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Survey uncovers pediatric-patient perspectives on plain language summaries.
Sharing the results of clinical research with trial participants and the public in a report that is understandable at the 6th-8th grade reading level, often referred to as a “lay summary” or a “plain language summary” (PLS), has coincided with a larger, patient-centric paradigm shift in the clinical research enterprise. Standardized practices and programs for PLS sharing to meet ethical, regulatory, and industry commitments have been established, published, and widely implemented within research sponsor organizations. However, sharing results with pediatric trial participants and the general pediatric community at large in an age-appropriate manner is an area with limited practical guidance and limited literature on practices to date.
At present, there are over 400,000 pediatric participants enrolled in clinical trials according to ClinicalTrals.gov. As a consequence of legislation passed over the last two decades, the number of pediatric trials is likely to increase further. While there are well established ethical mandates calling for sharing research results, as well as industry commitments1 and global good clinical research practice2, there are no specific references for age-appropriate results sharing to pediatric trial populations. The only legally binding mandate requiring a non-technical summary that is understandable for the general public, the European Union (EU) Clinical Trial Regulation (EU CTR 536/20143), is devoid of attention to this segment of clinical research stakeholders. However, the EU guidance4 for this regulation does suggest creation of an age‑appropriate PLS.
Beyond this guidance document, there are compelling arguments for investing resources toward establishing and publishing standardized practices for age-appropriate results sharing. The altruistic underpinnings of research participation are amplified in the pediatric space, where motivations are largely noted as for the benefit of future pediatric patients. In order to build trust among patients and public audiences, it is critical to provide accessible transparency in clinical development. Specific to pediatric audiences, sharing trial results is an expressed expectation of parents of potential and past research participants: 64% (n=500) of all parents stated they would be most interested in receiving a summary of the trial results, compared to only 38% who stated they received such a summary following their child’s participation in a clinical trial.5
Having collectively worked in the areas of pediatric clinical development excellence, PLS development, and PLS program implementation, we have identified some gaps between the current regulations that require aggregate results sharing and the guidances that provide recommendations to standardize age-appropriate aggregate results. We hope our own collaborative efforts to highlight these gaps in this article provide further support for the necessity of continued collaboration among industry, advocacy organizations, pediatric patients, their parents, and all other relevant stakeholders.
The specific topics we cover are the potential format, content, and design elements of a pediatric PLS. We also discuss some considerations around the importance of a co-creation process, as well as any implications around pediatric PLS dissemination. Weaved throughout the article are also insights from young members of the European Young Persons Advisory Network (eYPAGnet) and KIDS Barcelona (ages 12-19), as coordinated through Hospital Sant Joan de Déu in Barcelona, Spain.
There are several nuances to consider regarding the format, content, and design of a pediatric PLS. The EU regulation is the first of its kind to enforce the provision of pediatric summaries; however, practical guidance on how to produce an age appropriate PLS is lacking. The European Commission recently adopted the Good Lay Summary Practice (GLSP) guidance6, which is the first multi-stakeholder, multidisciplinary guidance document that includes general recommendations on pediatric results sharing. The GLSP guidance specifically encourages the use of and provides general good practices concerning age-appropriate formats for a pediatric PLS. However, concrete examples demonstrating the application of those principles are lacking.
Outside of the GLSP, the literature is limited in showcasing case studies and their learnings from those who have produced pediatric results summaries in an understandable manner for the intended audience. This is especially the case for ages 6 to 11 years, which falls below the 6th-grade reading level minimum noted in the EU guidance. As a whole, the industry still remains unclear on the best strategies that cater to the wide range of learning styles and cognitive developmental stages that span multiple age cohorts.
A case study published by Vashisht et al7 provides insights into what a pediatric PLS could look like; however, the pediatric user testing did not include testers below 9 years of age. A 6-year-old is just barely learning to read independently, while a 9- to 10-year-old can most likely read but would still benefit from visuals and pediatric-specific language to aid understanding. This calls for age cohort-specific content and design.
To better understand what might work for a pediatric audience, we conducted a small survey of youth from the eYPAGnet to learn more about their preferences related to a PLS. When asked how they would like to view the results of a clinical trial and the reason for their preference, all indicated a preference for a video (Figure 1), one of which stated: “videos can give a lot of information very fast. It's also very easy to explain difficult concepts by using animated scenes. For children, the goal is to get them to listen and understand as much as possible so videos can do that the fastest.”
The majority (70%) of youth participants indicated a preference to receive a digital PLS report, such as a link to a website, over a printed report (30%) (Figure 1), because it would be “easier to access” and paper could “get wet or lost.” Interestingly, most survey respondents indicated more than one preferred route of communication.
Opinions about specific content based on required elements4 called for in an EU PLS from survey participants are in Figure 2. The majority indicated that most of the elements were either important or very important. However, none of the survey participants indicated interest in knowing where the trial was conducted. Notably, the survey respondents placed importance on being provided with information to learn more about the trial. Anecdotally, sponsors have provided minimal information in this regard likely due to concerns around confidentiality of their plans for continued drug development. As such, sponsors may consider the benefits of an additional pediatric version of the PLS that contains only the elements that are appealing and understandable to a pediatric audience. This would of course be a separate PLS from the end-of-trial PLS4 required by the EU CTR.
Additionally, consistent messaging over a portfolio of closely associated pediatric trials can also be beneficial in fostering understanding. For example, several sister trials for nusinersen (SPINRAZA), Biogen’s treatment for spinal muscular atrophy (SMA), involved the same pool of participants, cascading into subsequent trials. To help foster a sense of alignment and community within these trials, each trial was associated with a certain animal (Figure 3) that was included in the corresponding pediatric PLS and other patient-facing materials. These animals were specifically chosen to align with key inclusion criteria for the associated trial, helping the participant understand their importance and rationale for participation in the trial. For example, the dolphin moving forward through the waves was chosen for a long-term extension trial, representing the uninterrupted high dosage and subsequent endurance of those pediatric participants.
Industry sponsors are increasingly engaging patients in the trial development process over a range of capacities. This includes during the protocol design stage, which allows for confirmation on the relevance and value of proposed endpoints to the target participant population of a given clinical trial. While co‑creation with the intended audience of a pediatric PLS would be the gold standard, the tight timelines for completion may prove challenging. This may especially be the case when there are a range of ages, thus requiring more than one cohort specific PLS. To add further complexity, the GLSP guidance suggests not only the inclusion of children in the preparation of a pediatric PLS, but also their parents.6
While it may not always be feasible to incorporate children and parents into the planning and design of a pediatric PLS, it is critical to include the applicable audience to pressure test a draft PLS in order to meet the intent of the regulation: to provide an understandable summary of the trial results to those who participated. Best practice, should be to engage age specific children and their parents very early in the process, ensuring opportunity for review and feedback.
The process for returning results to pediatric participants can also be challenging to maneuver. When a trial completes, investigators often serve as the liaison between the sponsor and the participants for results sharing. Complexity compounds when considering the often-lengthy timeframe between the participants’ last visit and when the final aggregate results are available. Consequently, efforts to locate participants may prove challenging for site investigators and can include additional costs to facilitate.
It is particularly important to note that sole reliance on dissemination via the upcoming EU Clinical Trials Information System (CTIS) will not be sufficient, as the platform will only allow for posting of a singular, end-of-trial summary that must include the required elements laid out by the regulation. The only exception noted is an interim summary if the protocol calls for an intermediate data analysis.8 This makes it impossible to provide a PLS for more than one age cohort or an accompanying adult version with all the required elements through the portal. As such, best practice would be for sponsors to consider additional methods of dissemination for any age-specific PLS in the desired formats (Figure 1), while using the portal to upload the required, end-of-trial PLS that includes all required elements.
Once available, there should be consideration for how the results can be effectively communicated to the participants. While a PLS should be written in a manner that is understandable at a lay level, younger trial participants will need assistance in understanding the report itself. In our survey, the majority (78%) of the youth participants noted that they’d like to talk with the doctors who did the clinical trial to learn about the results (Figure 4). One survey participant noted a feeling of confidence brought on by learning the trial results from the trial doctors themselves: “Being able to speak with the doctors that did the clinical trial would be really helpful because then I could ask them as many questions as I would like, making me feel confident about the results and the info given to me.” However, there were still about 55% of the survey participants who felt that talking with their primary doctor would be preferred, noting that “primary doctors have a balance between medical knowledge, and they also know you better than the researchers who made the clinical trial.”
The EU CTR is the first of its kind, calling for increased transparency, including the provision of a PLS at the end of a trial. However, there are nuances that sponsor must consider when standardizing practices for pediatric PLS development and program implementation.
While there is some newer guidance on creating an age specific PLS, concrete examples of how to put this into practice are sparse. Many pediatric clinical trials span multiple age cohorts, which would require multiple PLS versions to facilitate understanding. In our survey, while all respondents indicated a preference for the PLS to be in video format, most indicated additional preferences, including infographics, written reports with charts and graphs, or in a comic or story book style. Though multiple design formats may be complicated and costly, especially within six months of trial completion as the regulation requires, this should be considered a best practice if the end goal is to ensure comprehension for all ages included. This takes forethought and planning much earlier than what is the norm and is more complex in the pediatric space to ensure input from all ages of participants. Sponsors should also consider co-creation with pediatric participants, with an earlier involvement during the protocol design stage preferred. However, at minimum, sponsors should involve pediatric participants in the review of a PLS to ensure readability and value of the final document.
Sponsors should also conder how those results are communicated to pediatric participants. Our survey indicates mixed preferences with learning about the trial results from either the trial doctor or their primary care doctor; fewer respondents noted learning about the results from their parent(s) or guardian(s).
The regulations and guidance to date are a step in the right direction to support the intent to provide follow up and transparency to those who have chosen to volunteer in the name of clinical research. However, there is more to be done to ensure the spirit of the intent is met, especially when it comes to pediatric participants.
Sudipta Chakraborty, PhD is a Clinical Trial Transparency Strategy Lead for Biogen. Kirsten Sherman Cervati is the Senior Director & Global Head, Pediatric Research Partners for ICON. Behtash Bahador, MS
is the Associate Director of Health Literacy for CISCRP.
Begoña Nafría Escalera, Patient Engagement in Research Coordinator, Hospital Sant Joan de Déu, eYPAGnet, KIDS Barcelona survey participants