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Executive Summary

Upjohn could get an extended period of marketing exclusivity for its Ansaid (flurbiprofen) non-steroidal anti-inflammatory through an amendment to the FD&C Act. House Energy & Commerce Chairman Dingell (D-Mich.) told a Feb. 20 hearing before the Health Subcommittee that Upjohn's request should be handled through an FDA bill instead of via a special patent extension. If necessary, the Michigan Democrat is said to be ready to sponsor an exclusivity amendment and attach it to an appropriate FDA-related legislative vehicle. Upjohn helped to pave the way for the inclusion of its amendment in another bill by stepping forward as one of the first supporters for Dingell's FDA enforcement bill at the beginning of October last year ("The Pink Sheet" Oct. 7, p. 3). Upjohn's original patent was scheduled to expire in February 1991 but was extended two years under the 1984 Waxman/Hatch provision for new formulations of previously marketed compounds. Ansaid is an oral form of an ophthalmic solution, Ocufen, marketed by Allergan. Ocufen was approved two years before Ansaid. Private patent extension bills (HR 2255 and S 1165) are pending in the House and Senate Judiciary Committees, which held legislative hearings but have not yet scheduled markups ("The Pink Sheet" Aug. 5, p. 4 and Nov. 4, p. 10). The Judiciary Committees apparently are waiting for an analysis by the General Accounting Office on the merits of Upjohn's case. The committees will determine what action to take after reviewing the GAO report, which is due at the end of February. Upjohn Chairman Theodore Cooper, MD/PhD, said his firm is seeking extended market exclusivity from the Energy & Commerce Committee because it "finds itself facing the imminent expiration of the Ansaid patent without indication of further progress in the Judiciary Committees." The Ansaid NDA was filed in 1982 and approved 79 months later, in 1988. Upjohn maintains that the approval was delayed largely because FDA reviewers were tied up re-reviewing previously approved NSAIDs associated with severe adverse reactions and answering congressional inquiries into the drugs and the agency's NSAID review process. The re-reviews focused on Lilly's Oraflex, Pfizer's Feldene and J&J's Zomax and Suprol. FDA Pilot Drug Evaluation Staff Director John Harter, MD, testified at the Feb. 20 hearing that between April 1983 and December 1985, his division gave precedence to four full NDAs and 22 paper NDAs for generic drugs over the Ansaid review. Harter also said 10 NSAIDs already were on the market when the Ansaid NDA was submitted, and "26 higher priority applications were approved by the 'anti-inflammatory group' while Ansaid was under review." In addition, "the Ansaid application contained two separate formulations which were not bio-equivalent," Harter said. "Additional time was needed to reconcile the differences between the disparate formulations" and the "large number of supporting clinical studies" for each. When asked for rough approximations, Harter estimated that at least one year was lost for each of a series of difficulties FDA had with the Ansaid application. One year of review time was consumed in obtaining answers to agency questions about the design of clinical trials and to clarify information in the application. About two years of delay are attributable to the fact that FDA gave Ansaid a "C" rating and made it a low-priority review, Harter estimated. Combining the information on two bioinequivalent products also cost the Ansaid application a year's delay "because we tried to combine two applications at Upjohn's request and...they had to have tests run." When Ansaid reached the front of the review queue, FDA also was ready to review Upjohn's application to switch its other NSAID, Motrin, from Rx to OTC status. Because Upjohn gave the ibuprofen switch a higher priority than the Ansaid NDA and because the switch review consumed one year, Upjohn's decision delayed the Ansaid approval another year, Harter said. Cooper countered Harter's account of the relative priorities of the ibuprofen and Ansaid applications. The Upjohn exec testified that the Ansaid approval was a higher priority for the company, adding that the firm has "internal documents" to demonstrate "that our priority was Ansaid all through that process." The Upjohn CEO also said his firm disagreed with FDA's assigning a low-priority "C" rating to Ansaid. Cooper noted that the agency had no process to appeal the rating, that the leading NSAID today, Syntex' Naprosyn, had a "C" rating, and that the FDA has since "completely revised" the system. In response to a recommendation by the President's Counsel on Competitiveness, FDA has adopted a two-tier rating system ("P" for priority and "S" for standard reviews) in lieu of the A, B, C, classifications ("The Pink Sheet" Jan. 13, In Brief). In his opening statement, Health Subcommittee Chairman Waxman (D-Calif.) said he is "generally skeptical as to whether it is appropriate to extend the patent for drugs covered by the 1984 [Waxman/Hatch patent restoration] act." Waxman said he is "concerned that if we open up the 1984 act, we will be besieged by companies that believe they each have a compelling argument as to why their patents should be granted additional extensions of time." The California Democrat scheduled the hearing at the request of Dingell, who is from Michigan, where Upjohn is based. Dingell launched into a diatribe against "rather grotesque" dilatory new product reviews by FDA. With Harter on the hotseat at the hearing, he took the brunt of much of the attack. Most of the agency senior management was tied up with the final day of the breast implant advisory committee meeting at the time of Waxman's hearing. "Sloth, laziness, indifference and probably incompetence by FDA justifies enactment of this legislation," Dingell declared. He noted that investigations by his Oversight Subcommittee uncovered that the FDA generic drug approval process had been corrupted and that approvals of worthy generic products slowed to a trickle as the agency tried to prevent further abuse of the system. Similarly, FDA has inappropriately delayed marketing of worthy innovator products, Dingell continued. Referring to his Feb. 6 hearing on photopheresis for scleroderma, he said: "Our [sub]committee more recently has been looking into, again, the behavior of the FDA with regard to bringing new products to the marketplace. And there we found -- I can't say whether it was corruption of is quite possible that it was both" ("The Pink Sheet" Feb. 10, p. 6). Referring to Harter, who reviewed both the photopheresis and the Ansaid applications, Dingell said: "Interestingly enough, some of the people who have appeared before this committee today to discuss the legislation in question here, from FDA, have been involved in significant slowdowns, manifesting some rather remarkable lows of incompetence with regard to bringing new products expeditiously to the marketplace." Dingell said such delays are "intolerable, and it is a behavior which I intend to pursue with enormous vigor until it is perfectly and properly corrected." He added that he plans to assure that FDA "is properly motivated -- and I intend to see it motivated with fire and sword if necessary." The Michigan Democrat served notice that he does "not intend to permit [FDA] to engage in the kind of slothful misbehavior which we have seen here, and I do not intend to permit them to impose that kind of slothful, indifferent behavior on American industry without appropriate [legislative] redress." During a subsequent exchange with Generic Pharmaceutical Industry Association outside counsel Alfred Engelberg, Waxman said he didn't believe "slothful misbehavior" delayed Ansaid's approval. "I think that one could argue that bureaucracies move slowly" in reviewing applications and setting priorities, he said. But "it is probably a little unfair to say that FDA acts slowly because of sloth or incompetence." Engelberg testified that flurbiprofen has already received extended market protection under the 1984 law. Allergan's Ocufen received five years of exclusivity from the time of its approval, regardless of available patent life, plus a two-year extension of the patent on the compound. In addition, Upjohn's oral formulation has received a three-year non-patent extension as a new formulation and indication requiring clinical study. "This is not a hardship case," Engelberg commented. He projected that no generic competition to Ansaid can be expected on the U.S. market before late 1993. Furthermore, Engelberg said, oral flurbiprofen has been marketed overseas "since 1970." Its original developer Boots "clearly had the ability to obtain approval to market flurbiprofen in the U.S. at a much earlier date had it desired to do so," he maintained. However, he said, it delayed development rather than compete with its own product, Motrin, which was then the leading NSAID.

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