Resources:

• The Role of Skin Barrier Dysfunction in Atopic Dermatitis
• Understanding Tape Stripping and Its Use in Clinical Research
• Using Biomarkers in Clinical Research
• Art of Protocol Writing for Atopic Dematitis

Today marks a unique occasion as we are joined by our chief executive officer and medical director at Innovaderm, a company he pioneered in 2000, dedicated to the advancement of research in dermatology.

Join us as we dive into placebo response rate in atopic dermatitis (AD).  We will be exploring three crucial points in our discussion:

1. Key considerations
2. Ensuring a reasonable placebo response
3. How to interpret higher-than-expected rates

Let’s extend our warmest welcome to Innovaderm’s founder and CEO, Dr. Robert Bissonnette.

Placebo-Responder Rates 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 (QoL) 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.

Ensuring Reasonable Placebo-Response Rate — A Sponsor’s Guide

What is considered as a reasonable placebo-response rate?

Let’s consider what constitutes a reasonable response in an AD study conducted in patients with moderate to severe AD, where the primary endpoint is change from the baseline in EASI.

Is a 60% change reasonable? Many would argue that this is exceptionally high and problematic, as most studies do not observe a 60% change from baseline overtime.

Is a 0% change reasonable? Most would argue that it is not reasonable given that patients experiencing flare-ups followed by spontaneous improvements at baseline and screening and that some patients will improve because of higher adherence to moisturizer used. A 0% placebo response rate may suggest that there were issues with evaluations.

In fact, as an investigator, I cannot recall any large AD study with a 0% placebo response. Therefore, a reasonable response likely lies somewhere in between these extremes.

The goal is to conduct a trial that will generate accurate safety and efficacy data about the product being studied. A 60% placebo response is likely not ideal as it leaves very little room to demonstrate a difference between the active treatment and the placebo. Similarly, a 0% change is probably not ideal either, as if the same situation applies to the active treatment, the measured effect size will be less than the actual effect.

Disease Severity

It is important to set realistic expectations. As previously mentioned, patients with mild disease, for example, 1% BSA with mild IGA, treated with a topical drug, will have a significantly higher placebo response rate that those in a study with moderate to severe BSA 10, EASI 16+ using a systemic medication.

Experience

It is important to involve sites with a wealth of experience in conducting AD studies and that are accustomed to performing clinical evaluations of severity. It is beneficial to include sites with a proven track record of high-quality efficacy evaluations. CROs and sponsors frequently active in dermatology are likely to be aware of which sites consistently deliver high-quality results.

Monitoring

CROs and sponsors should consistently track changes in efficacy evaluations throughout the study to pinpoint outlier sites or sites where, as previously mentioned, the evaluations appear illogical.

Photographs

Photography can also be a useful tool. Despite the challenges of photographing AD due to its nature, requesting sites to capture images of the most severe areas can be beneficial. If, upon review, the photos from a study requiring moderate to severe patients consistently suggest a severity of almost clear or mild, then there is likely a problem that needs to be addressed.  

Analyzing High Placebo-Response Rates

Proof-of-Concept (POC) Studies

This is a scenario we occasionally encounter, particularly in smaller studies. With a smaller sample size, the likelihood of observing a higher than anticipated placebo response rate increases. However, this does not necessarily imply that the study was poorly conducted or that the evaluations were flawed. As previously mentioned, if many patients are enrolled during a flare-up, or if a few patients are using prohibited medications without informing the study team, a high placebo response rate might be observed.

When it occurs, it is crucial in a POC study to perform a comprehensive evaluation of the higher-than-expected placebo response to determine the effectiveness of the medication.  In these cases, the analysis of patient reported outcomes and biomarkers, especially very early after randomization, can help assess potential efficacy. This is particularly important in phase 2a and phase 1b studies. If early phase studies suggest that the medication is safe and effective, it will likely progress to a later phase study. If the conclusion is different, development in AD may be halted.

How to Handle High Placebo-Response Rates

1. Conducting Post-hoc Analyses

There are several approaches to address issues in clinical data analysis. One option is to conduct sub analyses, such as post-hoc analyses. For instance, if there is evidence that issues arise from data generated at specific sites or from a particular country. However, one should be cautious about this approach because selectively excluding data may increase the risk of type 1 errors.

2. Additional Endpoints

Another strategy we find valuable is to explore alternative endpoints beyond the primary ones. These endpoints should be independent of the evaluated outcomes. For instance:

1. Pruritus: almost all patients with AD will complain of pruritus and improvements in pruritus are expected if skin lesions improve.
2. Biomarkers: skin biopsies or tape stripping can reveal biomarkers that are more sensitive than visual evaluations, such as IGA or EASI. These biomarkers can provide additional evidence of treatment, especially if performed very early in the trial before patients could use prohibited or rescue medications.
3. QoL Questionnaires: assessing the patient’s QoL can provide valuable insights beyond clinical measures. It helps capture the impact of the disease on the patient’s well-being and daily functioning.

If biomarkers, pruritus, and QoL all move in the same direction, even if not statistically significant individually, it suggests the drug may be effective. In such cases, pursuing larger studies with larger sample size is warranted.  A holistic approach considering multiple endpoints can enhance our understanding of treatment effects and guide further research.

As we conclude another illuminating episode of Phase Forward, we find ourselves at the crossroads of science and progress. Remember that behind the jargon and statistics, lies stories of unwavering commitment, meticulous observation, and the pursuit of evidence that shapes our understanding of health and disease. Stay at the forefront of knowledge and innovation and follow Phase Forward on your preferred platform. My name is Valerie Coveney. Thank you for joining us. Until next time.

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. 

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