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Executive Summary

Ortho's Renova (tretinoin) should be approved "for improvement in appearance of fine wrinkling, mottled hyperpigmentation and roughness associated with photodamage," FDA's Dermatologic Drugs Advisory Committee unanimously recommended April 9. The committee's language modifies Ortho's proposed labeling by emphasizing the cosmetic nature of Renova's action. In its NDA for the .05% emollient cream, submitted in July 1989, the Johnson & Johnson subsidiary proposed an indication "for the treatment of photodamaged skin. Treatment benefits include reduction of fine wrinkling, mottled hyperpigmentation and roughness." Much of the committee discussion involved concerns that patients and physicians could misinterpret Renova labeling to mean that the product actually repairs photodamaged skin, as opposed to improving its appearance. Ortho consultant Barbara Gilchrest, MD, Boston University, explained that clinical trials involved three "key efficacy parameters." Two of the parameters "were composite evaluations by the investigator," rating the patient's "global" appearance as compared to baseline and to determine the change in "overall severity." To determine overall severity, Gilchrest explained, the investigator rated severity for each visit, "without reference to the rating assigned in earlier visits." The third parameter was the "patient's self-assessment" after treatment as compared to baseline. Other measures, such as skin surface replicas, "were selected to provide additional objective corroborative data," Gilchrest said. The investigators felt that skin replicas were beneficial in that "they are a completely blinded and quantitative means of assessing improvement in photodamage," she concluded. Finally, skin biopsies were taken to examine the histologic measures believed to be associated with photodamage. Committee member Pearl Grimes, MD, Department of Internal Medicine, Los Angeles, noted the need to distinguish "between improving the patient clinically and cosmetically in wrinkles and of photodamage." Another committee member, Jonathon Wilkin, MD, Ohio State University, agreed, and expressed concern that wrinkles and pigmentation could be taken for "decent surrogate biological endpoints of photodamage." Wilkin noted that the panel has not heard evidence demonstrating that reduction of the three clinical endpoints established in clinical trials with Renova will ultimately "affect photodamage." Committee Chairman Arnold Schroeter, MD, Wright State University School of Medicine, concurred, suggesting that by putting "photodamage into the claim, you are still... emphasizing photodamage rather than the claim which is actually what your data has proven to be efficacious for." Schroeter added that "we need to be very, very clear in labeling" to avoid any implication that treating "the three determinants that [Ortho] evaluated," can prevent skin cancer. Gilchrest maintained that photodamage has a "very major psycho-social impact" on patients because of the appearance of their skin. Any cosmetic "influence on the appearance of skin has a very definite benefit," Gilchrest said. Ortho conducted two multi-center and one single-center 24- month pivotal studies on 659 patients. The population was limited to patients with mild to moderate photoaging, because "patients with more severe photodamage often have premalignant skin lesions that require other forms of therapy and were not intended for evaluation," Gilchrest explained. Older patients who "by definition have greater intrinsic aging," also were excluded as were patients who had "visible actinic keratoses or a history of skin cancer." Because the effects of photodamage are most prominent among fair-skinned individuals, the studies were conducted solely on Caucasians. Committee consultant Harold Minus, MD, Howard University Hospital, Washington, D.C., suggested that labeling note that trials had been done "in a Caucasian population." The committee agreed to this revision. FDA Director of Anti-infective Drugs Division Murray Lumpkin, MD, voiced continued concern that the blinding of the studies could be broken due to outbreaks of retenoid dermatitis among patients treated with Renova. Gilchrest explained that "at the recommendation of FDA," the investigators used a "vehicle-controlled design," substituting a regimen of traditional skin care for a placebo. She maintained that the issue of unblinding is not so problematic, since irritation is most noticeable "at two weeks" whereas drug benefits are not seen until the fourth to sixth month. Also, she said, the "melanin concentrations corresponded quite nicely" with observations of Renova benefits. Global evaluation in clinicals demonstrated a statistically significant improvement ratio of "approximately 80%" for Renova, compared with about 40% for the vehicle alone without the active ingredient, Gilchrest explained. She noted the "consistent results for the three key efficacy parameters," with significant improvements found in overall severity and the three individual signs of fine wrinkles, mottled hyperpigmentation and roughness. Patient self-assessment of 50%-70% improvement "generally agreed with investigators' evaluations," Gilchrest said. To determine long-term efficacy and safety, Ortho extended the trials another 24 weeks and found that "clinical benefits are maintained" after 12 months of continuous use, Gilchrest said. The company then extended the trials for 24 more weeks to test the effects of less frequent applications of Renova. According to Gilchrest, benefits were "maintained or enhanced" in 80% of patients who reduced Renova use to three times weekly and in 70% of patients who used the drug once weekly. Among patients who stopped using the drug, 55%-65% experienced a partial reversal of benefits. Five percent of patients "discontinued therapy due to adverse experiences," Gilchrest said. Adverse reactions included erythema, dryness, burning and stinging but "remained mild throughout the study." "Very few systemic effects occurred," she explained, and those were "not believed to be related to therapy." Schroeter pointed out the lack of any carcinogenicity studies for Renova. R. W. Johnson Senior Director of Worldwide Regulatory Affairs Tom Koestler, PhD, explained that an ongoing study performed on CD-1 mice is currently approaching "termination" and "will be presented" to FDA. Lumpkin added that according to FDA guidelines, "approval wouldn't be given before data comes to the agency." FDA's Lumpkin concluded the agency's presentation on the Renova studies by saying: "We had no major differences with the sponsor as to the assessments that they gave the patients...The sponsor made a very good faith effort in this particular development program to be very proactively involved with the division and with the advisory committee." Ortho has had to overcome a number of hurdles en route to the recommendation for approval. Unapproved use for anti-aging purposes of Ortho's tretinoin for acne (Retin-A) was highlighted in a June 1991 hearing by Rep. Weiss (D-N.Y.) on illegal promotions of drugs and medical devices ("The Pink Sheet" June 17, 1991, p. 7). The product also has been before the Dermatologic Drugs Advisory Committee three times, albeit not for formal reviews of the NDA. Most recently, in May 1990 the committee reviewed issues of possible embryo toxicity and efficacy determinants but did not come to any definitive conclusions or statements of safety.

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