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Executive Summary

Dura Pharmaceuticals' efficacy data for Pentyde (pentigetide .5%) nasal solution for the treatment of seasonal allergic rhinitis should be reanalyzed, FDA's Pulmonary-Allergy Drugs Advisory Committee concluded at a March 23 meeting. Summarizing the panel consensus, Committee Chairman Leonard Bernstein, MD, University of Cincinnati Medical Center, said that "there is a hint of efficacy here" in the results of two pivotal trials for the five amino acid peptide allergy treatment, "but it's not ready for approval yet." He added: "We would certainly want to take another look at [Pentyde]" because "everybody's confused about the data." FDA and Dura should meet to try to "reach agreement on statistical issues" surrounding the clinical trials for Pentyde, he recommended. Dura said March 24 that it will meet with FDA to discuss how best to reanalyze the study results but is not optimistic that additional analysis will clear up the issues. Dura presented two pivotal placebo-controlled, randomized, double-blinded trials: a two-week, 10-center trial involving 389 patients and a 10-week, two-center study involving 67 patients. The primary clinical endpoints in both trials were severity and frequency of total nasal symptoms as evaluated by physicians and patients in diaries. Both studies found "significant reduction of nasal symptoms, whether it was physician evaluation of frequency [and] severity, or the patient diary recordings of severity," Dura consultant Richard O'Connor, MD, University of California-San Diego, told the committee. Patients evaluated only the severity, not the frequency, of nasal symptoms in their diaries. FDA medical officer Richard Nicklas, MD, and James Gebert, PhD, a statistician from the FDA Division of Biometrics, said they had several statistical questions about the design and analysis of the two pivotal trials for Pentyde. One concern arose after looking at the total nasal efficacy endpoint as three components - - runny nose, stuffy nose, and sneezing. From that perspective, "sneezing is the primary element driving these studies," Nicklas said. Dura agreed that Pentyde's runny nose measurement was not statistically significant in favor of the drug in either the frequency or severity evaluations by physicians in the 10-center study. The stuffy nose end-point was statistically significant in favor of Pentyde only in the physician evaluations for frequency in the 10-center study, O'Connor reported. Dura explained its difficulty in achieving statistical significance in the stuffy nose segment of the trial by saying that the saline control probably had an effect on nasal congestion in the placebo patients. FDA Pulmonary Drugs Group Leader Eileen Leonard, MD, emphasized that "saline was not treated as an active control in these trials" and said suggestions that saline alone may have effects on allergic rhinitis "have by no means been established." Another objection to the study raised during the meeting by FDA was that Dura only adjusted the data for baseline differences between the treatment and control groups when those differences were statistically significant. Members of the committee were concerned that the adjustment of some, but not all, baseline differences might have skewed the results of the study. Bernstein told Dura: "You should have been consistent in adjusting for the differences." As an example of the inconsistencies, FDA's Gebert said that if the patient diary results from the 10-center trial are adjusted for differences at baseline, "the results of that are not [statistically] significant." He also pointed out that "the primary analysis wasn't specified in the protocol" and suggested that the data analysis by Dura was "post hoc." Dura consultant Ronald Thisted, PhD, University of Chicago, acknowledged that the company had made "a bad scientific mistake" by not prespecifying the primary method of data analysis to be used, but, he said, "it doesn't invalidate" the data. "This was not a post hoc analysis," Thisted insisted. Dura consultant Gerald Yakatan, PhD, the president and CEO of Tanabe USA, said Dura had been led to believe that there were "no statistical problems" with the Pentyde data. Tanabe holds the marketing rights to Pentyde in Japan and other Asian countries. "We submitted our analyses two years ago and this is the first time we are hearing some of these issues," Yakatan told the committee. FDA's Nicklas repeatedly described the differences between the Pentyde-treated study group and the saline-treated group as being "marginal" and "not very great." Yakatan acknowledged that the differences "are not dramatic," but maintained that "the results of these trials are very similar to those for other approved [allergy] drugs." Thisted pointed out that the interpatient and intrapatient variability of allergic rhinitis symptoms and the variability in severity of allergy seasons were complicating factors in the trials. In other words, day-to-day patient allergy symptoms differed as did the weather and pollen conditions before and during the trials. Based on the discussion of statistics, the committee voted not to recommend approval for Pentyde by a vote of five against, one in favor and one abstention. In voting not to recommend Pentyde for approval, the committee members admitted that they were confused over which statistical argument to believe. "I don't know enough about this drug yet," committee member Joann Blessing-Moore, MD, Palo Alto, Calif., said. She added, however, that "I don't want to throw [the drug application] out." Harold Nelson, MD, National Jewish Center for Immunology and Respiratory Medicine, Denver, disagreed, commenting: "If a drug is effective you ought to be able to show it correcting for a non- significant difference in baseline. And, if it's so tenuous that making that correction makes the significant improvement go away, then it isn't a very impressive agent." Another difficulty discussed by the committee was their uncertainty about Pentyde's mechanism of action. "We don't know how this drug works," Bernstein said. Dura admitted that the mechanism of action of the peptide is not fully understood. Taking this factor into account, Barbara Gothe, MD, Case Western Reserve University, said: "I think it's premature to approve it, but it is promising." Dura consultant Yakatan noted that the company was invited to come before the advisory committee at the request of Office of Drug Evaluation I Director Robert Temple, MD. The nasal solution form of the drug received a nonapprovable letter from FDA in February 1991, but, Yakatan said, he understood that there was "a difference of opinion" within FDA about the drug's efficacy. The company had hoped the differences could be worked out within the pulmonary drugs division, Yakatan told the committee. Following the meeting, Dura reiterated its surprise at the many statistical objections by FDA. "It is certainly our belief that trials conducted by the company demonstrated both safety and efficacy," Dura President and CEO Cam Garner said in a March 23 reaction to the advisory committee's recommendations. "It is the company's intent to confer with the FDA and then decide how to proceed to gain marketing approval for Pentyde." Dura had announced that Pentyde would get a second look by an advisory committee in a prospectus for an initial public offering filed with the Securities & Exchange Commission in January ("The Pink Sheet" Jan. 13, T&G-6). A subcutaneous form of the peptide received a negative review by the pulmonary-allergy committee on Nov. 19, 1988. Dura completed the 2.5 mil. share offering on Feb. 6 at a price of $10 per share. The offering also included a 375,000 share over-allotment and raised approximately $26 mil.

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