Retention in Paediatric Rare Disease Clinical Trials  

Originally appeared in International Clinical Trials Summer 2025, pages 43-45

By Florence Mowlem, PhD, Chief Scientific Officer, uMotif 

How can the clinical research industry better engage caregivers and participants to tackle the unique challenges of retention in paediatric rare disease trials?

A rare disease is defined as a condition that affects less than 1 in 2000 people, and there are over 7000 known rare diseases, with approximately 70% starting in childhood (World Health Organisation, 2025). With the high costs of drug development and the small population affected, the barriers to profitability were seen as high. However, rare disease clinical trials are receiving greater focus in clinical research than ever before, marking a significant shift in the perception that these conditions were not commercially viable for drug development organisations to target.  

In no small part, regulatory incentives such as the EU’s Orphan designation have changed the landscape of investment in this area (Seoane-Vazquez et al., 2008). Additionally, improvement in understanding of these disorders and precision medicine, along with the voice of patient advocacy groups becoming louder, has driven momentum to progress treatments for rare disease. 

It is well known that participant dropout in clinical trials can impact study integrity, as well as leading to increased costs and delayed timelines. With an inherently small number of the population affected by a given rare disease, every participant holds exceptional importance in a paediatric rare disease clinical trial. Thus, a participant dropping out would have even greater impact on study success. 

Further, an increase in the launch of new treatments that target smaller populations – such as rare and genetic disorders – creates greater competition in the market (Smith et al., 2024), increasing the pressure to speed up the drug development process. 

There is a common misconception that if an individual remains in a clinical trial, then they are engaged; that is, retention and engagement are synonymous. However, this is not the case – one could be remaining in a trial due to the benefits it could potentially lead to, but not be engaged in the trial itself. Vice versa, one could be very engaged with the trial but drop out due to drug side effects. However, engagement does have the ability to increase retention rates. A study by the Clinical Trials Transformation Initiative (CTTI), found that – depending on the phase of the study – the incorporation of patient engagement activities can lead to a cumulative impact in net present value (NPV) of $62MM to $65MM per study, an increase in expected net present value (ENPV) of $35MM to $75MM per study, and accelerate drug launch by 1 ½ to 2 ½ years, through avoiding one protocol amendment and improving enrolment, adherence, and retention (Levitan et al., 2018). 

The role of caregivers

In paediatric clinical trials, patients’ caregivers play a central role in the trial and are the primary reporters. Furthermore, in rare disease, the participants themselves – even if of a chronological age they would be able to self-report if they experienced typical development – are often not able to communicate themselves on their health status, and so observer-reported outcomes (ObsROs) are typically the main source of outcome assessment.   

Caregivers are generally one of the most compliant groups in research, which is not surprising; however, they have incredibly complex lives, caring for a sick child, and so as a clinical research community we should be doing our utmost to reduce the burden of participation. Especially given that clinical trials are increasing in complexity; for example, a typical Phase III clinical trial during 2016-2021 had an average of 25.8 endpoints, up 37% since 2015 (Tuffs Center for the Study of Drug Development, 2023). 

Below, some strategies are outlined that can support retention in paediatric rare disease trials, recognizing the importance of engaging the right stakeholders through the entirety of the clinical research process, from protocol development to post-study feedback, to foster a seamless participant and site experience. 

Strategies to support retention

Input at protocol development stage

Gaining the right stakeholder input into study design is a factor for success, and this should include those who will be participating – including caregivers and site personnel. Historically, it has not been commonplace that these key study stakeholders have been included in this process. Fortunately, this perspective is changing, as gaining input from stakeholders can have an important influence on retention during the the trial. For example, the EMA’s Recommendation Paper on Decentralised Elements In Clinical Trials (REF), clearly states their early and sustained participation in this process may “help develop trust in the trial, facilitate recruitment, and promote adherence”. 

Often, patient advocacy groups are included in such activities or sponsors may have a patient steering panel that they consult regularly. However, it is important that sponsors obtain view from naive participants and those less familiar with clinical trial conduct and data capture methods, ensuring a variety of input is received. Further, in the case of paediatric rare disease, it is possible that there is nuance that would not be captured unless that exact population of participants and caregivers was consulted. 

Ultimately, both patient and site engagement during this stage of the clinical research process is likely to result in sites that are engaged and advocates for all aspects of the study design during conduct. 

eConsent

eConsent involves using digital technologies to facilitate the consenting process, whether that be on site or remote. Regardless of whether the consent document is being signed at site or remotely, or with wet-ink or electronic signature, offering the opportunity for caregivers to have the time to read the consent form outside of the clinic environment offers many benefits. Paediatric rare disease trials can be complex, and providing the time and space for caregivers to read and absorb the information and what will be required of participation in the trial is important, as well as the opportunity to discuss with others (e.g., family members or their healthcare team). Pre-reading also allows time for questions to be formulated and duly addressed with the site, and means caregivers do not have to read a plethora of complex information at a site visit when they have their child with them. eConsent also allows the information to be presented in a more user-friendly and engaging way, which facilitates comprehension. These factors have the ability to reduce trial dropout (Advarra, 2021). 

Data capture

Capturing clinical outcome assessment (COA) data electronically (from both caregivers and sites), can create a more streamlined process. Beyond more contemporaneously valid data, electronic data capture of COAs offers solutions to other limitations associated with paper-based assessments. The digitalized nature of the measurement can reduce patient burden (e.g., not having to independently remember to complete questionnaires by receiving pre-programmed alerts, not having to return the paper copies to site due to automatic upload of data), as well as the burden on trial staff who are not having to manually transcribe data into a data management system, which can be fraught with human error. Furthermore, the quantity of missing data is reduced. 

It is important to acknowledge a perception in the industry that by default eCOA systems generate high levels of compliance, regardless of the study design, including the measures used and the frequency with which they are captured. It is important to recognize that even the best eCOA system will not solve for poor study design and selecting long measures that are not relevant to participants. 

Development and validation of COAs is a long and laborious process. In pediatric rare disease, population, disease-specific measures can be lacking, and so a high number of measures may need to be used to capture the broad range of health status characteristics.  As such, many of the measures often include redundant (e.g., overlapping items) or irrelevant domains. Combined with the pressure to ensure that efficacy is shown in as many domains as possible, trials can easily have caregivers and sites completing up to 500 items or more in a given session. No matter how engaged a caregiver is in a trial, this can create real challenges to compliance and retention. 

As a sponsor, ensuring that you are strict with only measuring what you really need to, and what aligns with your protocol endpoints (of which such information can be gathered from caregivers when obtaining input during the protocol development process), can have a significant impact. 

From a data quality perspective, the optimal scenario involves the same caregiver providing responses to questionnaires consistently throughout the duration of the trial to enhance the reliability and uniformity of the reported data. However, in practice, it is often not realistic, nor feasible for a trial participant to have only one designated caregiver. For example, children may be looked after by grandparents several days per week, attend nursery, or have separated parents (Haenel & Mowlem, 2025). Planning for the eventuality of multiple caregivers capturing data about a participant from the outset provides the best opportunity to more seamlessly integrate data collection into the lives of participants and retain them in the trial. Data capture from multiple caregivers should be incorporated into your statistical analysis plan, and data capture systems set up to support multiple users reporting on a single participant (Mowlem, 2025). 

Engagement strategies during the trial

The concept of ‘patient engagement’ during a trial is sometimes treated as an ethical checkbox rather than a genuine value-driver. This should not be the case, especially given the evidence of its benefits on retention. 

One method for engagement during the trial is to ensure meaningful training, for both sites and participants. Ensuring sites are aware of why certain decisions were made for the trial – such as the use of digital technologies for data capture or using a bring-your-own-device (BYOD) strategy – helps site staff advocate for these elements with participants. Further, ensuring sites are effectively trained on systems is critical to mitigate potential issues. Often sites will only have one or two participants, given the nature of rare disease trials, and so site staff may not use these systems as often as those in trials with a higher number of participants. 

The same applies for participants. When participants have greater understanding of why the study was designed in a certain way, including why certain things are being measured, and the importance of the data capture to trial success, they are more likely to be engaged, have high compliance, and ultimately remain in the trial. 

Another way to make participants feel like a key stakeholder in the trial, and not just a data point, is to obtain feedback throughout the study. For example, utilising TransCelerate’s Study Participant Feedback Questionnaire (SPFQ), can provide insight into how participants are experiencing different aspects of the study and allow for resolution for the current study, or effective mitigation for future studies. 

Final thoughts

The strategies outlined in this article are important strategies for optimizing participation in paediatric rare disease clinical trials, and given the increase in the number of pediatric rare disease trials, ensuring the most effective strategies are being utilized is critical, and as an industry we must continue to innovate. 

We must ensure that participants and sites have a voice throughout the clinical research process, so they know they are not just a number, but key stakeholders that are valued and appreciated as part of the research journey. 

Ultimately, informed and engaged sites are likely to lead to more informed and engaged participants, leading to a positive impact on retention. 

References

Advarra (2021). Retention in clinical trials: keeping patients on protocols. https://www.advarra.com/resource-library/retention-in-clinical-trials-keeping-patients-on-protocols/ 

Haenel, E. & Mowlem, F.D. (2025). Data collection in clinical trials with multiple caregivers. Applied Clinical Trials. 34, 1 

Levitan B, Getz K, Eisenstein EL, Goldberg M, Harker M, Hesterlee S, Patrick-Lake B, Roberts JN, DiMasi J. Assessing the Financial Value of Patient Engagement: A Quantitative Approach from CTTI’s Patient Groups and Clinical Trials Project. Ther Innov Regul Sci. 2018 Mar;52(2):220-229. doi: 10.1177/2168479017716715.  

Mowlem, F.D. (2025). The uMotif Care Cluster Solution: Capturing Quality Data from Participants & Their Caregivers. https://umotif.com/blogs/the-umotif-care-cluster-solution-capturing-quality-data-from-participants-their-caregivers/ 

Seoane-Vazquez, E., Rodriguez-Monguio, R., Szeinbach, S. L., & Visaria, J. (2008). Incentives for orphan drug research and development in the United States. Orphanet Journal of Rare Diseases, 3(1), 33. doi:10.1186/1750-1172-3-33 

Smith, Z., DiMasi, J., & Getz, K. (2024, July/August). Dollar value of one day delay in drug development is now 20% of blockbuster era levels. Tufts CSDD Impact Report, 26(4). 

Tufts Center for the Study of Drug Development. (2023, May/June). Protocol design scope and execution burden continue to rise, most notably in Phase III (Impact Report, Vol. 25, No. 3).