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Executive Summary

SEA TONE's ORAL SCOPOLAMINE ANTIEMETIC: ANOTHER TRIAL IS NECESSARY to demonstrate efficacy, FDA representatives told Sea Tone at an OTC "feedback" meeting Dec. 17. Sea Tone requested the meeting to discuss the agency's decision that data to support the inclusion of oral scopolamine in the final monograph for antiemetic drug products are inadequate because the studies involved may have been unblinded ("The Pink Sheet" Aug. 19, T&G- 7). FDA reaffirmed its position at the meeting: "This is supposed to be the study to put this into the monograph, and, based on the problems we've seen, it would be impossible" to do that, OTC Division Branch Chief Helen Cothran said. Sea Tone's clinical trials evaluated the efficacy of 0.25 mg scopolamine versus placebo for preventing motion sickness in 88 patients on three separate boat trips into San Francisco Bay. Patients on scopolamine showed a consistently lower "sickness score" than patients on placebo. FDA decided that the data were invalid, however, because there was an obvious visual difference between drug and placebo. The agency was alerted to the problem by an article in the San Francisco Chronicle written by a reporter on the first boat, and published before the second and third boats were run. FDA then inspected the University of California-San Francisco Drug Studies Unit, which had conducted the study for Sea Tone. UCSF Drug Studies Unit Director Gary Steinman acknowledged that there was a visual difference between drug and placebo, since the capsules were transparent and the drug was obviously grainier than placebo. However, Steinman said, the subjects had very little opportunity to inspect the capsules between taking them out of the vial and swallowing them. After the first boat, he said, procedures were "tightened up" to ensure that subjects would not speculate on what they were taking, and staff reported no such conversations on the second and third boats. Even if patients were aware of a difference between the two capsules, Steinman added, they had no way of knowing which was drug and which placebo. "We believe that in fact all three boats were blinded," Steinman said. The FDAers at the meeting, however, felt that Sea Tone could not prove that unblinding did not occur. Drug and placebo were "not identical and were not obscured -- we're stuck with that," said Robert Young of the Compliance Office's clinical investigations branch. Young assured Steinman and Sea Tone President Kirt Schlander that, while the newspaper article served as an "alert" to the agency, "we would not invalidate a study based on a reporter." Because the article "made observations that accord with what we understand usually goes on" during clinical trials, Young added, "I asked that there be an inspection and that there be samples collected." Steinman noted that one reason he wanted to talk to the agency was that "none of what we spoke about and demonstrated to the inspectors seemed to be reflected in the [August] letter" in which FDA called the studies invalid. Young, Cothran, and representatives from FDA's Neuropharmaceutical and Biometrics Divisions stressed that the agency had no problems with the trial design itself. The protocol was devised by Office of Generic Drugs Director Roger Williams, MD, before he joined the agency and was discussed with FDA during a 1988 "feedback" meeting. The FDAers indicated that a single additional trial with about 30 subjects with the same protocol but using coated and sealed capsules would probably be adequate if the results correspond to what was seen in the initial studies. The agency officials stopped short of a full assurance, saying that they would have to meet internally with others in their respective divisions. Pressed by Schlander for a promise, the FDAers suggested that if he would write to the respective divisions, they would respond by the end of January. Schlander said that Sea Tone would probably do the additional study, but not until spring if it is to be conducted in San Francisco. Schlander reminded the agency that the continued delay in marketing the drug, Sea Tone's only product, is "financially devastating." He estimated that the company will eventually spend over $200,000 on the trials. Santa Rosa, Calif.-based Sea Tone's oral scopolamine has not been marketed since May 1988 when the final monograph was published. Schlander filed a citizen's petition after the meeting asking for permission to market his company's product while the review is ongoing. He was told by Cothran, however, that the agency's answer "would be the same as before."

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