Psoriasis Plaque Elevation Should Be Most Important Cardinal Sign In Trials

Psoriasis plaque elevation change should carry more weight than the two other cardinal signs for stable plaque psoriasis for treatments of the disease in clinical trials, FDA's Dermatologic and Ophthalmic Drugs Advisory Committee agreed at a March 20 meeting.

The two other cardinal signs, erythema and scaling, are too variable for accurate assessment of a drug's effectiveness, the panel agreed. "We can't give them major weight. So we're left with plaque elevation, which is the gold standard," committee member Fred Miller, MD, Geisinger Medical Center, said.

"We're depending greatly on the thickness of the plaque," committee Chair Joseph McGuire, MD, Stanford University, added, "and putting most of the weight on that." Other criteria the committee considered important included "How much is it reduced?" and "Is there redness?"

FDA solicited the committee's comments about factors that should be included in clinical trials for stable plaque psoriasis therapies as an aid in creating a guidance.

The committee concluded that moderate psoriasis should be the minimum severity allowed for entry into clinical trials but it said that the definition of 'moderate' should be clearly defined. There should be no minimal surface area of involvement, the committee recommended in agreeing that severity is a better criterion.

The committee did, however, determine that area of involvement should be included in the analysis of outcomes, but they were unsure as to how it should be factored in. "We absolutely have to factor [area of involvement] in," committee member Henry Lim, MD, Henry Ford Hospital, said, "but how I don't know."

The committee concluded that 'clear,' defined as complete clearing of a psoriasis plaque, was probably too stringent for approval and that '75% clear' was more appropriate. "Some effective treatments will never see the light of day if we require 'clear' for approval," New York physician Mark Lebwohl, MD, a guest speaker, said.

A dichotomous outcome for global evaluation that would include scaled measurements was favored over an all-category comparison as a primary endpoint, the committee determined. On a five-level scale, the top two most severe classifications would be one side of the dichotomy and the three remaining less severe ratings would be the other side.

Successful outcomes in global evaluations would include a measure of percentage of remission of lesions and a global assessment by the patient. The committee also recommended that a way to measure the duration of remission should be established.

Although durability of remission should not be required for approval, the committee agreed that it should be included in labeling. "I think it's a piece of information that's important to have but I do not think it's necessary for approval," Lim said.

"I think we would be very keen to, at a minimum, craft it into the labeling," FDA Dermatologic and Dental Drug Products Division Director Jonathan Wilkin, MD, maintained. "If a company thought they had a medication that would provide for a substantial remission then it would show up in the clinical trials section."

The committee agreed unanimously that quality of life data should not be used as a basis for approval but discussed including the information in the clinical trials section of labeling. "I have reservations about using quality of life as an endpoint for clinical studies or even as the basis for approval," guest speaker Robert Stern, MD, Beth Israel Deaconess Medical Center, said. "Quality of life is something that needs to be addressed...but it shouldn't be part of approval or package inserts at this point."

Lebwohl concurred, stating that surveys show that there is "hardly ever an impact on the patient's quality of life" as a result of treatement. "Some of the best treatments we have didn't affect quality of life," he added.

Wilkin suggested that quality of life data could be inserted into labeling. "We would be happy to accept as a secondary endpoint, meaning something that could be crafted into labeling, a well-structured patient global [assessment] at the end" of the study. Several committee members also supported this approach.

The committee favored matching anatomical site of affliction in studies because in some areas of the body, such as over bony prominences, lesions heal differently and vary in severity.