Dropout in clinical trials and in practice

Dropout rates in clinical trials and clinical settings represent a critical aspect of myopia research and patient care. High dropout rates can significantly impact the reliability and validity of clinical trial results, potentially leading to skewed outcomes and an incomplete understanding of treatment efficacy.¹ In clinical practice, patient attrition may result in suboptimal myopia control outcomes and increased healthcare costs. This article will go through what dropout means in research and clinical practice, factors influencing dropout rate and strategies to mitigate it.

Dropout is when participants or patients choose to leave or stop participating in a clinical trial or treatment regimen prematurely. This is typically a voluntary action and can occur for a number of reasons. Discontinuation in a study protocol is a broader term and can refer to the cessation of participation due to reasons that were initiated by either the participant or the study investigators, including not meeting ongoing study criteria, experiencing intolerable side effects, or for other safety concerns.² While both dropout and discontinuation lead to participants ending their study involvement before its scheduled conclusion, the key distinction lies in the initiator and reason behind ending the participation.² 

The reasons for dropout occurring are vast and varied and do not always pertain to the treatment. These can include:

• Disinclination
• Inconvenient study or clinic location
• Personal/family matters
• Scheduling conflicts
• Financial limitations
• Unmanaged expectations
• Forgetting to attend appointments
• Side effects of treatment
• Progressing myopia

In randomized controlled trials, dropout rates are monitored closely for several critical reasons. High dropout rates can compromise the internal validity and reliability of trial results, making it essential to address any significant loss of participants promptly.^3,4 Dropout rates in myopia control studies vary significantly across different treatment modalities, but there isn't a clear pattern that links dropout rates to a specific type of treatment. For example, among the atropine studies, dropout rates range from 5% to 20%.^5-7 Myopia control spectacle lenses have a dropout rate that ranges from 12% to 20%,^8-10 and myopia control soft contact lenses range from 8% to 25%.^11,12 Orthokeratology studies have shown dropout rates ranging from 7% to 54%.^13,14 

Clinical trial settings are inherently different from real-world settings,¹⁵ often requiring more adherence to specific protocols and providing less flexibility for participants. A retrospective study investigating the dropout rate for orthokeratology for myopia control from patients attending Hanyang Aier Eye Hospital was 2%.¹⁶ Orthokeratology, however, is one of the more complicated modalities in the myopia control suite due to its requirement for nightly lens wear, regular follow-up visits, and strict adherence to lens care protocols. The discrepancy between the high dropout rates observed in prospective orthokeratology studies (7% to 54%) and the lower dropout rate in the retrospective study (2%) might be due to the nature of the retrospective study, which involved real-world patients. These patients may exhibit higher adherence and motivation compared to participants in controlled trials, reflecting more accurate real-world adherence among those actively seeking treatment. 

Dropout in clinical trials can significantly impact both the reliability and validity of the results, primarily by introducing various forms of bias. When participants drop out, especially if the dropout is non-random, it can lead to attrition bias. Attrition bias occurs when the characteristics of those who drop out differ from those who remain, potentially skewing the study outcomes.¹⁵ This is why participants that drop out of a study must always be asked to provide a reason, so that it may be documented and included in the analysis.¹⁸  

Researchers often include methods like intention-to-treat (ITT) analysis to mitigate the impact of dropout.³ ITT analysis includes all participants as originally assigned, regardless of whether they completed the study. One of the main benefits of ITT analysis is that it mirrors real-world clinical scenarios by including all participants, even those who don't follow the treatment protocol exactly. This helps maintain the original balance between treatment groups and gives an unbiased view of the treatment's effect. It also keeps the sample size and randomization intact,¹⁸ ensuring the study remains powerful enough to detect differences and avoids drawing conclusions from selective or arbitrary subgroups. However, ITT has some drawbacks, such as potentially underestimating the treatment's true effect due to noncompliance and mixing different types of participants. This method can be overly cautious, leading to a higher chance of missing a true effect.^3,4

Minimizing dropout in clinical trials is essential to ensure reliable results and effective patient care. Several strategies can help address the factors that contribute to dropout:

• Enhancing patient communication: Clear, consistent, and empathetic communication helps in setting realistic expectations and may reduce dropout due to unmet expectations or misunderstandings about the treatment process.²⁰ Providing patients with more comprehensive information about the study at the outset can result in slower recruitment rates, yet lead to more reliable and continuous participation, thereby lowering the likelihood of patient dropout.²¹ 
• Improving study design and protocol flexibility: Designing studies that are patient-centric, considering their routine and potential barriers to participation, may help reduce dropout. This includes flexible scheduling and potentially using technology to allow remote participation when possible.
• Monitoring and follow-up: Regular monitoring for adverse effects and prompt management of any issues that arise may prevent dropout due to side effects or health concerns. Ensuring participants feel safe and cared for is crucial.
• Offering incentives: Appropriate incentives can be effective, especially in long-term studies. These might include compensation for time, travel vouchers, or health check-ups.

Applying these learnings about dropout in clinical trials to clinical practice can help to maintain patient continuity and compliance with treatment. Examples of steps to take can include comprehensive and ongoing patient communication, establishing strategies to manage delays or failures to book follow-up examinations, and ensuring collaborative discussion about any reasons for lack of adherence to treatment or follow-up. This can include asking the following questions in communication with patients both outside and inside the exam room.

• Is this treatment working for the patient, their family and their situation? 
• Is this treatment providing good vision and eye health outcomes? 
• Does anything need to be addressed to make the treatment or management plan easier for the patient and their family? 

Addressing dropout is a matter of improving study protocols and also enhancing the overall patient experience. Understanding the reasons behind dropout and implementing strategies to minimize it can enhance the validity of study results and improve clinical outcomes. By prioritizing clear communication, participant engagement, convenience, and support systems, researchers and eye care practitioners can reduce dropout rates and ensure that patients receive the full benefits of their treatment regimens.