SUPERPHARM BIO SAMPLE SWITCH ALLEGED; PRESENCE OF ANOTHER FIRM's CAPSULES AT AMERICAN THERAPEUTICS ALSO RAISES QUESTIONS; FDA REPORTS ON DRAGNET

FDA's intensive generic drug investigations have uncovered another potential bio sample switch and the suspicious appearance of a brandname company's capsules in a generic company's bio sample, according to testimony by Generic Drug Compliance Staff Deputy Director Paul Vogel reported at a Sept. 11 hearing of Rep. Dingell's (D-Mich) Energy and Commerce/Oversight Subcommittee. The clear-cut allegation of a switch is leveled against Superpharm. FDAer Vogel testified to Dingell that FDA inspectors discovered that Superpharm had submitted in vitro dissolution test data on an innovator product. Superpharm "misrepresented the test data as its own when, in fact, it was the test data conducted on the innovator's product," Vogel stated. The FDA investigator did not name the product; however, he noted that it has not been distributed since 1986. Vogel further said the FDA investigators found "a pattern of discrepancies and irregularities" in Superpharm's data for six products. Only one of those questioned products, lorazepam, is still being marketed, Vogel told the subcommittee. The agency previously said it was looking into Superpharm's application for diazepam. Vogel noted that Superpharm "voluntarily recently stopped distributing . . . diazepam." At American Therapeutics, FDA investigators found capsules marked with another firm's logo, Vogel told the subcommittee. He reported that capsules in a bio sample were found bearing "identifying marks used by a different manufacturer, not ATI." The FDA compliance official noted that "the batch records for that bioequivalence lot said that ATI's capsules had been used." The FDA compliance officer did not name the ATI product during his Capitol Hill testimony. However, he noted that the product was never marketed by ATI. The generic firm, Vogel said, withdrew its application while it was pending at FDA. According to Vogel, ATI explained that it withdrew the ANDA because it had difficulty "developing a formula that was equivalent to the innovator." ATI explained the discrepancy to FDA by saying that "the batch records were incorrect," Vogel said. The FDAer added that ATI acknowledged "that indeed they used excess tablets ]sic[ supplied by another firm that had been sent to them for some other contract manufacturing for a different product." David Weeda, an outside attorney for American Therapeutics with the D.C. law firm of Olsson, Frank, Weeda, refutes the implication that the other manufacturer's capsules implied a sample switch. In comments to "The Pink Sheet," he maintained "there has not been one allegation . . . that ATI substituted brandname products to do the bioequivalency study." Noting that ATI has performed private labeling for Squibb, Weeda said: "We suspect what Vogel was talking about was an R&D batch which had Squibb's name on the capsules. What occurred was they ]ATI[ had done an R&D lot. They did not have a ]requisite[ number of gelatin capsules on hand. They used the Squibb capsule to fill it." The Squibb capsules were made by the same manufacturer as ATI capsules, Weeda said. The attorney maintained that FDA was advised of the use of the Squibb capsules during the inspection. The discussion of potential bio sample switches at Superpharm and ATI were disclosed by Vogel as part of the agency's first detailed reports on the intensive investigations of manufacturing and bio testing practices in the generic industry. The agency began that process with for-cause investigations of 12 generic firms in April and May. During testimony at an earlier July 11 hearing before Dingell's subcommittee, FDA Commissioner Young said that a review of bioequivalence submissions would be one of the agency's priority inquiries. He suggested at that time that FDA was particularly interested in the bio submissions from six firms ("The Pink Sheet" July 17, p. 11). Five generic firms have now been mentioned publicly in relation to potential bio switches, but the agency says only two firms have been confirmed as switching bio products. In addition to the references to ATI and Superpharm at the Sept. 11 session, Vitarine has been charged with substituting SK&F's Dyazide for its generic application and similar substitutions for four other product applications. Concerns have also been raised by the House subcommittee about the bio test products for Bolar's generic version of Dyazide and thioridazine. FDA also said in July that it was looking into bio data from Pharmaceutical Basics for generic carbamazepine. Since that announcement, however, attorneys for Pharmaceutical Basics have maintained that the company per se will not be charged with any wrongdoing stemming from the investigation ("The Pink Sheet" Sept. 11, T&G-4). During the morning session of the Sept. 11 hearing, the subcommittee heard testimony from Vogel and three other FDA inspectors. Dingell's opening statement praised the FDA investigators and the agency's compliance effort. "The FDA witnesses here today," Dingell's statement declared, "are part of the solution, not part of the problem." To check the accuracy of ANDA submissions and back-up data, the FDA investigators have been taking copies of at least three ANDA applications with them on each inspection visit. The inspectors have been closely comparing the ANDAs with records viewed during the inspections to verify that the drugs were manufactured and tested in accordance with the approved applications. Routine inspections of an additional 20 generic drug manufacturers, including some brandname companies began at the start of September. Barr Labs and Mylan, two of the complainants about FDA favortism, are included in the current round of inspections. FDA started to inspect Barr in May at the same time that the firm testified at one of the first Dingell hearings. FDA halted that inspection after Dingell wrote to the agency suggesting that the timing implied a retaliatory move against the firm. FDA said that the for-cause inspections, begun last spring, are largely completed and that inspections of the 20 firms should be completed by mid-November keeping to the deadline for completion of inspections that was set by Commissioner Young in August ("The Pink Sheet" Aug. 28, p. 5). Also, FDA said, the review of the 30 most prescribed generically available products is 60% completed. In the for-cause inspections of 12 firms, FDA told Dingell it found a wide variety of misconduct, including deviations in manufacturing processes, unapproved changes made in drug formulations to deliberate falsification of production records and misstatements made in ANDA filings. Able Labs and Zenith were the only firms to come through the first round of inspections with basically clean reports. For Zenith, that conclusion is a bittersweet postscript to the hard going that the firm experienced with FDA in 1987 and 1988. The close FDA attention two years ago was difficult for the firm and contributed to a bankruptcy filing but it apparently worked to assure compliance by Zenith. Zenith recently filed a plan for coming out of Chapter 11 with new funding from Wyvern Partners ("The Pink Sheet" July 3, T&G-17). Because of the extent of the recordkeeping irregularities alleged by FDA at Par and Vitarine, the Dingell subcommittee focused on these two firms. The lead FDA investigator for the Par inspection, Gary Tunkavige, noted that he found unapproved deviations in the manufacture and formulations of three ANDAs that he was asked to investigate. Tunkavige, an FDA investigator for 12 years, also discovered that some R&D lab results were kept on scrap paper or in unofficial notebooks, and only later added to the official record. The practice of adding information later, Tunkavige observed, "provides an opportunity to selectively report data . . . would also help to conceal product test failures, and would not permit detection during later regulatory audits." Tunkavige noted that he was told that Ashok Patel, former senior VP and secretary of regulatory affairs, had "given instructions to employees in ]the[ lab to make changes in data." FDA also discovered that Par used a second, informal record to keep production and test data. Showing a copy of a typical black-cover school composition book marked "off-the-record," Tunkavige reported the book contains notes on unauthorized reworking of products, use of unauthorized equipment and facilities, and the false recreation of a batch record. One off-book notation indicates that an unauthorized ingredient was added to two lots of megestrol acetate tablets, the FDA investigator pointed out. Another entry discussed an assay problem with hydrocortisone cream 0.5%. According to the book, Tunkavige said, employees tried to "evaporate water to increase the potency." Another notation says: "Everything kept off the record, Jay knows about this." The FDAer added that "Jay" is believed to be Jay Patel, Par's former director of quality assurance. Jay Patel was requested to testify at the Dingell hearing but declined to answer questions based on his Fifth Amendment protections. Tunkavige also related requesting surplus tablets from Par on the bioequivalence study performed on a generic version of Maxzide. When he asked for the bio samples, Tunkavige said he was provided with tablets taken from a current production batch. Par informed FDA of the switch at a July 21 meeting after which the firm initiated a voluntary recall of its generic version of Maxzide ("The Pink Sheet" July 31, p. 15). The switch was attributed to Par Senior VP R. K. Patel. On the day following the Sept. 11 hearing, Par announced that R. K. Patel "has resigned from all of his positions with Par and with its subsidiary, Quad Pharmaceuticals." Senior VP Ashok Patel, one of the founders of Par, previously admitted paying illegal gratuities to an FDA employee. He resigned from the company in April. During November and December inspections, FDA apparently found that Quad had ANDAs with numerous material false statements. FDA inspector Douglas Poucher, who also has 12 years of experience in the field, told the subcommittee that drug validation batches that were described in ANDAs as being production batches were actually made in R&D labs and that key records were "missing, falsified, or in disarray." Former Quad President Dilip Shah was sentenced on Sept. 13 in Maryland Federal Court to 18 months incarceration with a $ 250,000 fine and two years probation for giving illegal gratuities. The chief investigator for the inspection of Vitarine Labs was Laurence Daurio, a 15-year FDA veteran. He testified that the first phase of Vitarine's inspection generated information that batch sizes had been overstated, that there were discrepancies between Vitarine's records and FDA's, and that batch and inventory records were missing. These disclosures led to the mid-May recall of 12 drugs ("The Pink Sheet" June 5, T&G-14). Vitarine execs told Daurio in May that the firm was stopping distribution of 25 products because Steve Colton, former VP of research and development had been involved with the production of these products and that he "had not been producing the batches as set forth in the batch records." The falsified Vitarine batch records were confirmed, Daurio added, from information in a research notebook that was kept by a subordinate of Colton. The Dingell subcommittee also tried to question Colton at the Sept. 11 hearing. He was eventually dismissed as a witness because he declined to testify (see related story, below). Daurio pointed out that Vitarine had informed him of five cases in which innovator products were substituted for Vitarine's generic versions in bioequivalence studies. The drugs are generic Dyazide, verapamil SR, albuterol SR, propranolol LA and methylprednisolone. The generic version of Dyazide was the only product marketed by Vitarine. Daurio noted that field inspectors have collected samples of all Vitarine products from the company and from two contract testing labs, PharmaKinetics and Biodecision Labs. Several exchanges during the hearing indicated the potential for future recommendations to the Justice Department for prosecution. During FDAer Vogel's discussion of the inspection at Pharmaceutical Basics, Inc., for example, the investigator referred to a Class I recall situation in December 1987 at a company which later became a subsidiary of PBI. My-K Labs undertook a Class I recall of one lot of antihistamine in December 1987 after a bottle was found to contain haloperidol. PBI later acquired My-K in July 1988. Vogel noted that Kun Chae Bae was president of My-K at the time. Rep. Wyden (D-Ore.) then asked Vogel: "With respect to that gentleman and the complaint, has there been a referral to the Department of Justice for criminal prosecution?" Vogel replied that he could not comment on an ongoing investigation. Similarly in relation to an inspection at Sidmak, Vogel said FDA determined that a superpotency problem may have been tied to the work of an outside testing lab. Vogel said Quality Research Labs caused the problem because it "had fabricated the test values for the strength of the active ingredient." Wyden again pointedly asked the FDAer if investigation of the lab involves "consideration of possible criminal misbehavior." Vogel said he could not comment. Rep. Walgren (D-Penn.) asked Vogel whether an investigation of Pharmafair, involves "possible criminal misbehavior." Vogel again declined to comment. In 1983, the FDAer reported, FDA had recommended that the Department of Justice prosecute Pharmafair for counterfeiting drugs.