Opinion ID: 545552
Heading Depth: 2
Heading Rank: 1

Heading: Development of E-Ferol

Text: 6 The development of E-Ferol was prompted by the need for an intravenous form of vitamin E to combat retrolental fibroplasia (RLF), a disease that causes impaired vision or permanent blindness in premature infants. Many neonatologists, physicians specializing in the care of premature infants, considered vitamin E to be useful in reducing the incidence and severity of RLF. The two principal forms of vitamin E available to neonatologists in the early 1980's were an oral preparation and an intramuscular injection, both of which were sold as nutritional supplements and not represented as safe and effective for use in premature infants. 9 For some years prior to the development of E-Ferol, Carter-Glogau had been manufacturing a vitamin E intramuscular product (E-Ferol IM) for OJF. This product was labeled as a nutritional supplement and was not approved by the FDA. Although its labeling contained no reference to RLF, E-Ferol IM was used by some neonatologists to treat this disease. 10 However, like the oral form of vitamin E, E-Ferol IM had drawbacks that made it difficult to administer to premature infants. 7 In April 1982, one of Carter-Glogau's customers wrote Carter to ask whether an intravenous form of vitamin E could be developed, noting that [t]here must be a Hell of a market out there. Carter expressed a reluctance to develop such a product. In his responses to the customer's inquiry, he stated that the amount of polysorbates needed may be detrimental, and pointed out that fat emulsions for IV use ... are very tricky products and fraught with particular size problems. 8 In August 1982, Madison wrote Carter to see if he could develop for OJF a high potency intravenous form of vitamin E for use in premature infants. He informed Carter that Hoffmann-LaRoche, a large pharmaceutical company, was testing an injectable vitamin E product for the treatment of RLF in an effort to obtain FDA approval of the product. Madison wrote that he was afraid that when Roche gets their Vitamin E approved, we will lose the business, unless you can come up with something. Madison's letter clearly indicated that the primary purpose of the product he was proposing would be to treat RLF, and stated, We could always label it for Vitamin E supplementation. Hiland received a copy of this letter. Several weeks later, Madison sent Carter a follow-up letter recommending a dosage level sufficient to alleviate RLF. 9 In his responses to Madison's inquiries, Carter expressed serious safety concerns regarding the development of an intravenous vitamin E product, stating in part: If we make some attempt to solubilize the Vitamin E and use the wrong proportions and kill a few infants, we'd have some serious problems. Carter was specifically concerned about developing such a product without proper clinical testing. He wrote Madison that: 10 The administration of this product intravenously in neonatals without appropriate clinical work concerning toxicity will undoubtedly lead to an exposure in terms of product liability which neither you nor we may wish to assume. 11 After all, one neonatal death is one too many. 12 Carter suggested to Madison that the best way to proceed would be to wait until Hoffmann-LaRoche came out with the benchmark product so that they could then copy its formulation, thereby taking advantage of Hoffman-LaRoche's toxicity studies. This was Carter-Glogau's usual mode of operation. 13 Carter and Madison resumed their dialogue about vitamin E early in the summer of 1983. Notwithstanding the strong safety concerns he had expressed less than a year earlier, Carter went ahead and developed a high potency intravenous vitamin E product (E-Ferol) for OJF. He did so despite knowledge that Hoffmann-LaRoche was still engaged in clinical testing of its intravenous vitamin E product and had not received approval from the FDA to market it. Carter personally made the final decisions as to E-Ferol's formulation, including the type of vitamin E and the types and proportions of polysorbate the product would contain. Carter admitted that at the time he made these decisions, he did not even know what level of polysorbates was safe for injection into premature infants. At no time did Carter do testing or research of any kind to determine whether E-Ferol's formulation would be safe and effective for use in premature infants. Nor did he ever request OJF to do any testing. Carter testified that he instead relied on Madison as the expert on E-Ferol, even though Madison had no formal scientific training. 14 In the summer of 1983, Madison requested and received authorization from Hiland to explore the possibility of having Carter-Glogau supply OJF with the high potency vitamin E intravenous product being formulated by Carter. Madison informed Hiland that its primary use would be for the treatment of RLF and that Hoffmann-LaRoche was testing a similar product under FDA guidelines. Hiland subsequently approved the addition of E-Ferol to OJF's product line. Only Hiland had the authority to authorize such an addition. OJF never did any testing to determine whether E-Ferol would be safe and effective for use in premature infants. Nor did Hiland or Madison ever ask Carter-Glogau to perform such testing.