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U.K. AND SWEDEN DO NOT PLAN REGULATORY ACTION AGAINST PIROXICAM, FDA SAYS; AGENCY ANNOYED BY HRG's USE OF IMMINENT HAZARD PETITION IN FELDENE SITUATION

Executive Summary

The U.K. and Swedish drug regulatory authorities do not plan any further restrictions against piroxicam, FDA reported in a summary of foreign regulatory activity prepared for its answer to the Health Research Group petition to ban Feldene's use by the elderly. "The British do not plan, and have not taken, any regulatory action with regard to piroxicam although they have a large number of reports of G.I. problems with the drug," FDA reported. FDA speculated that the increase in reports of adverse reactions from piroxicam in England might be the result of an overall increase in drug reaction reporting in that country. FDA questioned foreign governments about their plans for piroxicam to answer to HRG's allegation that the U.S. agency was being less diligent than its counterparts in reviewing the possibility of increased gastrointestinal side effective from use of the NSAID. "While the actions of foreign regulatory agencies and one foreign medical association cannot themselves provide a basis for U.S. regulatory actions," FDA said, "the expressed concerns of these bodies are cited by HRG as evidence that problems with piroxicam are widely recognized." In its survey of the countries mentioned by HRG, FDA found two countries (Ireland and West Germany) with more restrictive labeling and one country (Australia) with a safety and efficacy review underway. The other four countries indicated no regulatory action had occurred or was planned. HRG Director Sidney Wolfe responded to the denial of the imminent hazard petition by comparing FDA to an overseas regulatory body. Wolfe declared: "Even in Germany, despite its horrendous history in protecting people, there are specific warnings for older people about the use of Feldene." FDA Questions HRG's Use Of "Imminent Hazard" Petition For Feldene Labeling Change The tone of Wolfe's response indicates an unusual level of acrimony between the agency and HRG regarding the piroxicam petition. The attitude at FDA towards the HRG petition was very similar. A number of comments throughout the 60-page response to the petition prepared by the Center for Drugs indicates a highly critical view of HRG's arguments and procedures in seeking a piroxicam labeling change. Primary among FDA staff complaints apparently was the use of the "imminent hazard" procedures to seek a labeling restriction. The agency directly states a warning that it does not consider the piroxicam review as setting a precedent for imminent hazard petitions. The imminent hazard procedure, FDA said, "is not normally an appropriate vehicle for consideration of labeling changes, such as those proposed in this petition." FDA's decision to expedite the piroxicam review in response to the petition, the agency said, "should not be considered a precedent for considering, as subject to the imminent hazard procedure, proposed labeling changes that would, if adopted, promote the safe use of new drugs." Similarly, in a footnote, the agency reiterates that "inasmuch as HRG did not request an outright ban on the drug's presence in the marketplace it is not clear that HRG's petition in fact qualifies as an imminent hazard petition. HRG's petition might be more properly characterized as simply a citizen's petition requesting a labeling change." The agency rushed to complete a review of the piroxicam data and had a state report ready for Com. Young within four months of the HRG petition. The final review process for the document in the Center for Drugs and Biologics took half a month of top staff time. FDA noted that it had already asked Pfizer, prior to HRG's petition, "to analyze their extensive clinical trial data to see whether it could shed light on the question of the relative risk of serious G.I. toxicity of piroxicam and other NSAIDs." That advance work "made it possible for Pfizer to complete a partial analysis of data pooled from all controlled trials," FDA pointed out. In addition to procedural complaints about the HRG petition, FDA did little to disguise its opinion of HRG's use of adverse reaction data. In its summary, FDA said that HRG "ignored rudimentary precautions needed to evaluate" spontaneous report data. HRG Asks For FDA Review Of Pfizer ADR Reporting The agency added: "It is well known that comparative ADR (adverse drug reaction) analyses to estimate relative toxicity of one drug against another must, at a minimum, adjust for the time since marketing approval for each drug." The agency pointed out that of the 99 G.I. fatalities alleged by HRG only 20 were domestic fatalities. Sixty-eight of the reports were discarded by FDA's reanalysis because they were foreign cases, cases from special postmarketing studies, or duplicate or miscoded reports. Eleven cases were not upper G.I. events. On July 8, the day following the rejection of the HRG petition, the consumer advocacy group wrote to FDA again seeking an investigation into Pfizer's adverse reaction reporting practices. HRG also asked FDA to review press statements by the Natl. Alliance of Senior Citizens in favor of Feldene use as promotional material from Pfizer. HRG said that "Pfizer has just admitted that he drug company paid for NASC's April 15, 1986, massive mail campaign that touted the virtues of Feldene to physicians all over the country." FOREIGN REGULATORY PLANS FOR PIROXICAM: SUMMARY OF FDA CONTACTS WITH OTHER AGENCIES The following summaries are reproduced from FDA's analysis of foreign regulatory positions on piroxicam use in the elderly. The summaries were included in a May 19 report on piroxicam prepared for Com. Young by FDA's Center for Drugs. Great Britain: The British do not plan, and have not taken, any regulatory action with regard to piroxicam, although they had a large number of reports of G.I. problems with the drug. This was thought to be caused in part by the present surge in overall reporting in Great Britain and by reports generated by Dr. Inman's postmarketing study. In March of 1986, the Cmte. on the Safety of Medicines stated "it is not yet possible to conclude with confidence that any one member of the class is more toxic than another." Sweden: No regulatory action is planned at the present time. Although early data analysis suggested that piroxicam was associated with a high rate of G.I. toxicity, more recent experience has not borne out this observation. Canada: At present, regulatory action has not been taken. Ireland: No response was received in answer to our inquiry. However, Ireland has the most severe labeling restrictions for piroxicam. Norway: No regulatory action occurred, not is any planned, although they have discussed a possible recommendation that the dose for the elderly should be reduced to 10 mg per day. Germany: No recent regulatory action has taken place. The labeling for piroxicam contains a relative contraindication for the elderly. Australia: In its March 17 post-hearing submission and its Feb. 28 hearing presentation, HRG describes piroxicam's regulatory status in Australia. Piroxicam is approved for marketing in Australia, but is not included in the Pharmaceutical Benefits Scheme. HRG notes that there is concern about toxicity in doses above 20 mg/day. Australia is currently conducting a review of the general safety data on piroxicam.
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