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On Monday, July 12, 2004, two Food and Drug Administration advisory committees--the Dermatologic and Ophthalmic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee--meeting in a joint session voted to recommend against approving the drug oral tazarotene (brand name Tazoral) for the treatment of moderate to very severe psoriasis.
Technically, the committees voted on whether they found "a favorable balance of risks and benefits which would support approval of this product." They said, "no" by a vote of 9 to 3, with 4 abstentions. The FDA is not legally bound to follow the advisory committees
recommendations, but it usually does. The original deadline for a decision by the FDA was September 26, but that may change.
The decision came after Allergan, the company that manufactures the drug, presented evidence about oral tazarotene's efficacy and safety, and agreed to a proposed program to track patient, physician and pharmacy compliance.
The National Psoriasis Foundation testified on behalf of the drug with moving accounts from patients who have used oral tazarotene, and from Dale White, the vice president of the Board of Trustees, whose son has psoriasis. Said White to the committees as he encouraged them to recommend approving oral tazarotene, "By expanding the array of choices available to treat this serious chronic disease, [the committees] empower patients to choose the treatment that works best for them."
Janey Freeman, a psoriasis patient from Yantis, Texas, was diagnosed with psoriasis at age 34. After using steroids, tar, light, creams, occlusion, methotrexate and shampoos with varying degrees of success, she enrolled in the Tazoral clinical trial. She had 60 percent improvement, and experienced mild joint pain and dry skin.
After describing how psoriasis substantially altered her life choices, she said that "I believe Tazoral should be available to patients that it might help."
Tyrone Gorey, a patient from Newcastle, California, agreed with the need for "more tools" to treat his psoriasis. "I was really embarrassed because I had psoriasis on 45 percent of my body." After being in the oral tazarotene clinical trial, he became 95 percent clear. "The confidence of not having psoriasis is huge, and so rewarding to not worry about this problem."
However, the committee expressed concern over reports of bone mineral density loss, potential off-label use of the drug for acne and the chance of pregnancy. Oral tazarotene is a probable teratogen (an agent that can cause malformations of a developing embryo or fetus). In clinical trials the drug did not accumulate in the body and cleared rapidly when treatment stopped. This may make it an option for women of childbearing potential who are excluded from other retinoids due to the risk of these drugs causing severe birth defects.
In answer to a question about bone mineral density, Mark Lebwohl, M.D., professor and chairman of the Mt. Sinai School of Medicine of New York University, and a member of the Psoriasis Foundation's Medical Board, said that the data "compares favorably to other retinoids."
To a question about off-label use, Patricia Walker, M.D., Ph.D., Allergan's Vice President of Skin Care Clinical Research and Development, said that Allergan wouldn't promote it for off-label use. Said Walker, "the program does protect vulnerable populations by tracking the known marketing databases."
The answers were not enough to assuage the concerns of the committees, however. The vote will next go to the FDA, which will consider the arguments and evidence put forth during the joint committee hearing.
Oral tazarotene, an oral retinoid, selectively targets two receptors in the skin, and clears out of the bloodstream significantly faster than other retinoids. It is taken as a once daily oral medication in a 4.5 milligrams (mg) dose. It should not be confused with Tazorac, which is a topical retinoid available in gel and cream formulations that has been available since 1997 for the treatment of psoriasis.
Results from two phase III studies of oral tazarotene found that patients experienced peak clearing at four weeks after the treatment period, with no significant side effects. Adult patients with plaque psoriasis covering at least 10 percent of their body surface took 4.5 mg once daily for up to 52 weeks. More than half of the patients achieved moderate to complete clearing by week 12. The majority of patients maintained improvement throughout the treatment period and for at least 12 weeks post treatment.
The most common adverse events were mild, and included dry skin, joint pain, muscle ache, infection, back pain, headache and itch.
The National Psoriasis Foundation will continue to urge the FDA to support the approval of oral tazarotene. The FDA will likely make its decision by end of September.
Extensive background information presented during the hearing is available at http://www.fda.gov/ohrms/dockets/ac/cder04.html#Dermatologic
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