work with a broad spectrum of pharmaceutical companies in preparation of more than 20 Policy 0070-compliant submissions, Kinapse has distilled some optimal compliance strategies and practices. These are important if firms are to get the most from their investments-and set the course for where they need to be in the long term, for instance as Policy 0070 enters phase 2 where original data sets (individual patient data) will require anonymization too.

	Given that Policy 0070 is an evolving requirement, effective strategies will be those that take into account longer term requirements as well as what is being demanded of firms now.

	Policy 0070 was first introduced in January 2015, with guidance on CSR anonymization published in March 2016, and the first submission made public that October. Phase 2 of Policy 0070, which will require that life sciences companies provide anonymized copies of all of their clinical trial data, is coming down the line, albeit that there isn’t currently a known timeline for this next stage. It is something companies should prepare for nonetheless, as it will require a more systematic and repeatable process than most companies have in place currently.

	Do not wait to start planning how to tackle document anonymization. Once companies submit a marketing authorization application to EMA, the guidance specifies that they should ideally take no more than 180 days to provide the equivalent anonymized content for the designated EMA portal, where anyone can look at it. Four and a half months might sound like a long time, but it isn’t really. While there are about 100 different ways we can address a company’s anonymization needs for a given submission package, those options are reduced the closer firms are to the public submission’s deadline. The tightest timeframe Kinapse has worked to so far has been two months-although we still delivered as planned, this was far from ideal.

Be realistic about the scale of the task, and what will be required

	Life sciences companies of all sizes have quickly realized that EMA Policy 0070 compliance is not something they can easily manage themselves. The requirements are still very new, so expertise and experience is hard to come by. It’s also easy to underestimate the need for communication and collaboration between different stakeholders to arrive at what’s needed.

	Where firms have tried to fulfill their own requirements internally, they have generally become unstuck-forced to rely on manual redaction, without any quantitative risk assessment or way of measuring and demonstrating success. The entire process is slow and cumbersome, and for each new document they must start from scratch. Ensuring consistency is an additional challenge. And as EMA encourages more sophisticated forms of anonymization, companies could find themselves having to justify why they have defaulted to the lowest-value option in terms of preserving data utility.

	We project that the vast majority of Policy 0070 compliance work will be outsourced to specialist service providers in time, because it will make no sense for companies to try to do it themselves. Using a specialist service provider offers greater efficiency and reliability, not least through the chance to centralise activities. It is probably also the best route to accessing enabling technology and tools-including smart algorithms/machine learning, which over time produce faster and more accurate results by building on each anonymization cycle.

	Anonymization methods geared to de-identification generally rely on IT to maintain data integrity, measure and manage risk, and provide auditable evidence of measures that have been taken. These techniques can deliver benefits starting at 60% improvements in time and cost efficiency compared to non-technology enabled anonymization processes.

	Managed service providers will also keep abreast of data security as they process documents, keeping companies compliant with GDPR and other data safeguarding measures. For clinical trial sponsors, this all adds up to the lowest-risk and most efficient option for managing compliance.

Don’t view redaction as the definitive solution. 

	Other than in exceptional cases, defaulting to redaction as a strategy is a false economy. It is not in the spirit of clinical data transparency and it adds the least value for everyone concerned. As international requirements dovetail with EMA’s ambitions, and as Policy 0070 enters its next phase, redaction’s limitations will be exposed. This will mean that any money spent on redaction processes and work now will not count, and companies will have to invest afresh in alternative anonymization strategies. Keep in mind that EMA has now established a dedicated anonymization taskforce

 to help sponsors come up with ideal methods and techniques for maintaining data utility.

	Once companies have accepted the need for professional help, they will need to decide what kind of outsourced service is appropriate for their requirements. Some service providers offer advisory services, but not the practical operational delivery-and vice versa. Some are light on technology; others focus too much on technology, to the detriment of human quality control. So there is a balance to be struck.

	The optimum combination, particularly at this early and evolving stage of the Policy 0070 compliance cycle, is probably going to be an end-to-end service that can take companies on the whole journey, and ensure nothing is left to chance. Checking out practical project delivery/real-world experience of any service partner, as well as their formal credentials and capabilities, will also be important to minimize risk.

	There is no doubt that the demands of EMA Policy 0070 are considerable, but real industry progress can’t happen without some degree of pain, and putting off the inevitable will simply make matters worse. Cutting corners is not recommended for the same reason-the costs and pain will merely end up being greater and more drawn out. Far better to start out as you mean to go on, and to get the right help and advice up front.

: it always helps to have a purpose, so make sure the key stakeholders understand and buy into this. Again, this is something your service provider should be able to help with.

 is the Head of Development Operations at 

 European Medicines Agency policy on publication of clinical data for medicinal products for human use, EMA, October 2014: 

http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/10/WC500174796.pdf

 How will GDPR impact Life Sciences organisations, Kinapse, February 2018: 

https://kinapse.com/insight/gdpr-life-sciences/

 Public release of clinical information, Health Canada, February 2018: 

https://www.canada.ca/en/health-canada/programs/consultation-public-release-clinical-information-drug-submissions-medical-device-applications.html?wbdisable=true

 What’s not shared-building on the FDA’s transparency momentum, BMJ blog, January 2018: 

https://blogs.bmj.com/bmj/2018/01/31/tianjing-li-whats-not-shared-building-on-the-transparency-momentum/

 Questions and Answers on the External Guidance of Policy 0070 on Clinical Data Publication, EMA, September 2017: 

http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2017/04/WC500225881.pdf

 EMA Technical Anonymisation Group (TAG): Call for applications, March 2017: 

http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2017/03/WC500224906.pdf

With the EU’s new General Data Protection Regulation coming into force in May this year, the impetus for life sciences firms to cement their data management strategies has increased.

Pooja Phogat

Articles

EMA’s Demands for Plain-Language Summaries for Clinical Trial Results that can be Understood by Anyone Could Create new Challenges for Sponsors

Optimal Strategies for Compliance with EMA Policy 0070 on the External Publication of Clinical Data