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FOREIGN LABELING AND "DEAR DOCTOR" LETTER UPDATES TO NDA SUBMISSIONS ARE BEING CONSIDERED BY FDA AS OUTGROWTH OF MERITAL INVESTIGATION BY WEISS

Executive Summary

NDA sponsors may have to submit information on foreign-approved labeling and significant changes in non-U.S. labeling and marketing status as part of the NDA application for U.S. approval. According to a just-released House Government Operations Committee Report, "FDA has stated that it will consider 'whether we should modify regulations and/or guidelines to request certain information of this sort.'" FDA informed the House Intergovernmental Relations Subcommittee (chaired by N.Y. Democrat Weiss) of its interest in requiring more foreign labeling/marketing status information in November of 1986. The House subcommittee had previously questioned FDA about its ability to keep abreast of changes in foreign labeling during the investigation of the 1986 withdrawal of Hoechst-Roussel's antidepressant Merital (nomifensine). The House report on "FDA's Regulation of the New Drug Merital" (#100-206) observes that the agency "did not receive a copy of any German labeling for Merital prior to approving the drug." FDA told the subcommittee, the report says, that "it does not require sponsors to submit to it all labeling for a new drug approved in other nations that is either under investigation or has been approved for marketing in the U.S." The House committee declared that "such a requirement could provide valuable additional information on the manner in which foreign regulatory authorities as well as sponsors view a new drug under review in the U.S." FDA told the Weiss subcommittee that "notice of [a] pending British action [in early 1986] and associated Dear Doctor letters, provided more than a year after our approval action, and changes in promotion . . . are very much the sort of information we would like as soon as possible and, in the present case, were based on new information that we would also have liked to see promptly." If FDA accedes to the Weiss subcommittee pressure for requiring more information about product labeling overseas, it would, in effect, be another step toward standard international labeling. The House report maintains that the foreign labeling update in the case of Merital would have been useful as a way to alert FDA of a 1984 change in German labeling to warn physicians about "immunologically caused" side effects. The report says that FDA labeling was changed to address that issue 22 months after it was added to the German data sheet. In addition to foreign labeling changes, the House report also urges FDA to require submission of foreign warning or information letters to medical practitioners and update reports on foreign regulatory activities. The information updating recommendations forms one of five findings in the House committee report. In the case of Merital, the House committee contends that an evaluation of the product by the Australian drug regulatory agency in May 1981 noted allergic reactions to nomifensine. The Australian subsidiary of Hoechst was informed of the Australian department's view in August of 1983, but FDA did not learn of "this evaluation until [the Weiss subcommittee staff] brought it to the agency's attention on July 14, 1986." The report similarly maintains that Hoechst withdrew an application for marketing of nomifensine in mid-1984 when Swedish authorities noted that the "incidence of fever and liver reactions was unacceptably high." FDA, the House report says, "does not currently require sponsors to submit evaluative material obtained from foreign regulatory bodies regarding new drugs under review in the U.S. The committee believes such a requirement could prove invaluable in enabling FDA to review how potentially important aspects of a new drug under its review are perceived and handled by other regulators." While concurring with the Weiss subcommittee's suggestion to look at ways of updating foreign regulatory information, FDA is objecting to another recommendation about added information sources for reviewers. The Weiss staff used a MEDLARS search (a database of medical literature put together by the National Library of Medicine) to look retrospectively for adverse effect reports on nomifensine. The House report urges FDA to "ensure that its reviewers avail themselves of the agency's access to this important computer technology." However, FDA has told the Weiss subcommittee that it is not interested in performing general fishing trips for information about drugs during NDA reviews. In November 1986, FDA wrote to the subcommittee about routine database searches during NDA reviews and said that "neither the reviewers nor the library has sufficient time or resources for routine searches not directed at specific questions." As another way to expand its search of literature, the House committee asked FDA to reinstate a requirement for submission of all copies of relevant journal articles "that may be pertinent to [FDA's] evaluation of the safety and efficacy of a new drug under review, including translations of all such publications appearing in foreign languages." The Weiss report continues to criticize Hoechst for alleged adverse reaction reporting delays. "Based on an examination of submissions made to FDA by Hoechst after approval of Merital, the subcommittee's investigation has revealed that the company failed to report to FDA at least 30 drug-associated deaths known to it prior to that approval," the House report declares [emphasis marked as in the report]. At the House hearing on Merital in May 1986, FDA Neuropharmacological Drugs Division Director Paul Leber stated that FDA felt at the time of approval that that Merital "had been marketed for a long time in Europe with a very good safety record." At the time of the hearing, FDA believed there had been 27-30 cases of hemolytic anemia/hemolysis reported to the agency prior to approval of the drug. The House committee report alleges that "Hoechst had received at least 108 reports of hemolytic anemia/hemolysis prior to the drug's approval." The Weiss subcommittee maintains that in mid-June 1986 it "informed FDA of a number of other Merital-associated deaths that may have involved allergic reactions to the drug that were known to Hoechst prior to the drug's U.S. approval but were not reported to FDA until after approval." FDA is apparently continuing to search for information on Hoechst's reporting practices regarding Merital. In November 1986, the agency declined to answer Weiss subcommittee questions on specific alleged delays in reporting. The agency said "it was conducting an investigation of this matter." More recently, the agency has continued to pursue reporting chronolgies in the Merital situation. According to a footnote in the House report, a recent FDA investigation observations report (an FD 483 in March 1987) notes that a thrombocytopenia-related death of a Belgian patient was known to the Hoechst U.S. affiliate by mid-June 1984. The report to FDA was made in May 1986. The House report, however, does note that Hoechst reported two of three foreign fatal hemolytic anemia reactions in early 1986 as 15-day reports. The company was not technically required to report the events as 15-day reports because labeling, at that point, noted the potential for hemolytic anemia. The report notes, however, that: "The committee believes that, in executing its mandate to protect the public from the toxic effects of new drugs, FDA should not exempt the report of any death associated with an approved new drug, regardless of the contents of the drug's approved labeling, from the 15-day alert reporting requirement." A footnote to the report states that FDA, in a Nov. 5, 1986 letter said: "We expect drug firms to adopt procedures to ensure that adverse reaction information is expeditiously communicated among company officials and affiliates. Thus, the timeclock will generally be considered as running when the foreign affiliate receives the information indicating that the 15-day criteria have been met. The result of this is that U.S. applicants are responsible for establishing reasonable mechanisms to ensure rapid information transfer from their foreign affiliates." MERITAL INVESTIGATION RECOMMENDATIONS FROM WEISS SUBCOMMITTEE The following recommendations have been reproduced by "The Pink Sheet" from the conclusion of the July 8 report by the House Committee on Government Operations. The committee recommends that the Secretary of Health and Human Services take prompt action to assure the correction of the deficiencies identified in this report. The committee specifically recommends that: 1. FDA ensure timely receipt and review of all important publications in the world literature pertinent to evaluating the safety and efficacy of a new drug under review, including translations of all such publications appearing in foreign languages. In this regard, FDA should require its scientists to review relevant bibliographical listings from the Medical Literature Analysis and Retrieval System (MEDLARS) concerning such drugs, particularly before approving them for marketing. 2. FDA require sponsors to submit information relating to the marketing and investigation of new drugs under review in the United States, including (a) all labeling approved by foreign regulatory agencies; (b) all standardized warning or information letters distributed to practitioners, pharmacists, and other health professionals in foreign nations; and (c) accounts of all important regulatory developments concerning such drugs in foreign countries. 3. FDA ensure that sponsors submit to it timely and full reports of all information in their possession possibly bearing on the safety of a new drug under review. FDA should take steps to ensure that its personnel correctly interpret and strictly enforce all legal adverse reaction reporting requirements. 4. FDA amend its adverse reaction reporting regulations to (a) require timely reports of all deaths, whether or not "unexpected," associated with the foreign use of a new drug approved for marketing in the United States; (b) precisely define a "significant increase" in the frequency of an adverse effect reported for a new drug under investigation that must be promptly brought to the agency's attention. 5. FDA prevent the marketing of any new drug whose efficacy is not supported by "substantial evidence" derived from "adequate and well-controlled" clinical studies, as required by Section 505(d) of the Food, Drug, and Cosmetic Act. In determining whether such evidence has been provided, FDA should give appropriate weight to all controlled clinical trials that demonstrate, or fail to demonstrate, the drug's efficacy for its intended use.
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