Working from the non-regulatory guidance and templates
Beyond the regulation itself, a writer of a lay summary of trial results can draw on guidance and templates from other bodies: the return-of-results guidance and toolkit that a multi-stakeholder workgroup published while official guidance was still missing, the summaries a non-profit piloted with sponsors, approved lay documents that a summary can borrow from, and the Good Lay Summary Practice guidance, which a later multi-stakeholder initiative saw adopted by the European Commission, together with how it was agreed and what it left open.
The role of non-regulatory guidance
As of July 2015 no regulatory guidance on lay summaries had been produced, and a writer could use other resources in the interim: the templates, guidance and examples published by the Harvard workgroup and by the Center for Information and Study on Clinical Research Participation, whose work the European Medicines Agency and the US Food and Drug Administration support. In April 2015 a representative of the European Medicines Agency said informally that although regulatory guidance might not be produced for some time, it might help in the interim to review the work of the Harvard workgroup.
Guidance cannot address all situations, and precedents may be of more value; until precedents are available, the work of the Harvard workgroup and of the Center for Information and Study on Clinical Research Participation should provide a solid foundation.
Detailed guidance on how to prepare the lay summary is available from the European Medicines Agency and from other health or clinical trial disclosure organisations and patient groups interested in the document.
Initiatives to discuss and standardise the content of plain language materials will undoubtedly help improve the quality of the information and address some of the challenges, but given the variety of studies undertaken in clinical development the task is more of a mountain than a molehill.
The return-of-results guidance and toolkit
The Harvard workgroup is the Multi-Regional Clinical Trials Center at Harvard Return of Results Workgroup, a multi-stakeholder group whose 54 members include individual pharmaceutical companies such as Pfizer and Merck, the Pharmaceutical Research and Manufacturers of America, the European Federation of Pharmaceutical Industries and Associations, academics, patient advocacy groups including the European Patients' Forum, and non-profit centres including the Center for Information and Study on Clinical Research Participation. The Multi-Regional Clinical Trials Center is a research and policy centre that aims to identify and deliver ethical, actionable and practical solutions for the global clinical trial enterprise. The workgroup convened from January to September 2014 to agree guidance that sponsors could use to encourage the return of results. It calls lay summaries research result summaries and states that, although its focus is returning results to trial participants, its recommendations are congruent with the European Medicines Agency's mandate to post results on the EU database.
The workgroup published two documents in March 2015. The Return of Results Guidance is a practical guide covering process development from before the study begins through to delivering results and obtaining feedback, timing, document reviewers, format, content, style tips, how to convey numerical results and risk and benefit information, and readability (user) testing. It is a comprehensive document that considers the logistical challenges of delivering results and how they can be tackled. The linked Return of Results Toolkit carries templates for Phase 1 and for Phase 2/3 studies and for early trial closure, and a reviewer checklist. A disclaimer notes that while both consider the perspectives of the US Food and Drug Administration and the European Medicines Agency, they are not intended to supplant or interpret any regulation or official guidance.
The toolkit suggests how to translate endpoints into lay language in a table that gives a description of each type of endpoint beside an example in simple, plain language. For a mortality or overall-survival non-inferiority trial, the description says that the goal of the trial was to see whether one treatment or the other helped patients with the disease or condition live longer. It explains that non-inferiority trials seek to show that any difference between the two treatments is small enough to conclude that the new drug has at least some effect or, in many cases, an effect not too much smaller than the active control. Non-inferiority endpoints are designed to show that a new treatment is not worse than the control by a pre-specified amount, the non-inferiority margin, and efficacy can in fact be worse if there are other benefits, such as fewer side effects. The plain-language example has one version for a trial with no effect and one for a trial with an effect. With no effect, it says that patients in both groups lived about the same amount of time, no matter what treatment they got. With an effect, it gives the middle (average) amount of time patients in the study lived, notes that some lived a shorter time and some longer, and says that people in one group lived about 15 months and people in the other about 12 months, so the first group lived about 3 months longer. A further example says that the study showed a new insulin formulation was not much worse than standard insulin therapy at reducing the level of HbA1c in patients with type 1 diabetes.
For a patient-reported outcome, the description says that the trial studied patients' answers about what the questionnaire mainly measures, such as a symptom like pain, quality of life, psychosocial aspects, burden or economics, and whether the measurement changed depending on which treatment a patient got. It then names the primary endpoint, the scale it is based on, what that scale measures and how this changes over time. The example says that pain levels were measured on a known scale of pain, stiffness and how well people can climb stairs, stand or bend, with questions asked at each study visit. It says that patients given tanezumab had less knee pain than patients in the other group, and that knee pain was lowered in about 1 in 2 people (50%) in the tanezumab group and about 1 in 4 people (25%) in the other.
The toolkit also gives practical examples of neutral, non-promotional language in a table that pairs language to avoid with language to consider. This study proved that using drug A to prevent the condition is effective becomes a statement that people with the condition who got drug A had the primary endpoint. Drug A works better than drug B, but some people didn't tolerate it as well becomes a statement that more people in this study got the study endpoint with drug A and also had more safety events that interfered with their daily lives, with the specific events listed. Drug A is better tolerated than drug B becomes a comparison: fewer patients who took drug A than drug B had the named adverse events. A claim that a combined treatment did not extend life over one of its drugs alone, but that people felt better and lived longer with it, becomes a statement that both groups had the same kind of outcomes, that those on the combined treatment had milder named safety events, and that how long they lived depended on how they felt when they started. And study groups had the same results; more studies are provided after acceptance for publication in a peer-reviewed journal becomes a statement that there was no effect in the treatment arms or no difference between the groups, and that all groups still had pain and numbness in their fingers or toes (called neuropathy).
The non-profit's pilot summaries
The Center for Information and Study on Clinical Research Participation is an independent non-profit dedicated to educating the public and patients about clinical research, and in 2011 it began piloting programmes with Pfizer and Eli Lilly to return results to participants and collect their feedback. From 2011 it worked with several global pharmaceutical companies to help translate the technical results of clinical studies into lay summaries. The pilot summaries were written at a validated sixth-to-eighth-grade reading level, meaning ages 11 to 14, and four examples, two from each company, have been published on its website. Its research found a dramatic improvement in participants' understanding of the trials after reading the summaries, and that over 90% of volunteers were satisfied with their level of understanding. The US Food and Drug Administration suggested that the programme should be adopted industry-wide.
Approved lay documents to borrow from
Lay documents that have already been approved can be consulted for lay terminology. Descriptions of methodology may be taken from the applicable informed consent document, and lay glossaries used for adverse events. Patient information leaflets supply examples of lay safety information and can be reached through the electronic Medicines Compendium or sponsor websites. Regulatory guidance on those leaflets is available, including advice on lay terminology, preferred formatting, such as using bold rather than italics and underlining, and readability testing. On the European Medicines Agency's website, lay language on risk and benefit can be reviewed in European public assessment reports, which carry the final assessment for centrally approved or rejected products, and in lay summaries of risk management plans. Patient-oriented websites may also be helpful to consult, such as Cancer Research UK, which publishes lay descriptions of oncology studies for patients. Medical writers may also be interested in the European Medicines Agency's medical terms simplifier, a glossary of lay-language terms commonly used in the agency's communications for the public.
The Good Lay Summary Practice guidance
The EU's guidelines on the content of lay summaries left questions about how summaries are collaboratively planned, prepared and disseminated. The European Forum for Good Clinical Practice and the European Federation of Pharmaceutical Industries and Associations led a Roadmap Initiative for Good Lay Summary Practice, which set out to provide guidance on how to plan, write, translate and disseminate lay summaries and how best to involve patients in the process. The European Forum for Good Clinical Practice is a not-for-profit organisation established by and for those with an interest in the development of medicines and medical technologies, and the European Federation of Pharmaceutical Industries and Associations represents the biopharmaceutical industry operating in Europe.
The Roadmap Initiative published Good Lay Summary Practice in 2021. The European Commission issued it to support medical writers in preparing and writing a good lay summary, and it includes recommendations on patient involvement, presenting data and the use of lay language. It describes the requirements for a lay summary and gives many recommendations. It gives best practices on the planning, preparation, translation and dissemination of lay summaries, with many links to very good resources. Practitioners highly recommend it, one of them as a very comprehensive guidance document. The role of patients is worked out very practically throughout the guideline, without avoiding the complexities this may sometimes create, and academic researchers and small and medium enterprises are offered a stepwise approach to implementing it. In June 2021 the recommendations were expected to provide a wealth of useful detail, including considerations in planning and designing lay summaries, guidance on writing paediatric lay summaries and the tricky issue of translation, together with links to glossaries of lay terminology.
Good Lay Summary Practice was the first guidance developed by a bottom-up multi-stakeholder initiative to be adopted as regulatory guidance. It has been adopted by the Clinical Trials Expert Group, a working group of the European Commission. The final document is posted on EudraLex, the website where all European laws are published. It remains the accepted industry standard for creating and delivering high-quality lay summaries.
How the guidance was agreed
The obligation to prepare lay summaries for all clinical trials was apparently added very late to the European regulation: the European Forum for Good Clinical Practice had helped prepare parts of the regulation, but at that time informing the public about the results of clinical trials was not discussed, and the obligation surprised the forum when the regulation appeared in 2014. The mandate to inform the public systematically about the outcomes of clinical trials triggered a lot of interest and excitement. The forum and the European Federation of Pharmaceutical Industries and Associations held a first workshop in 2015 on what preparing and disseminating summaries would mean for sponsors, and learned there of the work of TransCelerate and of the Multi-Regional Clinical Trials Center, whose return-of-results workgroup produced the return-of-results guidance and toolkit. TransCelerate Biopharma is a not-for-profit entity whose mission is to collaborate across the global biopharmaceutical development community to identify, design and facilitate solutions to drive the delivery of new medicines. The workshop made clear that stakeholders would need more detailed guidance on the content and structure of lay summaries. The regulation did not give sufficient guidance for a successful and compliant implementation of lay summaries, and many stakeholders, among them sponsors of clinical studies and patient organisations, raised the need for more comprehensive guidance.
After the European expert group issued its guidance on the structure and content of lay summaries, the two organisations held a second workshop to review it. It concluded that knowing the requirements and the best ways to present the content was not enough: an overall process for planning, preparation, translation and dissemination was needed, and, most importantly, producing lay summaries should involve patients systematically, which existing guidance did not include at the time. Patients were strongly represented at that workshop and made it very clear that without them the process could not succeed. The two organisations created the Roadmap Initiative to bring together commercial and academic sponsors, patients, patient organisations, not-for-profit organisations, medical writers, lay language specialists and translators and jointly develop guidance on how to set up an overall lay summary process, and it was kicked off in 2019.
The guidance's development was started by a group of enthusiasts who wanted to provide clinical trial data in an understandable way. More than 60 organisations from Europe and the United States contributed, among them patients and international patient organisations, large pharmaceutical companies and small and medium enterprises, academic groups and research networks, not-for-profit organisations and clinical research organisations, and they worked together for more than three years towards a final guideline that was then accepted into regulation.
The initiative's structure was an international core management team and, initially, five task forces, each led by a core team member and a patient or patient representative: principles and processes of implementation beyond existing guidance; competencies needed to write and translate summaries; dissemination within and beyond the European Medicines Agency's portal; creation, translation, dissemination and funding, particularly for academia and small and medium enterprises; and suitable technology to reach patients, health care professionals and the public, including summaries for trials in children. Getting participants to contribute rather than listen in was hard, and regular meetings, regular updates and building awareness kept the task forces to their timelines and produced proposals. Within the initiative, keeping the academic group engaged was at times difficult, and there were moments of distress when some colleagues in major pharmaceutical companies wanted very specific points included.
Involving the Commission at the draft stages was an idea developed within the core management team: the team thought that guidance issued by the regulators was the most effective way to support the implementation of good lay summary practice, and believed that official release and recognition would make it far more powerful than if it came from a group of enthusiastic individuals who wanted to improve the world. In spring 2020 a first draft went to the Commission in a very early discussion; the Commission said it was in principle interested in collaborating towards a guidance, saw this aspect of transparency as a good way to support the overall goals of the new regulation, and, as the core management team did, supported the plan for a widespread public consultation on the draft in summer 2020, after which the two sides agreed to reconvene.
For the 2020 consultation the draft was posted on the forum's website and spread through members' networks, and it drew many comments on its structure and many detailed recommendations from all stakeholders. Integrating them into a second draft was a major challenge. The public consultation also found the draft of about 100 pages far too long and complex, especially for academic sponsors and investigators, and in need of some kind of summary, so the team split it into a Quick Guide of principles and basic information and a Handbook of detailed guidance, recommendations and experience, and took that to the Commission. Keeping all stakeholders invested during the difficult discussions with the Commission that followed was a major challenge too.
The Clinical Trials Expert Group, in full the Commission Expert Group on Clinical Trials, provides the Commission with advice and expertise on clinical trials in relation to the preparation and implementation of legislation and policy initiatives; it is part of the Directorate Santé and consists of 54 representatives of the national regulatory authorities and ethics committees of all European member states. The Commission forwarded the revised draft to that expert group for comment and review, and the group returned many comments and several topics on which it disagreed. The group insisted that the guidance be primarily European because it relates to the European regulation, so the need for summaries for patients in international and global trials, and of patients everywhere to have access to them, was not a priority for the group; this disappointed some representatives of global pharmaceutical companies, and after a tough discussion a compromise was reached, building on the goodwill of all stakeholders.
The Commission would not go into indirect dissemination, the dissemination of summaries through company or third-party websites, because it felt guidance on it was not appropriate while no broadly agreed standard for that kind of dissemination existed, which disappointed some representatives of large pharmaceutical companies hoping for guidance on disseminating summaries compliantly. The core management team agreed to take the topic up again and work it out in full for another discussion with the regulators, and that discussion in spring 2021 was one of the most critical moments, when it was really unclear whether an agreed document would result.
In June 2021 further revisions of the recommendations were still being considered. Coming to a final document took nine months of intense interaction between all the initiative's stakeholders and the Commission. Many members of the initiative helped overcome difficult moments, and the Commission and the expert group appreciated that this was a multi-stakeholder initiative with strong patient involvement and were willing to accept that they could not have created something better, since whatever they produced could only have been top-down and probably not as relevant and practical as the document the initiative produced. One of those who led the initiative holds that it was of critical importance that the initiative was driven by a neutral body, a role the European Forum for Good Clinical Practice filled, that the ongoing substantial involvement of patients was another key factor, that the guideline was driven not by large pharmaceutical companies or academia but by balancing the efforts of all stakeholder groups in an open and fair way, and that for academic research and small and medium enterprises it was important to be offered a stepwise approach to implementation.
What the guidance left open
The involvement of academia was an ongoing issue that came in waves. Academia was hard to engage at first because it was largely unaware of the requirement, and its biggest problem is one of timing: a lay summary is written very late in a trial, when funding is often no longer available because conduct-related activities have subsided, and current funding procedures make writing one after the end of the project impossible. That problem remained unsolved, so the initiative agreed that it would also need to work with the large funding bodies to make them aware of it. About 40% of trials in Europe are conducted by academia, which makes encouraging academic researchers to meet the obligation a key issue for the initiative. The initiative saw a need to continue discussions with the Commission's Directorate-General for Research and Innovation, which funds much academic clinical research, and to keep informing national funding organisations about the requirement and its resource needs, since they need to change their requirements and funding conditions to meet the costs of lay summaries.
The initiative also wanted to reopen indirect dissemination, sponsors' option of making lay summaries available on their websites, with the regulators: although lay summaries are a European requirement, all patients in a global trial and the global public have the right to be informed about results wherever they are, which needs defined processes and an appropriate framework.
Most importantly, it saw a need to keep spreading word of the guidance's availability to all parties potentially involved in preparing lay summaries. National webinars and workshops were planned, along with training programmes for stakeholders and the public on best practice in preparing lay summaries and an independent website as the central communication tool and repository for the guidance's activities and content. Making the guidance available in more languages could be a next step, and the initiative should continue to provide a platform for best practice, such as providing lay summaries for children. One of those who led the initiative believed that, with so much interest in transparency and in the results of clinical studies during the COVID-19 crisis, there was a window of opportunity to make providing lay summaries a part of the normal clinical trials process, and that the initiative would make those results more readily available to patients and the public.