How to Manage Placebo Response Rate in Atopic Dermatitis (AD) - Placebo-Response Rates in AD

Table of contents

1. Factors Influencing Placebo-Responder Rate in AD 
2. Additional Factors Influencing Placebo-Responder Rate in AD

Welcome to the first article in the series on placebo response rate in atopic dermatitis. This series aim to explore strategies on how to ensure a reasonable response rate and dive into the analysis of high response rates in AD. This inaugural article will explore the various factors influencing placebo response rates, including the disease under study, mode of administration, primary endpoint, length of the placebo-controlled period, and the assessor’s experience and proficiency. It will also discuss the unique challenges posed by AD, the role of different endpoints, and the importance of evaluator experience.

Factors Influencing Placebo-Responder Rate in AD

The placebo response rate in dermatology clinical trials is influenced by various factors including the indication itself, the mode of administration, the primary endpoint, the length of the placebo-controlled period, and the assessor’s experience and proficiency in conducting the assessments.

1. Indication

The disease under study can greatly affect the placebo response rate. For instance, in studies focusing on topical treatments for basal cell carcinoma, the placebo response rate tends to be quite low. This is because the primary outcome is typically the absence of any remaining tumor in the surgically removed area, a very objective measure. In addition, spontaneous remissions of basal cell carcinoma are rare. Similarly, for stable inflammatory conditions like extensive alopecia areata, the placebo response rate is also low due to the stability of the disease and the relative simplicity of the evaluations.

AD presents a completely different scenario. It is a disease characterized by fluctuations, with many patients experiencing periodic flares followed by improvement. Clinical assessments of disease severity are often difficult and the use of moisturizers, which is allowed in almost all trials, is an effective treatment for AD. Therefore, it is not surprising that placebo response rates in AD trials are often higher than for other inflammatory skin diseases.  

2. Mode of Administration

Mode of administration plays a crucial role. As mentioned previously, a vehicle that is ointment-based or an emulsion containing a high proportion of lipids is an effective AD treatment. In clinical trials with topical medications, patients are educated on the amount of topical product to be applied and must fill daily diaries to show that they used the product according to protocol. This creates a high treatment adherence which in turn will boost vehicle treatment response which is not really a placebo anymore.

3. Primary Endpoint

In AD, the primary endpoint is usually the Investigator’s Global Assessment (IGA) or the Eczema Area Severity Index (EASI). However, as previously mentioned, both are quite challenging evaluations. Evaluating Body Surface Area (BSA) presents difficulties, especially when lesions are mild or almost clear, making it hard to distinguish between normal skin and diseased skin.

Richly pigmented skin can add additional challenges to evaluations. Dermatologists who are not accustomed to evaluating AD in patients with darker skin may find it particularly difficult, especially since erythema is hard to see. Moreover, conditions like ichthyosis and xerosis, which are more visible on darker skin are usually not considered in AD evaluations.

Excoriations also pose a unique difficulty, not because they are hard to see or evaluate, but because they are included in some endpoints like EASI and excluded in others like the Validated Investigator for Atopic Dermatitis (vIGA-AD) IGA scale.

4. Experience

Lastly, and importantly, experience of evaluators. It is crucial to collaborate with investigators who have prior experience in AD clinical research. Ideally, investigators, especially those with more limited experience in AD clinical trials, would also be using some of these endpoints in their practice. For instance, if EASI is the primary endpoint and evaluators regularly use EASI to obtain third party coverage where they practice, the quality of evaluations in the clinical trial will be higher. Learning to conduct a thorough EASI evaluation takes time.

Another strategy that should be used by CROs or sponsors, is to internally monitor changes in EASI and IGA to ensure they make sense clinically. If there are discrepancies between the BSA, IGA or EASI, or if the results do not align, it is important to reach out to the sites to understand the issue:

• Could it be a misunderstanding of the evaluations by the Principal Investigator (PI)?
• Could there be other problems?

It is crucial to address these issues while the study is ongoing instead of waiting for the end of the study. It is worth noting that some sites excel at evaluating AD, while others do not. Therefore, it is beneficial for CROs and sponsors to collaborate with sites that have proven to be proficient in this area.

Additional Factors Influencing Placebo-Responder Rate in AD

Compliance

There are several other significant factors to consider. One of the most challenging yet crucial factors is the patient’s compliance with protocol restrictions regarding concurrent treatments. Most AD studies permit patients to use moisturizing creams, but no other active treatments, except for protocol-specific rescue treatments. Given the highly pruritic nature of the disease and its substantial impact on quality of life and sleep, it is understandable that some patients may not adhere to these restrictions and may be using other active medications without informing the study team. 

Diagnosis

Another critical consideration is ensuring that patients included in the study have been correctly diagnosed. Diagnosing AD, especially when it manifests in adulthood, is not straightforward. Assessors rely on certain criteria, but they are not always easy to evaluate. As a CRO, we have encountered cases where, upon reviewing photos, we had doubts about the diagnosis for the majority or all patients recruited at certain sites.

Severity

Lastly, a well-known factor to consider is the patient’s baseline severity. If patients have a low baseline severity, the placebo response rates tend to be higher and more variable.

In sum, managing placebo response rates in AD clinical trials is a multifaceted task that requires a deep understanding of various factors. From the disease under study to the mode of administration, primary endpoint, and the assessor’s experience, each aspect plays a crucial role.

Let’s shape the future of research and make a difference in the industry, gain Innovaderm’s support in your upcoming trial and propel your study to new heights. 

About the Author

Robert Bissonnette, MD, FRCPC

Founder and CEO of Innovaderm Research

Dr. Robert Bissonnette is the CEO and medical director at Innovaderm, the company he established in 2000. For more than 20 years, Dr. Bissonnette has dedicated his efforts towards the advancement of research in dermatology. Dr. Bissonnette has conducted nearly 200 studies ranging from POC to phase IV trials. As a Key Opinion Leader in AD and psoriasis, he has extensive knowledge of clinical dermatology, clinical research, and the dermatology market, and is a great asset to Innovaderm’s clients. Dr. Bissonnette has published more than 265 articles and book chapters and delivers lectures on various aspects of dermatology at national and international conferences.

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