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A 50% reduction in the Psoriasis Area and Severity Index (PASI 50) is a clinically significant endpoint in the assessment of psoriasis

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Abstract

A 75% reduction in the Psoriasis Area and Severity Index (PASI) score (PASI 75) is the current benchmark of primary endpoints for most clinical trials of psoriasis. Many consider this endpoint to be too stringent as it places potentially useful therapies at risk of failing to demonstrate efficacy. We hypothesized that a 50% reduction in the PASI score (PASI 50) represents a meaningful change in a person's life and thus is a better primary endpoint. To test this hypothesis, we analyzed PASI scores, quality of life (QoL) data, and desired re-treatment scores from a number of clinical trials in addition to studying individual elements that make up the PASI. This analysis shows (1) the PASI score is not linearly reflective of psoriasis severity (eg, a reduction in area of 95% without a change in redness, scaliness, and induration translates to only a 66% reduction in PASI); conversely, a drop in erythema, scale, and induration from an average of 3 to 1 would not lead to a 75% reduction in PASI; (2) treatment with methotrexate, an effective psoriasis therapy, more frequently reaches PASI 50 than PASI 75 as evidenced by a recent open trial in which 63% of patients achieved PASI 50 versus 26% achieving PASI 75; (3) improvement in QoL exists at PASI 50, using the Dermatology Quality of Life Index, as documented in several recently completed large clinical trials; (4) patients achieving PASI 75 frequently defer therapy until they are well below PASI 50; a clinical trial where retreatment was patient initiated showed patients did not re-treat until their PASI dropped to an average of 20% improvement from baseline; and (5) effective, meaningful therapies are consistently differentiated from placebo at PASI 50 as evidenced by histologic and photographic parameters of clinical trials of alefacept, efalizumab, and etanercept. We conclude that PASI 50 equates to a clinically meaningful improvement in psoriasis and represents a discerning primary endpoint.

Section snippets

Emergence of PASI 75 as a primary endpoint

In recent years, the US Food and Drug Administration (FDA) and pharmaceutical companies have used a reduction from baseline PASI score of ≥75%, termed PASI 75, as the benchmark of primary endpoints in assessing therapies for psoriasis.14, 15, 16 This endpoint stemmed from 1998 deliberations between the FDA and the Dermatology Advisory Council.17 No formal conclusions were reached at this meeting, and the FDA has not offered formal guidelines on the matter. Patients reaching PASI 75 experience

Consideration of PASI 50 as a primary endpoint

After assessment of PASI and QoL data, it is our consensus that PASI 50, or a reduction in PASI score of ≥50%, consistently demonstrates clinically meaningful improvement and represents an appropriate primary endpoint for clinical trials. This position is supported by several lines of evidence: (1) the PASI score is not linearly reflective of psoriasis severity, and thus PASI 50 can represent far greater than 50% improvement in disease activity; (2) treatment with methotrexate, a very effective

Improvements in PASI score do not linearly reflect improvement in psoriasis

An improvement in PASI score does not correlate in a 1:1 ratio with improvement in disease and can underestimate improvement. Consider how the PASI scoring system works.8 Erythema, induration, and scale are each measured on a 0-4 scale: 0 is none, 1 is barely perceptible, 2 is slight, 3 is moderate, and 4 is severe. Area is nonlinear and is measured using a 1-6 scale (1 is <10% body surface area (BSA) involvement, 2 is 10%-<30% BSA, 3 is 30%-<50% BSA, 4 is 50%-<70% BSA, 5 is 70%-<90% BSA and 6

PASI improvement with a known effective therapy

Improvement of psoriasis with methotrexate provides additional evidence that PASI 50 equates to clinically meaningful improvement. Methotrexate is currently the established “gold standard” of therapy when considering systemic agents for this disease. While it is recognized as having considerable side effects, there is no question that it is a highly effective psoriasis treatment. In a past survey of dermatologists that ranked reasons for using ultraviolet B (UVB) versus psoralen plus

Improvements in quality of life measures exist at PASI 50

In addition to a statistical differentiation from placebo using an objective measure, the Medical Advisory Board of the National Psoriasis Foundation affirms that a therapeutic agent that predictably enhances QoL for patients with psoriasis provides clinically meaningful improvement.31 With large enough sample sizes, very small changes in lesion severity between drug and placebo can reach statistical significance. It is acknowledged that if enough patients were entered into a clinical trial,

Patients who achieved high PASI scores delay re-treatment to levels below PASI 50

Evaluating re-treatment desires of patients gives additional evidence that PASI 50 is a clinically meaningful endpoint. In two phase II trials of alefacept, patients who had achieved an improvement in PASI of 75% from their original baseline and who had been taken off active medication were given the option to restart alefacept at their discretion (S. Ertel, personal communication, Sept 12, 2002). With this freedom, the patients allowed their PASI score to drop to an average of 20% improvement

Effective medications are differentiated from placebo at PASI 50

A clinically significant treatment must provide an improvement that has a statistically significant P value (<.05), compared to placebo, in a properly blinded and powered, placebo-controlled clinical trial.31 Additionally, an objective endpoint that measures the clinically meaningful treatment would be useless if it could not differentiate active drugs from placebos.

In 3 recent placebo-controlled trials of alefacept,19 efalizumab,* and etanercept,50 statistical differences from placebo were

Governing agencies, physicians, insurance carriers, and patients should embrace PASI 50 as clinically meaningful improvement

Reduction in the PASI score of at least 50% affords improvement in QoL, provides statistical differentiation from placebo, and represents true improvement. If a particular therapy is developed that consistently helps patients achieve a PASI 50 response but not a PASI 75 response, such a therapy could be highly beneficial to patients even though it would not meet current regulatory requirements for FDA approval. It is our position that regulatory bodies wanting to use a reduction in PASI as a

Acknowledgements

The Medical Advisory Board of the National Psoriasis Foundation has been interested in determining whether a reduction in PASI of 50% from baseline as a result of therapeutic intervention is clinically meaningful. After due deliberation the Board voted to direct a writing committee to generate an evidence-based assessment of this issue. The position represented herein is the completion of this assignment.

The members of the Medical Advisory Board of the National Psoriasis Foundation are Jerry

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    Funding sources: none.

    Disclosure: The commercial associations, current or over the past 5 years, that might pose a conflict of interest including consultant arrangements, honoraria, stock or other equity ownership, research grants and support are the following: Christopher S. Carlin, MD—Roche Pharmaceuticals; Steven R. Feldman, MD, PhD—Amgen, Bristol-Meyers Squibb Dermatology, Connetics Corporation, Novartis, Dermatology Foundation, American Society of Dermatologic Surgery, Ortho Pharmaceuticals, Aventis Pharmaceuticals, Roche Dermatology, Photomedex, Genetech, Biogen, Galderma, and 3M; James G. Krueger, MD—Amgen, Biogen, Boehringer, Centocor, Genentech, Pfizer, and Protein Design Labs; Alan Menter, MD—Abbott, Amgen, Biogen, Centocor, Corixa, Genentech, Otsuka, Roche, and Serona; and Gerald Krueger, MD—Allergan, Amgen, Biogen, Centocor, Fujisawa, Genetech, Isis, Roche Pharmaceuticals, Serona, and Watson.

    A portion of the information contained in this manuscript was presented in poster form at the International Investigative Dermatology meeting of the Society of Investigational Dermatology from April 30-May 4, 2003.

    Accepted for publication September 13, 2003.

    Reprints not available from authors.

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