The 11th European Medical Writers Association (EMWA) symposium, entitled ‘Clinical trial disclosure and transparency: impact on medical writing and communication (Clinical Trial Regulation EU 536/2014)’ took place on 11 May. The symposium explored this topic trough presentations and panel discussions, focusing on insights particularly relevant to medical writers and communications professionals.
A summary of the symposium is provided below to benefit those who were unable to attend, and as a timely reminder of the key topics for those who did.
EMA transparency journey and impact on its stakeholders
- Transparent reporting of clinical trial information is fundamental to a well-informed decision-making process around public health issues.
- Medical writing and communications professionals have a critical role to play in preparing the documentation required for transparent registration and reporting of clinical trials, mandated by EU laws.
Kicking off the day, Slavka Baronikova (EMWA Conference Director; Galapagos) welcomed attendees to this year’s symposium. Kathy Thomas (Medical Writing, Disclosure and Transparency Consultant) then began proceedings, outlining how the last 20 years have seen an increased emphasis on clinical trial disclosure and transparency, supported by initiatives to encourage prospective registration of clinical trials and timely disclosure of results in publicly available databases. Medical publication professionals play a crucial role in preparing various documentation supporting these clinical trial disclosures, which need to fulfil the reporting requirements of relevant laws (ie Clinical Trials Regulation EU 536/2014 [EU CTR] in the EU), while protecting the identities of patients participating in trials and the commercial interests of trial sponsors. As of January 2023, all clinical trials conducted in the EU and in countries belonging to the European Economic Area (EEA) must conform with the EU CTR. So it is important that medical writers of regulatory documents as well as publication professionals understand the requirements and implications for involved stakeholders.
All trials conducted in the EU must conform with the EU CTR, so is important that medical publication professionals understand its requirements and the implications for involved stakeholders.
Morgane De Verdiere (European Medicines Agency [EMA]) described how transparency is a core value of the EMA and is key to building trust with patients and general public, healthcare professionals (HCPs), media, public health bodies, pharmaceutical industry, and academia.
- ensures decisions the regulator makes are well founded and more likely to be supported
- raises awareness of EMA recommendations that impact the public
- allows the EMA to communicate key public health messages and address questions of concern from the public
- counter misinformation about healthcare matters.
Public health emergencies crystalise the need for transparency. An example is the
COVID-19 pandemic, when the EMA had to adapt quickly to keep its audiences informed. Examples of its approach to transparency included holding public hearings on YouTube to explain how an accelerated vaccine approval process was possible, introducing a ‘rolling review’ process for pharmaceutical companies to submit data for drug assessments on an ongoing basis, and providing frequent updates—using accessible language—on the EMA website regarding safety events associated with vaccination. The pandemic demanded increased transparency from the EMA to ensure public trust in the regulators and their decisions.
De Verdiere moved on to discuss the impact of the recently introduced EU CTR (sometimes also referred to as the new Regulation) on the medical writing community, with the implementation of the EU portal and database — Clinical Trials Information System (CTIS) designed to harmonise the submission, assessment, and supervision of clinical trials established under the EU CTR across the EU and EEA. Combined with supporting legislation (EU CTR), CTIS will facilitate the conduct of multinational trials, enable wider collaboration and access to clinical research data, ensure that the EU remains a desirable location in which to conduct clinical research, and further reinforce the trust that underpins the approval of medicines. De Verdiere explained the evolution of the CTIS transparency rules, which are currently being reviewed to better balance transparency (ie full disclosure of clinical trial information) by allowing pharmaceutical companies some opportunity to defer the disclosure of commercially sensitive information.
De Verdiere concluded that transparency is fundamental to empowering patients and HCPs to make informed decisions about health issues and treatments. Balancing this need for transparency with the need to allow companies to invest in and protect their technologies requires a flexible and adaptable approach from the regulator.
Balancing need for transparency with the need to allow companies to invest in and protect their technologies requires a flexible and adaptable approach.
EFPIA perspective on the EU CTR
- EU law now requires many clinical trial regulatory documents to be made publicly available.
- The law provides tools for sponsors to protect their intellectual property, but there needs to be balance between transparent reporting and protecting the ability of industry to innovate.
Silvia Garcia (European Federation of Pharmaceutical Industries and Associations [EFPIA]) opened the second session of the morning by reiterating the mission statement of EFPIA to foster a collaborative environment for the development and delivery of new therapies in Europe. Garcia then outlined EFPIA’s principles for responsible clinical trial data sharing. As pointed out, while most EFPIA members have transparency measures and policies that go beyond the commitments of the EFPIA principles, these required updates to reflect modern data sharing initiatives, which include clinical trials registries (eg ClinicalTrials.gov), multi-sponsor data sharing platforms, and open access publication of clinical trial results. EFPIA began a member consultation process in 2020 to assess compliance rates and ways to improve transparency in data sharing, and submitted revised wording for the principles for board endorsement in April 2023. Compliance rates following the consultation process are very close to 100%.
Polyana Bastos (Johnson & Johnson; EFPIA) provided an industry perspective on the implications of the EU CTR, with a particular focus on how and when companies should use the option to defer submission of clinical trial information to CTIS to protect their commercially confidential information (CCI). As of January 2023, the EU CTR requires most clinical trial application documents to be published on the EMA’s CTIS platform. Protected personal data (PPD) can be redacted in the published (freely open to public) documents, while CCI can be protected by deferring publication for several years, with the timescale depending on the category of clinical trial (a longer deferral period is allowed for earlier stage trials). The intention is to allow sponsors to protect their CCI, but to avoid extensive redactions of the trial information when it is ultimately published.
CCI can be protected by deferring publication for several years…The intention is to allow sponsors to protect their CCI, but to avoid extensive redactions of the trial information when it is ultimately published.
In addition, Bastos described how EFPIA has been working with the EMA to develop practical solutions for sponsors to protect their intellectual property. Using the example of a dose finding clinical trial, where disclosure of dosing information could potentially preclude a successful patent application, a potential solution was identified to allow submission of ‘dummy data’ for specific fields in CTIS. Implementing such solutions would require technical modifications to the CTIS system, but would also require a balance to be struck between transparent reporting of clinical trial information and protecting sponsors’ intellectual property and encouraging innovation.
Clinical trial start up: sponsor perspective
- A focus on transparency and attention to PPD and CCI should be integrated throughout the clinical trial working process.
The morning continued with an overview of the impact of the EU CTR from the sponsor perspective, delivered by Merete Jorgensen (Merete J Consulting). To set the scene, Jorgensen reaffirmed the vision of the EU CTR, which includes:
- making the EU more attractive for clinical trial sponsors
- ensuring consistent rules between EU member countries
- strengthening data transparency.
Jorgensen noted that in contrast to the previous law on disclosure of clinical trial information – the EU Clinical Trials Directive (CTD), clinical trial documents entered as part of a clinical trial application (CTA) and during the lifetime of the clinical trial under the EU CTR must be uploaded to CTIS. All information, except personal data, information on quality aspects of the investigational medicinal product (IMP), and communication between member states, will eventually be made public. This means that everyone working in clinical development and regulatory functions must have the legally-binding disclosure and transparency requirements in mind.
The vision of the EU CTR…includes making the EU more attractive for clinical trial sponsors, ensuring consistent rules between EU member countries, and strengthening data transparency.
Jorgensen stressed the need, right from the beginning of the working process, to pay attention to the following definitions:
|Any information from which a person
(a data subject) can, or potentially can, be identified. For example, no PPD regarding trial participants can be included in the documents. In contrast, principal investigator names must be made public.
|Any information submitted to CTIS that is not in the public domain, that must be protected for critical business reasons
(ie where disclosure could undermine legitimate economic interests of the information owner).
To help adhere to requirements for protecting PPD, such as the General Data Protection Regulation (GDPR), Jorgensen explained it is possible to upload 2 versions of each document at the same time, with only the first being made public. Jorgensen provided several suggestions to help medical writers protect PPD and CCI. She emphasised minimisation, ie thinking carefully about whether the information is necessary for regulatory purposes. Remaining information may need to be redacted, or possibly anonymised (although the extent of anonymisation required is a matter of debate). As for CCI, documents dealing with quality of the IMP are not published; therefore, medical writers should ensure to distinguish these from other documents.
Jorgensen’s talk concluded with the impact of the EU CTR on clinical study reports (CSRs). CSRs are the only documents that are not subject to deferral. CSR are due for upload to CTIS 30 days after marketing authorisation is granted, the procedure is finalised, or the marketing authorisation application is withdrawn. The version of the CSR released is that submitted as part of a marketing authorisation application, highlighting the increased transparency required by the new regulations.
Paula Nixon (AstraZeneca) went on to discuss the company’s experience of the transition from the EU CTD to EU CTR. Nixon explained that we are currently in period 2 of the transition, meaning that all initial CTAs must be submitted using the new EU portal and are governed by the new Regulation. In period 3 (effective from 31 January 2025), all clinical trials will be governed by the EU CTR, regardless of whether the initial clinical trial submission was under the EU CTD.
Nixon explained that one of the greatest benefits of the EU CTR is the harmonisation across the EU/EEA, with one system, one process, and one approval. The CTA process, from validation through to a decision, should take 60–106 days, including a period for questions and requests for more information. Medical writers must be mindful that requests for information (RFI) are subject to a response time of 12 calendar days and this may include making a protocol amendment. With this, Nixon encouraged a mindset shift from reliance on protocol amendments towards aspiring to get the CTA right the first time. Ultimately, more time and effort spent on initial preparation lends itself to a smoother CTA review and approval process. Nixon highlighted some additional considerations for the planning phase, such as whether the study design is optimal or could yet be simplified, and whether patient groups have been consulted, looking ahead to potential queries during CTA review.
Nixon also shared key takeaways around CCI:
- CCI is not static and evolves over time. It is challenging, but important, to predict what might be CCI later, at the time the document is released (eg 5 years later, after deferral).
- Only critical CCI can be redacted. The level of redaction should be balanced with the requested deferral duration.
Nixon wrapped up her presentation with several proactive considerations for preparing clinical trial documents. Above all, Nixon recommended flagging potential CCI in a document from the outset, rather than identifying CCI after completion. Not only does this speed up the redaction process, but more critically, highlights the level of CCI in a document, opening up discussions with clinical teams about the best way forward. Medical writers should play a central role in this activity and process.
Nixon recommended flagging potential CCI in a document from the outset…Not only does this speed up the redaction process, but opens up discussions with clinical teams about the best way forward. Medical writers should play the central role in this activity and process.
Clinical trials conduct: industry perspective
- Medical writers can play a key role in transitioning clinical trials from the EU CTD to the EU CTR.
Next up, Sarah Bly (Worldwide Clinical Trials) covered the impact of the EU CTR from the industry perspective. The main focus of Bly’s talk was considerations for studies currently running under the EU CTD that will have at least one active EU site on 31 January 2025, when the next phase of the transition to the EU CTR begins. As part of the transition, multinational clinical trials will need to be transitioned as a single multi-country CTA, using either:
- A harmonised protocol: a protocol approved across all member state countries (MSCs) under the EU CTD, where there are no differences between countries.
- A consolidated protocol: a protocol with differing procedures between MSCs, but with an identical protocol document for all countries.
Medical writers might be brought in to help prepare the required documents for the transition: a cover letter, an EU CTR application in CTIS, and a harmonised/consolidated protocol for multi-country trials. For clinical trials already approved under the EU CTD, the transition should be seen as an administrative step. This is reflected in the assessment timeline: applications are approved within 60 days unless requests for information are raised. RFIs are typically raised when there is a discrepancy between the submitted documents and those approved under the EU CTD.
Next, Bly discussed a change in terminology with the EU CTR, from ‘amendment’ to ‘modification’. Bly noted that as with amendments, modifications can be substantial or non-substantial, and directed the audience to several examples.
The last portion of Bly’s presentation covered notifications, including those required via CTIS within 15 days from the start of the trial (usually the start of recruitment), the end of recruitment, and the end of the trial (usually the last visit of the last participant in MSCs).
Bly also discussed circumstantial event notifications, with temporary halt and restart, early termination, and unexpected events notifications required within 15 days after the event. Serious breach and urgent safety measure notifications must be made within 7 days.
Bly highlighted that given their knowledge of the study protocol, medical writers may be consulted about whether urgent protocol modifications are needed in light of serious breaches or unexpected events.
Given their knowledge of the study protocol, medical writers may be consulted about whether urgent protocol modifications are needed in light of serious breaches or unexpected events.
Clinical trials conduct: PV perspective – EU CTR and publication of RMPs – impact on DSURs and RMPs
- Defining processes up-front to identify and redact CCI in risk management plans (RMPs) can help meet tight timelines. Medical writers can play a key role.
After a brief summary of the morning sessions by Lisa Chamberlain James (Trilogy Writing & Consulting Ltd), Sven Schirp (Boehringer Ingelheim) kicked off the first afternoon session.
Schirp discussed the impact of the EU CTR on processes relevant for the creation of development safety update reports (DSURs) and RMPs. The reference safety information (RSI) included in the investigator’s brochure presents a list of preferred terms for serious adverse events that are considered to be expected. The RSI used to identify any serious unexpected serious adverse reactions (SUSARs) for the DSUR must be that in effect at the start of the annual reporting period, defined by the EU CTR as the version most recently approved in at least one member state where the trial is ongoing. Further, when determining expectedness of an event, the date of event onset must be matched with the RSI in place at the time. Schirp also noted that in light of the EU CTR, subject identifiers cannot be included in the DSUR, while methods used to assess signals during the reporting interval must be described.
In the second part of his talk, Schirp discussed how the EMA has begun making RMPs publicly available, with full publication of redacted RMPs containing new active substances—or of particular public interest—now routine. Consequently, the marketing authorisation holder (MAH) needs to be prepared to provide a redacted version of the RMP within a short time period. Schirp signposted the audience to detailed guidance for identifying CCI, noting that medical writers may be brought in to provide guidance on what should be considered CCI (and thus redacted) or to propose specific sections for legal review. Given the limited timeframe for redactions, Schirp recommended defining a clear process to identify and redact PPD and CCI in advance.
Clinical trials results reporting and dissemination
- Writing in lay language is crucial for effective dissemination of clinical trial information, with training needed to hone this skill.
- Patient involvement in the planning, development, translation, and dissemination of lay summaries is recommended to ensure these meet patient needs.
- Many sources of guidance are availability regarding regulations and best practice for scientific publications.
Chamberlain James opened the session with a discussion of lay summaries of clinical trial results, emphasising that alongside moral obligations to communicate findings in plain language, failed communication can have a significant impact on adherence and even the rate of adverse drug reactions.
Chamberlain James discussed the problems medical writers may face when developing lay summaries of clinical trial results, given no approved template is available. Chamberlain James signposted attendees to Annex V of the EU CTR, outlining 10 topics that must be covered in lay summaries:
- Clinical trial identification (eg title, protocol number, EU trial number), to help readers find the trial
- Name and contact details of the sponsor
- General information about the trial (eg when, where, and why the trial was conducted, and main objectives)
- Study population (eg location, age, gender, inclusion and exclusion criteria)
- Investigational medicinal products used
- Adverse reactions and their frequency
- Overall results
- Comments on the outcome
- Next steps, ie whether follow up trials are foreseen
- Signposting to where additional information can be found.
Although these requirements are a useful starting point, they are not without problems. For example, trial titles and eligibility criteria can be very long and filled with technical language. While guidelines recommend including ‘key’ criteria, these are not defined and must be judged by writers and clinical teams – but what is ‘key’ for patients? What name do we use for the investigational medicinal product? Often names can be very long, a chemical name, or just a number. In the instance of multiple brand names, should all brand names be listed? Study designs can also be very complex – if the study includes blinding, should the importance of this be explained? Chamberlain James noted there is a fine line between informing and teaching, and to inform, you need to give a certain amount of context and background information. She also discussed requirements for provision of a protocol synopsis in lay language. This raises similar issues to lay summaries of trial results, with additional challenges arising through the ethical considerations section (such as tone, cultural sensitivities, and context), as well as the tight page limit.
Chamberlain James emphasised that writing in lay language is not as simple as changing ‘difficult’ words to simple ones, given the potential for errors in ‘translation’ – providing reassurance that ChatGPT is not going to replace medical writers. Chamberlain James concluded her presentation by underscoring the value of medical writers training and testing their lay summary writing skills, highlighting a well-known Albert Einstein quote.
“If you can’t explain it simply, you don’t understand it well enough.” – Albert Einstein
Next, Jan Geissler (Patvocates) discussed dissemination of trial results from the perspective of patients with severe diseases. To set the scene, Geissler highlighted patients typically have many questions following diagnosis or disease progression, but often do not receive satisfactory answers, given time pressures in the healthcare system and the lack of materials available for HCPs to share. Information from patient organisations can help to fill this gap. Scientific publications can also be a great source, but these need to be findable, accessible, and understandable.
Geissler stressed that a ‘one size fits all’ strategy for communication rarely works, given the heterogeneous ‘patient’ audience (which can encompass carers, patient advocates, patient organisation representatives, and expert patients). For instance, text-based plain language summaries, infographics, videos, and detailed publications all have different levels of accessibility and suit different audiences. Geissler emphasised the importance of patient involvement during planning, development, translation, and dissemination: for example, patient involvement during planning will identify which endpoints are most important, meaning lay summaries are more likely to meet the needs of patients. Patient organisations can help identify a representative group of patients to contribute.
On a final note, Geissler spoke of the frustrations experienced by patients when clinical trial results are published in peer reviewed journals a long time before the lay summary becomes available (mandated by 12 months after the protocol-defined end of the trial for many studies). Patients need timely access to the latest data to make informed decisions – a year can be a very long time for a patient. Time is of the essence, and it could be lifesaving.
Patients need timely access to the latest data to make informed decisions –a year can be a very long time for a patient.
In the final talk of this session, John Gonzalez (Solanum Medical Communications) explored the impact of the EU CTR on peer reviewed publications. Gonzalez signposted to the many different sources of scientific publications guidance available, including regulations, Good Publication Practice (GPP), International Committee of Medical Journal Editors (ICMJE) recommendations and reporting guidelines compiled by the EQUATOR Network. Although the guidance put forward by these sources varies, Gonalez noted:
- Often scientific journals require pre-registration of clinical trials as a condition of consideration for publication.
- Guidance requires the timely dissemination of clinical trial results – and more recently, encourages publication of Phase I trial findings.
Gonzalez also discussed documentation required by journals as well as EU CTR timing requirements for posting data and documents, which depend on the type of study. He noted consistency between trial protocol and results postings on public registries and information reported in peer reviewed publications is key (especially around the primary endpoint, for example). Any discrepancies, including expected information not being reported, are likely to be scrutinised. In closing, Gonzalez noted the EU CTR will increase transparency, and the more data published, the better for patients.
Consistency between trial postings on public registries and information reported in peer reviewed publications is key…Any discrepancies, including expected information not reported, are likely to be scrutinised.
Panel session: ask the experts
The day’s proceedings concluded with a panel discussion and Q&A session, with Morgane De Verdiere, Polyana Bastos, John Gonzalez, Aman Khera (Worldwide Clinical Trials), Merete Jorgensen, Paula Nixon, Silvia Garcia, Pooja Phogat, (Krystellis), Art Gertel (MedSciCom), and Priti Nagda (Taylor & Francis) the panellists. Key points included are summarised below.
The importance of involving patients throughout the clinical trial process
The panellists agreed that engagement and consultation with patients/patient advisory boards was key for determining the direction of clinical trial research and making patients aware of clinical trials they can participate in. The COVID-19 pandemic demonstrated that virtual approaches and decentralisation could enhance participation in clinical trials: there are no new drugs without clinical trials, and no clinical trials without patients. Patients should also be involved in publishing the results, including having patients as authors where appropriate. A case was made for mandatory open access publication of a plain language summary for every clinical trial conducted. From a regulator’s perspective, patient consultation during the review of lay summaries and safety communications is essential, and new law is being discussed to elevate the role of the patient in regulatory activities.
From a regulator’s perspective, patient consultation during the review of lay summaries and safety communications is essential.
The importance of balancing transparency and the ability of the pharmaceutical industry to innovate through protection of intellectual property
The panel acknowledged the need for transparent reporting of clinical trial information to maintain public trust. Extensive redaction of published information—even for legitimate reasons—can undermine this trust and damage the credibility of the industry. On the other hand, disclosure of confidential information could lead to discontinuation of a product’s development, which is ultimately bad for patients. Guidance from the EMA on how and when to redact or defer the disclosure of CCI was welcomed by industry, but it was important to understand that the guidance was not exhaustive, and the context of each case mattered.
Effective and transparent two-way communication is key to tackling misinformation
The panel thought that it was important to listen carefully to social media platforms, including to identify sources of misinformation more quickly and respond with robust evidence. The COVID-19 pandemic highlighted peer review as a hallmark of reliable information, so publishing peer reviewed research to counter misinformation is a vital strategy.
Implications of the EU CTR for multinational trials including countries outside the EU
The panel discussed the practicalities of EU CTR requirements for submitting study protocols that may contain country specific requirements, for example. Acknowledging it was still a learning process regarding best practice, and whether it was necessary to submit country specific protocols for countries outside the EU, one approach could be including all country specific requirements in an appendix to the submission.
Considering the broader impact of clinical trials on the environment
While the latest EU CTR law will increase the focus on environmental risk assessment, this is not within the remit of the information included in RMPs. However, the panel noted that environmental impact assessment has become part of the wider conversation surrounding clinical trial conduct, with various guidelines being developed or in place in different territories, such as the National Institute for Health and Care Research (NIHR) carbon reduction guidelines.
Written as part of a Media Partnership between EMWA and The Publication Plan, by Aspire Scientific, a proudly independent medical writing and communications agency led by experienced and dedicated industry experts.