Opinion ID: 545552
Heading Depth: 2
Heading Rank: 3

Heading: Adverse Reaction Reports and Revision of Labeling

Text: 21 During the five months that E-Ferol was on the market, OJF received numerous inquiries about the product and three reports of severe adverse reactions associated with its use. Each of the reports related similar unusual symptoms, and two of them included infant deaths associated with E-Ferol. 22 Inquiries and complaints about OJF products were directed to Madison. In December 1983, he received a telephone call from Dr. David Easa, a neonatologist at Kapiolani Hospital in Honolulu, Hawaii, who reported that two premature infants under his care had developed unusual symptoms after receiving E-Ferol. Madison testified that he immediately advised Hiland of this report. Hiland denied this, claiming that he did not learn of the Hawaii report until after the recall of E-Ferol in April 1984. 23 On January 26, 1984, Dr. Carl Bodenstein, a neonatologist at Sacred Heart Medical Center in Spokane, Washington, telephoned Madison to report that E-Ferol may have caused the deaths of three premature infants and serious illness in a fourth. Bodenstein told Madison that the surviving infant's blood contained excessively high levels of vitamin E. Madison informed Hiland of Bodenstein's call and sent him a memorandum describing the report the next day. 24 Hiland halted the distribution of E-Ferol and took charge of the investigation into the validity of the Spokane report. He instructed Madison to notify Carter, consult with Fainberg, do a literature search on the safety of vitamin E and polysorbates, contact other neonatal units to see if they had experienced similar problems, and obtain more information from Bodenstein. No effort was made to advise hospitals to which E-Ferol had been distributed that OJF had received a report associating the product with the deaths of premature infants. The OJF sales force was instead instructed to tell customers that E-Ferol was unavailable because it was on back order. Madison testified that when he asked Hiland what he should say to hospitals inquiring about the product, Hiland told him not to mention the Spokane report. Hiland denied giving Madison such a directive. Twelve days after the distribution of E-Ferol had been suspended, Hiland made the decision to resume all shipments of the product. 25 The evidence at trial established that Madison's investigation into the Spokane incident was woefully inadequate, even when measured by the limited instructions Hiland had given him. For his part, Hiland knew when he ordered the resumption of shipments that Bodenstein had not in fact been successfully contacted for additional information. Hiland did not ask Madison for a written report of his investigation. Nor did he inquire into the extent of Madison's literature search, or ask him how many hospitals he had contacted. The Spokane report was far and away the most serious adverse reaction report Hiland had ever encountered. Yet, he assigned the investigative tasks to Madison despite knowing that Madison had no medical or other scientific training to evaluate such reports, aside from his experience in the pharmaceutical industry. Five months prior to the Spokane incident, Hiland wrote an evaluation criticizing Madison for jumping to conclusions, reaching conclusions or opinions without giving enough thought and consideration to the overall problem, and working on too many different areas without concluding on any one issue. 26 Carter was also informed by Madison on January 26, 1984 of the Spokane report. A few days later, Madison sent Carter a copy of the same memorandum he had given Hiland regarding the report. From this memorandum, Carter knew that Bodenstein was questioning both E-Ferol's dosage recommendation and its high polysorbate content. Madison informed Carter that OJF had temporarily stopped shipping E-Ferol while the Spokane report was being investigated. Carter did nothing to determine the accuracy of this report, even though it was the most serious adverse reaction report he had ever received, and was precisely the type of incident he had feared when he expressed serious concerns in the summer and fall of 1982 about the potential for infant deaths. Carter testified that he simply forgot the safety concerns he had previously put in writing. In late February, Carter asked Madison what he should do with the third lot of E-Ferol Carter-Glogau was holding. When Madison told him to ship the lot to OJF, Carter did so without asking for any details about OJF's investigation into the Spokane report. 27 On January 26 and 27, 1984, Hiland discussed the Spokane report with John Lemker, an attorney who represented OJF in food and drug matters. After reading E-Ferol's package insert, which he had not previously been asked to review, Lemker advised Hiland that the references to RLF made the product a drug and that the FDA would probably consider it to be a new drug. Lemker further advised that OJF stop shipping E-Ferol and contact experts for an evaluation of the drug. Fainberg also recommended to Hiland that shipments of E-Ferol be ceased. Hiland never informed Lemker and Fainberg of his subsequent decision to resume shipments of E-Ferol with its existing package insert. 28 After his discussions with Lemker and Fainberg, Hiland directed Madison to work with them and Carter to revise E-Ferol's labeling. After seeing one of the proposed insert revisions, Hiland returned it to Madison with a note stating, This insert really reads as if it's a drug. With Hiland and Carter aware of the changes being made, Madison prepared a revised package insert that deleted all references to RLF, greatly reduced the recommended dosage so it conformed with nutritional dosages, and added a warning that levels of vitamin E in the blood should not exceed a certain amount. The revised labeling was finalized in March 1983, but was never included with any shipments of E-Ferol. Hiland testified that he allowed the shipments to resume before the revised insert was packaged because it had no safety issues, but rather only technical changes. 29 In a memorandum dated March 27, 1984, Madison advised Hiland of a third adverse reaction report. This report came from Melanie Sandlin, a pharmacist at the University of Tennessee Hospital, who informed Madison that the hospital had stopped administering E-Ferol because of four premature infant deaths associated with its use. Hiland testified he did not order that shipments of E-Ferol be stopped because he thought the manner in which OJF had received the report was unusual. 12 Hiland's only response to the Tennessee report was to write Madison a note asking him to follow up with the hospital and make sure that the pharmacist had received some literature Madison had sent her. 30 Shipments of E-Ferol with the old package insert continued until April 6, 1984, when the FDA contacted OJF and requested that shipments be ceased because of reports associating the product with serious adverse reactions and deaths. Five days later, OJF initiated a total recall of E-Ferol, which resulted in its permanent removal from the market.