Points to Consider for Clinical Efficacy Evaluation of Drugs for Palmoplantar Pustulosis — PMDA Early Consideration Summary

In Plain Language

The document discusses how to assess whether drugs improve palmoplantar pustulosis (PPP), a condition involving recurring pustules on the palms and soles. It notes that the disease label does not necessarily describe the same pattern of illness in Japan and in Europe or the United States. In regulatory submissions discussed by PMDA, the PPP Area and Severity Index (PPPASI) total score was used, but there is no consensus on the smallest change in that score that patients would consider clinically meaningful. The document therefore says efficacy should be interpreted comprehensively, including results on improvement thresholds and quality of life as secondary endpoints. It also says that assessment at Week 24 may be considered, that long-term treatment results such as Week 52 may be important, and that more substantial improvement measures may be desirable in future clinical practice.

What This Guidance Covers

This is an administrative notice addressed to industry groups and dated January 23, 2025. It presents a brief provisional summary of reviewers’ current thinking about clinical efficacy assessment for drugs to treat PPP. The notice explains that PMDA discussed the topic with relevant parties, including academia and industry, at the annual meeting of the Japan Society of Clinical Trials and Research in March 2024; the summary of that discussion was published in an article, and a copy was posted on the PMDA website as early regulatory considerations for PPP drug development.

The considerations concern clinical efficacy evaluation: how treatment effects might be measured and interpreted in clinical trials. The notice focuses on the PPPASI total score, improvement rates based on that score, quality-of-life assessment using DLQI, and the timing of efficacy assessment. It does not set out a complete trial protocol, specify a particular drug or population, or provide a numerical threshold for the least clinically meaningful change in PPPASI total score.

The disease description is important to the scope. The notice says PPP is characterized by recurrent and multiple aseptic pustules on the palms and soles. It also cautions that the condition referred to as PPP in Japan and that referred to as PPP in Europe and the United States are not necessarily the same pathological condition. In Europe and the United States, PPP generally refers to the palmoplantar-localized form of pustular psoriasis, described as rare. In Japan, PPP is not necessarily rare and is described as primarily associated with focal infections and smoking habit; lesions begin as vesicles that rapidly become pustules.

Why It Matters

The document responds to uncertainty about how to interpret changes in a commonly used clinical score. PPPASI total score was used as an assessment scale in regulatory submissions, with the primary endpoint being change from baseline in PPPASI total score at Week 16. PMDA says it has generally accepted applicants’ explanations of this primary endpoint, but has also pointed out that there is no consensus on the least clinically meaningful change in the total score.

In practical terms, a score can change without there being a shared understanding of how large a change must be to represent a meaningful clinical improvement. The document does not propose a replacement threshold. Instead, it highlights other results that can help interpret efficacy: the proportion of patients reaching a specified degree of PPPASI improvement, patients’ quality-of-life assessment, and assessments at time points that take account of symptom fluctuations and the generally slow onset of biologics’ effects on PPP.

The notice also recognizes that measurement of skin findings and lesion area is not the whole picture of treatment efficacy. It states that quality-of-life assessment is important, while currently considering it appropriate to evaluate PPPASI total score primarily for assessing the severity of skin findings and lesion area. This distinction helps explain why the document presents PPPASI and quality-of-life measures as complementary rather than interchangeable.

Key Recommendations

1. At present, primarily evaluating the PPPASI total score is considered appropriate for assessing the severity of skin findings and lesion area. The notice reports that PPPASI total score was used in regulatory submissions, with change from baseline at Week 16 as the primary endpoint. It also states that, at present, primarily evaluating PPPASI total score is considered appropriate for assessing the severity of skin findings and lesion area.

2. Interpret efficacy using additional endpoints as well. PMDA considers the percentage of patients achieving a specified improvement in PPPASI total score important to interpreting a drug’s efficacy. The example given is the PPPASI 50 achievement rate: the percentage of patients whose PPPASI total score improved by 50% or more from baseline. The document says that results for such endpoints should be included as secondary endpoints.

3. Include quality-of-life results in the overall interpretation. The notice identifies quality-of-life assessment using DLQI as important in evaluating efficacy for PPP, and says these results should be included as secondary endpoints. It does not say that DLQI replaces PPPASI total score as the primary way to assess skin severity and lesion area.

4. Consider assessment at a later time point. In view of symptom fluctuations in PPP and the generally slow onset of the effect of biologics on PPP, the primary endpoint may be evaluated at Week 24. The wording is that it “may” be evaluated at that time; the notice does not say that Week 24 must replace Week 16 in every study.

5. Consider efficacy over longer treatment. The efficacy of long-term treatment, such as at Week 52, may also be considered an important endpoint. The notice identifies this as a consideration, rather than setting a universal requirement for every clinical trial.

6. Keep future, more substantial improvement measures in view. Endpoints closer to clinical remission, such as PPPASI 75 achievement rate, may be desirable in the future from the perspective of clinical practice. The document presents this as a future-facing consideration, not as a current required endpoint.

These points should be read together: the document keeps PPPASI total score central to assessment of skin severity and lesion area, while using improvement rates, quality-of-life findings, and appropriately considered assessment timing to support a broader interpretation of efficacy.

Practical Implications

Interpretation for sponsors and study teams: the notice points to a need to explain not only the selected primary endpoint and assessment time, but also how supporting endpoints contribute to understanding treatment effects. A development team considering a PPP trial can use the document to identify the questions its efficacy assessment may need to address: what happens to the PPPASI total score, how many patients achieve a specified degree of improvement, and how patients’ quality of life changes.

The lack of consensus on the least clinically meaningful change means the document does not supply a single score-change threshold that resolves interpretation. Teams should avoid presenting a numerical change as clinically meaningful on the authority of this notice alone. The secondary endpoint examples help show how responder proportions and quality-of-life results can add context, while preserving the stated role of PPPASI total score in assessing skin findings and lesion area.

Interpretation for trial planning: the discussion of Week 24 and Week 52 draws attention to the relationship between assessment timing and the clinical course described in the notice. Symptoms fluctuate, and biologics generally have a slow onset of effect on PPP. Accordingly, a team considering when to assess efficacy may find the document’s time-point discussion relevant. It does not, however, prescribe a single schedule for all products or trials.

Interpretation for regulatory and clinical teams: the document can help frame discussion of the endpoint package and the intended interpretation of results. Its wording distinguishes current assessment practice from possible future directions: PPPASI total score is currently considered appropriate as the primary assessment of skin findings and lesion area, while PPPASI 75 is described as potentially desirable in the future from a clinical-practice perspective.

Technical Details

The endpoint terms in the notice describe different summaries of treatment outcome:

• Change from baseline in PPPASI total score: compares a patient’s score at a specified follow-up time with the score at the start of the study. The primary endpoint in the submissions described in the notice was this change at Week 16.
• PPPASI 50 achievement rate: the percentage of patients whose PPPASI total score improved by 50% or more from baseline. This is an example of a responder endpoint, meaning it counts the proportion of patients who reach a stated improvement threshold rather than summarising only the score change.
• PPPASI 75 achievement rate: an endpoint closer to clinical remission that the notice says may be desirable in the future from the clinical-practice perspective. The notice does not provide a separate definition or calculation for it.
• DLQI: the named quality-of-life measure identified in the notice. The notice describes quality-of-life assessment as important, but does not expand the abbreviation or explain its scoring.

The measurement strategy described is therefore a set of complementary outcomes: PPPASI total score primarily addresses skin findings and lesion area; achievement rates show how many patients reach specified levels of score improvement; and DLQI contributes a quality-of-life perspective. The notice asks that the latter types of results be considered as secondary endpoints when interpreting efficacy.

For timing, the document gives a rationale rather than a formula or decision rule. It points to fluctuations in PPP symptoms and the generally slow onset of biologics’ effects on PPP, then notes that the primary endpoint may be evaluated at Week 24 and that long-term treatment efficacy, such as at Week 52, may be considered important. It does not specify how to choose between Week 16 and Week 24, how long-term results should be analysed, or how missing observations should be handled.

Who Should Read It

This notice is relevant to sponsors and development teams planning clinical efficacy evaluation for drugs intended to treat PPP. It may also be useful to biostatisticians and clinical scientists selecting or interpreting endpoints; clinical operations teams planning the timing of assessments; medical writers preparing study rationales or results summaries; and regulatory affairs staff reviewing how efficacy evidence is presented. Investigators and other professionals involved in PPP research may find the discussion useful when considering the roles of skin severity, responder outcomes, quality of life, and longer-term assessment.

Official PMDA Source

• Official title: Points to Consider for Clinical Efficacy Evaluation of Drugs for Palmoplantar Pustulosis (Early consideration)
• Issuing body: Office of New Drug IV, Pharmaceuticals and Medical Devices Agency
• Date on cover: January 23, 2025
• Official PMDA PDF: View the PMDA PDF
• PMDA Early Consideration list page: View the PMDA list page

Source: Pharmaceuticals and Medical Devices Agency (PMDA) website, PMDA Early Consideration list page. This page was created by editing and summarising the PMDA document.

Consult the official document; this summary does not replace it. PMDA provides the English version for reference, and the Japanese original prevails if the two differ. PMDA describes Early Consideration documents as reference information reflecting its views at the time of publication; those views may change as scientific knowledge develops.

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