Court Opinion

ID: 9860040
Source: CourtListenerOpinion
Date Created: 2023-09-24 23:08:08.042949+00
Date Added: 2024-06-11T11:17:09.640390
License: Public Domain

JUSTICE HARTMAN, concurring in part and dissenting in part: I concur, not in the discussions, but in the dispositions, only, reached by the majority under Parts I, II, and III of the preceding opinion; however, I respectfully dissent from Part IV of the majority opinion for the reasons which follow. The majority suggests that millions of periocular injections of corticosteroids such as Depo-Medrol were successfully made prior to the Proctor occurrence in November 1983. The basis for such an astronomical figure seems to be in opening remarks for defendant doctor, Dr. Michael J. Davis, made by his counsel, who told the jury that his client used an injection technique in connection with cataract patients and other patients in whom Dr. Davis had injected "everything from Depo-Medrol to anesthetic agents to antibiotics” 3,500 times in the eyes of his patients during the preceding 18 years. Counsel argued further that "there are some one million of 'these’ injections that are given in the United States each year.” There was no breakdown as to how many of "these millions” of intraocular injections involved Depo-Medrol, how many involved soluble corticosteroids rather than Depo-Medrol, how many involved anesthetic agents and how many involved antibiotics. The record shows that Dr. Davis was merely estimating what would be a "fair and reasonable” guess of how many times the technique of intraocular injections was used in general, but that Depo-Medrol was used by him on an average of about 89 times per year. Therefore, the opening statement by Dr. Davis’ lawyer referred to the number of times the intraocular injection technique was used, not how many of these injections were made with Depo-Medrol. It is important to make the foregoing distinction because Depo-Medrol is neither an anesthetic agent nor antibiotic, nor is it soluble, but it is a substance made to be released in the body over a period of six to eight weeks in human tissue with a lot of blood supply; however, the human eye does not possess such a blood supply. Depositing Depo-Medrol, which the record showed is an insoluble, toxic material, into the eye meant that the drug would remain in the eye for a relatively long time. Because of its insolubility, its crystals had an effect on the body’s response to it when inserted, including increased intraocular pressure and other trauma. It became a foreign body in the eye, which was very difficult, if not impossible, to remove once injected into the eye. Upjohn, as its manufacturer, knew or should have known this, more so than anyone else, and must be held to the standard of an expert in the field. (McEwen v. Ortho Pharmaceutical Corp. (1974), 270 Or. 375, 528 P.2d 522.) Accordingly, Upjohn had a "continuous duty *** to warn physicians of the dangers incident to prescribing the drug, to keep abreast of scientific developments touching upon the manufacturer’s product and to notify the medical profession of any additional side effects discovered from its use.” (Emphasis added.) Schenebeck v. Sterling Drug, Inc. (8th Cir. 1970), 423 F.2d 919, 922. The evidence showed that Upjohn had available to it pharmacologists, toxicologists, experimental laboratories, experts in animal studies, and laboratory animals. If Upjohn did not know what it should have known, it failed in its duty as an expert. It did not fulfill its duty as an expert merely by waiting for what it considered sufficient proof of a cause-effect relationship before advising the medical profession with an appropriate alert or warning of the possibility of risk in the use of one of its products. (See Mahr v. G.D. Searle & Co. (1979), 72 Ill. App. 3d 540, 564, 390 N.E.2d 1214, appeal denied (1979), 79 Ill. 2d 612 (Mohr).) Nor can failure to do so be excused merely by the fact that the potentially endangered users are few in number. (Mahr, 72 Ill. App. 3d at 560; Crocker v. Winthrop Laboratories, Division of Sterling Drug, Inc. (Tex. 1974), 514 S.W.2d 429, 432.) Contrary to the majority’s suggestion that the inadvertent injection of Depo-Medrol into plaintiff’s eye somehow relieves Upjohn of its responsibility, the injury here clearly was within the scope of the dangerous propensities of the drug for which Upjohn must be held accountable. McMahon v. Eli Lilly & Co. (7th Cir. 1985), 774 F.2d 830, 835. The record showed the jury that Upjohn knew of these dangerous propensities before the instant occurrence took place in 1983. The jury heard evidence that there was no reference in the 1983 label or insert that subconjunctival use of Depo-Medrol as practiced upon plaintiff in this case was not recommended by Upjohn, nor was there ever Federal Food and Drug Administration (FDA) approval for such application. There was no mention on the label that 1 cc of the drug for use about and around the eye was an excessive dosage, according to one of its own expert employees. (See 275 Ill. App. 3d at 608 n.3.) Tissue atrophy developed in some patients after injection, which could be considered as evidence of a toxic effect, also known by Upjohn before 1983. (See 275 Ill. App. 3d at 608 n.3.) The 1983 package insert made no reference to the fact, known by its employee, that the drug should be administered intramuscularly as "probably the predominant steroid effect is going to be a systemic effect anyway.” (See 275 Ill. App. 3d at 608 n.3.) Nor did it point out that this preparation was a suspension and not a solution, and that the crystalline material in the area of sensitive subconjunctival tissue could be the cause in itself for injury. (See 275 Ill. App. 3d at 608 n.3.) Dr. Philip D. Walson, plaintiff’s expert, was of the opinion that, given Upjohn’s knowledge of the foregoing facts in 1962, the drug company should have warned that periocular use of the drug was not recommended and, under the adverse reaction section of the warning, should have listed the toxicity of the drug. The jury heard this evidence. The record revealed that the FDA had approved the use of Depo-Medrol only for certain other uses, including three specific means of administration: intramuscularly, intra-articularly and intralesionally; none of those approved uses included the periocular use to which the drug was put in this case. Federal law required Upjohn to include package inserts and labeling recommendations which referred only to the three approved forms of administration for its product. Dr. Davis should not have used it as he did and Upjohn should have warned him and others of its potentially harmful effects which Upjohn knew about soon after it went on the market. The majority finds no duty to warn in this case because, it argues, the "medical community” was aware in 1983 of the risk of vision loss and physicians were "learned intermediaries” who required no such warnings since they already knew of the dangers. (See Mahr, 72 Ill. App. 3d 540, 390 N.E.2d 1214.) The record supports a contrary conclusion, however, which the jury here reached. No physician or expert witness testified that the medical community knew what Upjohn knew with respect to dangerous toxicity and irremovability of this drug, once injected into the eye, as Upjohn knew of these characteristics, but shared with no one except its own employees. The relevant history of the development of this drug, as shown by the record, reveals that by 1961, Upjohn had learned that some ophthalmologists were administering Depo-Medrol through periocular injection as an "off-label” use. The evidence shows that Upjohn fostered and encouraged this unapproved, off-label use as experimentation on human beings with no prior basic scientific studies made. This unauthorized use became more widespread in the next two decades, although Upjohn never secured FDA approval for it and never set forth the use, warnings or directions for such periocular injections on its labels or in its literature. None of the dangers attendant to such use, or any reported deleterious side effects which may have developed of which Upjohn was apprised, were made known to the prescribing or treating physicians, the "learned intermediaries,” who made this unauthorized use of it. Dr. Davis testified that he did not know of the drug’s dangerous propensities, or he would not have used it. Dr. Thomas Deutsch, Upjohn’s own expert, testified that, until he testified in this case, he did not know that Depo-Medrol would be difficult or impossible to remove once injected into the eye. What record evidence is there then to support the hypothesis that the "medical community knew” of these dangerous propensities? None is cited by the majority opinion; yet, it holds as a matter of law that "the medical community knew, and that is enough.” (275 Ill. App. 3d at 609.) Such an unsupported conclusion flies in the face of established authority. Tongate v. Wyeth Laboratories (1991), 220 Ill. App. 3d 952, 963, 580 N.E.2d 1220 {Tongate). A drug such as Depo-Medrol may be deemed unreasonably dangerous absent an adequate warning accompanying the product because the product may be "unavoidably unsafe” without such a warning. (Kirk v. Michael Reese Hospital & Medical Center (1987), 117 Ill. 2d 507, 517, 513 N.E.2d 387; Lawson v. G.D. Searle & Co. (1976), 64 Ill. 2d 543, 550-51, 356 N.E.2d 773.) A manufacturer of ethical drugs cannot evade its responsibilities in warning physicians of dangers and risks attendant to the use of its products, by hoping, as in the present case, that the doctors will learn of the dangers themselves. Upjohn’s duty to warn was nondelegable; the failure of prescribing and treating physicians to learn of the risks of a drug from other sources does not relieve the manufacturer of liability for harm resulting from its own failure to adequately warn. (Mahr, 72 Ill. App. 3d at 566.) This was made clear in Mahr, 72 Ill. App. 3d at 561-62, in which the court stated: "The nature of prescription drugs and the ethics involved in the professional practice of medicine are such that it is a physician who decides what medications, if any, a patient is to take. Thus, while the manufacturer’s duty to warn is for the benefit of the ultimate consumer of its products, the physician, in the role of a learned intermediary, is the person to whom the warnings are to be communicated. (Crocker v. Winthrop Laboratories; Ethicon, Inc. v. Parten; Stevens v. Parke, Davis & Co.; Carmichael v. Reitz (1971), 17 Cal. App. 3d 958, 95 Cal. Rptr. 381.) Contrary to Searle’s position, however, the adequacy of the communication of the warning is not judged solely by reference to the information supplied by the manufacturer to the prescribing physicians. *** Searle had the duty to adequately communicate the adverse effects of Enovid to all members of the medical profession who came into contact with Sandra Brewer in a decision-making capacity during the time she was using the drug.” (Emphasis added.) The majority inexplicably would distinguish Mahr on the ground that "the Enovid in Mahr was used by the decedent in an on-label manner” and, therefore, the manufacturer had "the duty to warn physicians of the adverse effects associated with the on-label use of a drug.” (275 Ill. App. 3d at 611.) The majority then makes the astonishing assertion, citing no authority whatsoever, that any "minimally trained physician should know” that these are "risks attendant with the non-approved use of a drug.” (275 Ill. App. 3d at 611.) One is not told who a "minimally trained” physician would be and, more importantly, why a "minimally trained” physician should know more about the risks of Upjohn’s Depo-Medrol than, say, experts in the field of ophthalmology, two of whom testified in this case that they did not know of the toxicity or irremovability of the drug once injected into the eye, which is involved in this case. The jury heard this evidence. More perplexing is the assertion by the majority that although "on-label” users should be warned of risks attendant to drug use, "off-label” users need not be, even though Upjohn knew of and encouraged this use. Worse, the majority would exonerate Upjohn from liability, as a matter of law, under the circumstances of this case, although Upjohn knew of the risks, yet did not share this knowledge with members of the profession acting in decision-making capacities in administering drugs to their patients, and encouraged misleading publicity and resultant unapproved use. Significantly, Upjohn knew how to warn, and did warn, doctors against certain uses of Depo-Medrol by advising these "learned intermediaries,” for example, against intrathecal administration of this drug, which it printed on the insert distributed with the drug in 1983, before the instant insertion of Depo-Medrol into plaintiff’s eye. Why warn "minimally trained” physicians against this use? The question answers itself. Upjohn, in another line or two of print on the insert, easily could have mentioned potential adverse reactions to the drug when injected intraocularly, of which it had learned over a period of preceding years from drug experience reports. (See 275 Ill. App. 3d at 608 n.3 & Appendix.) It did not advise these "learned intermediaries” of the potential adverse consequences of which by this time it had become aware, so that a physician could decide intelligently whether or not to use or continue to use the drug on any given patient. When doctors are properly warned of the possibility of side effects and advised of the symptoms accompanying them, the chances that injury to the patient can be avoided are enhanced, particularly if it takes place slowly, as in the case with the injury in question here. Sterling Drug, Inc. v. Cornish (8th Cir. 1966), 370 F.2d 82, 85. As previously mentioned, information regarding questionable reactions or side effects to this Upjohn product was contained in drug experience reports in Upjohn’s possession, but not shared by it with the medical community. A physician, nurse, patient, pharmacist or someone in the hospital would contact the drug company and report the reaction or side effect. From June of 1963 through September of 1983, Upjohn received numerous adverse drug experience reports relating to repository Depo-Medrol therapy for intraocular disorders. Some of these are abstracted in the Appendix attached to this dissent. It should be noted, however, that in Dr. Walson’s experience, the frequency of drug experience reports is less than the adverse effects which actually occur; in other words, not every adverse reaction was reported. He noted that the observations contained in drug experience reports to Upjohn, such as abscesses at the injection site, sloughing at the subconjunctiva; swelling at the injection site, residue being left in the area where the eye was injected, increased ocular pressure after the injection, blurred vision, anaphylaxis, and sudden blindness, could be evidence of the toxicity of the drug. He held the opinion that loss of vision, small white spots of residue, diminished vision and any kind of allergic response could also indicate toxicity of the drug. According to Dr. Walson, being on notice of that kind of information from the 1960’s up to 1983, there were methodologies and scientific means available to Upjohn to confirm or disaffirm the toxicity of the drug. In his opinion, Upjohn should have included a warning on its label or package insert which said, in effect, do not use the drug in that way, and if so used, this is what may be seen.5 This was never done. In light of this imbalance of access to information about adverse propensities of Depo-Medrol, it is difficult to fathom the basis for the majority’s assertion that physicians had knowledge of the risks equal to Upjohn’s. The jury heard Upjohn’s Dr. Samuel Stubbs testify. He was in charge of Depo-Medrol development. He did not know about the pharmacokinetic effects of Depo-Medrol when used in a local injection rather than systemic. He did not know that the drug would be difficult to remove from the eye. Dr. Stubbs never had anyone investigate by animal studies whether the drug would be toxic if it got into the eye. Prior to November 7, 1983, Dr. Stubbs never asked any Upjohn in-house personnel whether or not it would be difficult to remove the substance once it was injected into the eye. A drug company cannot absolve itself from the duty to warn by pointing to the unauthorized use of its drug by physicians with whom it has not shared its knowledge of dangerous side effects and injury. Violation of its duty to warn is even more egregious in this case since, as the evidence heard by the jury demonstrated, Upjohn participated in disseminating misleading information concerning the use of its drug to the "learned intermediaries.” Ironically, some of these very reports became part of the "literature” which was supposed to inform the "learned intermediaries” about application of the drug intraocularly. See, e.g., text preceding footnotes 2, 5 and 7. Upjohn actually encouraged and promoted this off-label use of its product by certain physicians through financial support, technical assistance, and abundant supplies of the drug during the period when Upjohn was receiving adverse information concerning this use of the drug. Persons at Upjohn who were most intimately familiar with Depo-Medrol and its potential harmful effects made the following observation, as Upjohn records in its brief: "In 1965, Dr. Samuel Stubbs, the Upjohn employee responsible for monitoring Depo-Medrol, collected articles in the medical literature and data supplied by these physicians, and prepared a report for internal use by the company. *** Based on that report, Dr. Stubbs and his immediate supervisor recommended that Upjohn consider filing a supplemental NDA to obtain FDA approval for periocular administration of the drug, even though Dr. Stubbs thought it was likely to be administered in that manner to only 'a limited number of patients.’ *** Without FDA approval, Upjohn could not include that use of the drug as an approved route of administration on the Depo-Medrol labeling.” (Emphasis added.) Dr. Stubbs, himself, questioned the reliability and the basic approach taken by some purportedly "independent studies” conducted by these certain physicians on their patients, as to both the safety and the efficacy of Depo-Medrol for periocular use. He knew that the so-called "studies” were conducted in an admittedly sloppy, ineffective, and dangerous fashion upon human subjects. Yet, these were the same "studies” actively encouraged and supported by Upjohn, studies which were advertised to the medical community by disseminating 2,500 reprints of an article extolling this FDA-unapproved use. The reprints were provided to doctors and hospitals by Upjohn employees, knowing all the while that this was an experimental use without benefit of prior basic scientific tests to show whether the drug could be utilized this way without harming humans. The jury heard this evidence. Upjohn provided, in many instances without charge, vials upon vials of Depo-Medrol to these experimenters; it did not caution these off-label users that no animal studies had yet been initiated to test the reaction of the drug upon living tissue before embarking upon human use. Instead, Dr. Porter Crawford, another Upjohn employee responsible for monitoring Depo-Medrol at one time, responded to one such request for vials of the drug for this off-label experimentation as follows: "Thank you very much for your recent letter and for your interest in Depo-Medrol for subconjunctival injection in the treatment of uveitis. We do not have any reports concerning this use for the preparation and we would very much like for you to evaluate it in this way.” (Emphasis added.) The record shows that Dr. Crawford sent to other such users more vials of Depo-Medrol and asked the doctors to let him know when they needed additional supplies. Dr. Crawford noted that Upjohn would "be anxious to learn how it performs when used this way.” Upjohn also provided funds to these off-label experimenters. Dr. Crawford, through Upjohn, provided one such doctor with $3,000 and another with $2,400 to support such projects. One such doctor, by letter dated December 31, 1959, indicated that he would mention his results with Depo-Medrol at a speech he would shortly be giving. This doctor later noted in a letter to Upjohn that he had given two talks in Chicago in the fall of 1960, during which he described the advantages of the use of Depo-Medrol for subconjunctival injections; yet in the same letter, he went on to admit that the "experimental work *** fell flat since we are unable to find anything in the aqueous.” (Emphasis added.)6  An article on the use of Depo-Medrol was written by the corresponding experimenting doctor in 1961, who later informed Dr. Crawford, on August 31, 1961, of the completion of the article, noting, however, that he was unable to use any of his animal experiments because the results were ”very unsatisfactory.” (Emphasis added.) Upjohn nevertheless ordered and distr ibuted 2,500 reprints of the article, 500 for "hospital sales” and 2,000 for "sales education,” thus becoming part of the "literature” to which the ophthalmic community was exposed. On November 16, 1961, Upjohn also requested reprints of another experimenting doctor’s article for distribution, which also mentioned the use of subconjunctival injections of Depo-Medrol.7 More "fodder” priming the sales pump. On March 8, 1963, Dr. Stubbs wrote to a different experimenting doctor, requesting case histories on the patients he had treated with Depo-Medrol, indicating that Upjohn needed the case reports to supplement its original new drug application. Dr. Stubbs informed him that Upjohn would compensate him for his time, and that of his secretary, in preparing the case reports. In response, by letter dated March 14, 1963, this doctor told Dr. Stubbs that he would begin working on the case reports and requested that Upjohn meanwhile send him more Depo-Medrol. On March 19, 1963, Upjohn sent him more vials of Depo-Medrol, without mentioning the information and precautions suggested by its Dr. Gerard to its salesmen in 1962. See 275 Ill. App. 3d at 608 n.3. Harry P. Davis, Jr., another of Upjohn’s sales representatives, wrote to Mr. Crissman, at the Upjohn Company in Cleveland, Ohio, on June 12, 1963, informing him that two Ohio physicians were using Depo-Medrol for "severe, chronic or acute, uveitis by retrobulbar injection,” but that neither "learned intermediary” was aware that anything had been published on the use of this drug. Dr. Stubbs wrote to these two Ohio doctors on June 26, 1963, informing them that Upjohn was interested in their use of Depo-Medrol and requesting that they send Upjohn case reports of their experience with the drug. Dr. Stubbs further stated that if they were interested in publishing their work, he would make the "services of The Upjohn Writing Staff’ available to them. In addition, Dr. Stubbs offered to pay for their secretary’s time, and compensate the doctors for work on the case reports, thereby admittedly intending to "plant the seed” in those doctors’ minds about publishing an article and making the Upjohn writing staff available for that purpose. On July 1, 1963, the Ohio doctors responded with eight case reports. Dr. Stubbs turned this material over to Harold Tucker, one of Upjohn’s medical writers, to determine whether it could be turned into a publication.8 An article written as a result of Upjohn’s expert assistance proclaimed that positive results from the subconjunctival injection of Depo-Medrol had been confirmed by others!9  Upjohn’s own expert, Dr. Stubbs, questioned the validity of the so-called studies. On September 19, 1963, he wrote to Jack Toole, Upjohn’s hospital representative, regarding the data, stating: "I’m enclosing a copy of the letter I have written to him, and it is a mild rebuff for the lousy data he sent us. This sort of thing may have gone through before the new F.D.A. regulations, but it certainly doesn’t go now, and at the risk of not getting any more data at all I feel it’s time to start setting down on some of these rather loose individuales [szc], I think [this doctor] is a good friend of ours and I don’t have to [sic] many qualms that he is going to be upset, but really the stuff that he let you send to me is almost worthless for reasons as I mentioned in the letter to him.” (Emphasis added.)10  Dr. Stubbs nevertheless indicated that he was forwarding more vials of Depo-Medrol to this doctor, followed by another supply of Depo-Medrol, on January 21, 1964. The practice of publicizing unapproved uses of drugs, when sponsored by the pharmaceutical company, is not approved by the FDA as proper advertising; it resulted in continuing, unapproved, potentially dangerous use. Dr. Stubbs was aware that those experimeriting physicians would subsequently write publications which appeared in medical journals,11 for which Upjohn paid secretarial and editorial expenses. These writings, of course, would be addressed to the medical community and become available to ophthalmologists, thereby becoming part of the "current medical literature” so incredibly touted by the majority as part of the "standard of medical expertise” as a matter of law. Upjohn stipulated that prior to November 7, 1983, it "had the capacity to perform in-house or refer out-of-house [experiments] to be done by private consultants research in the form of animal studies and all four phases of human studies.” Upjohn had in its employ, or available to it, physicians, toxicologists, pharmacologists, statisticians and epidemiologists. Dr. Stubbs admitted that the animal tissue tolerance studies could have been performed if the company had wanted to do them. Such studies were already ongoing with other applications of the drug. Upjohn had the money, the personnel, the animals and the staffing to do that kind of testing if someone at Upjohn decided it should be done. If Upjohn had begun the animal tissue tolerance studies on the periocular use of Depo-Medrol in 1969 or 1970, it would have had the results well in advance of the casualty involved in this and, perhaps, other cases. The majority concludes that the medical community knew that Depo-Medrol was not recommended for periocular administration because it was not listed on Upjohn’s labeling and knew of the risk of vision loss following accidental intraocular injection of the drug. The majority’s decision defies precedent and, as demonstrated by the preceding analysis, ignores the facts of this particular case. The unanswered question persists: who in the medical community knew about the adverse effects of Depo-Medrol, which the majority holds as a matter of law? Certainly neither Dr. Davis nor the number of doctors whom Upjohn sponsored in the human experimental off-label use of its drug were aware of its dangers. Plaintiffs’ expert testified that ophthalmologists were not aware of the true facts but believed that periocular use of Depo-Medrol was safe and efficacious. Significantly, in fact, Upjohn’s own expert, Dr. Thomas Deutsch, an ophthalmologist who might qualify as a "minimally trained” expert, testified he himself did not learn that periocular injections of Depo-Medrol were difficult or impossible to withdraw and were an unlabeled use until after he became an expert in this case. Doctors who have not been sufficiently warned of the harmful effects of a drug cannot be considered "learned intermediaries” and the adequacy of warnings is a question of fact, not law, for the jury to determine, as it did in the instant case. (Tongate, 220 Ill. App. 3d at 963; Batteast v. Wyeth Laboratories, Inc. (1988), 172 Ill. App. 3d 114, 127, 526 N.E.3d 428.) The majority’s decision to the contrary here is, tragically, wrong. What did the medical community know? The evidence conclusively demonstrates that Upjohn promoted, encouraged and advertised the off-label use of this drug by providing financial and technical assistance to a limited number of members of the medical community without attempting to communicate to these physicians and medical community at large the dangers and risks attendant to this use. The majority bases its decision, in part, upon the expectation that physicians will keep abreast of current medical literature. As has been shown, part of the literature, which Upjohn helped to generate, "planting the seed” in doctors’ minds about contributing to the literature, and thereby helping to mislead the specialized ophthalmic community as to the potential harmful effects attendant to the intraocular injection of a drug which could be impossible to remove. Worse, the majority view, that the existence of literature in such a case constitutes knowledge on the part of doctors and the medical community equal to that of a drug’s manufacturer, would encourage more writings of the type found in this case, fostered by the very defendant upon whom responsibility should be fixed. Such an insidious situation as here existed should be neither countenanced, encouraged nor condoned. Upon this record, the jury had the right to conclude that Upjohn violated its duty to adequately warn and that it be held accountable under these circumstances. The jury did just that. To interfere with this verdict, except perhaps for a remittitur, is unauthorized by law and unwarranted by the facts. For these reasons, I dissent. APPENDIX Plaintiffs exhibit 120 was a list prepared by Dr. Samuel Stubbs from 1965 until 1983 containing drug experience reports with various patients of which Upjohn had notice, abstracted in part as follows: June 18, 1963 — five abscesses developed in three patients given subconjunctival injections of Depo-Medrol; abscesses resulted from increased particle size in the suspension. June 20, 1963 — patient developed a sterile abscess around the Depo-Medrol which was lying subconjunctivally; abscess ruptured; Depo-Medrol removed and the abscess evacuated; no side effects after removal. October 21, 1964 — patient’s sloughing of conjunctiva at the site of subconjunctival injection, with a gradual decrease in reaction; not completely restored through surgery which necessitated cutting through involved tissues. February 18, 1965 — three patients exhibited pain, upper lid swelling, sheets of subconjunctival hematoma, and marked chemosis. The symptoms cleared slowly. March 20, 1967 — more than five different patients with "swelling, redness and fluctuation.” May 1968 — patient developed gray white residue which remained subconjunctivally six to eight weeks after injection. September 26, 1968 — whitish residue left behind after Depo-Medrol injected; persists for many weeks after steroid activity ceased, gradually disappeared; similar reports noted by many other people. February 21, 1991 — injection led to red, swollen eyelid and blurred vision. May 1971 — adverse reactions filed — report of subconjunctival injection site inflammation and report of increased intraocular pressure. May 1972 — deposit remaining at the injection site; report of a glaucoma-like picture in association with subconjunctival administration of Depo-Medrol. July 1974 — several patients exhibited white precipitate that remained in the injection site for a period of one or two months. White deposit caused sufficient concern that physician stopped using the drug. September 25, 1974 — injection of 1 cc Depo-Medrol resulted in an immediate loss of vision. '^/a hours later had NLP in both eyes. Paralysis of upgaze. No pupillary response. White material in arterioles of fundus. Mental confusion. 36 hr later vision began to return. Fundus showed scattered retinal edema. Vision now OD — CF at 10-12 degrees OS — CF at 18-20 degrees. Atrophy of temporal iris OD. Cloudy vitreous OD.” February 1976 — increase in intraocular pressure; patient discharging Depo-Medrol "through three sites in necrotic conjunctiva in the lower fornix”; injection site incised — piece of soft off-white tissue was removed; acute inflammatory reaction to the drug. Following removal of this material, the corneal oedema cleared almost immediately and patient made a good recovery. September 1977 — accidental injection of Depo-Medrol into the eye of a patient when trying to inject subconjunctivally; patient lost vision. December 1977 — blindness in one eye following an injection of the drug into the turbinate area of the nose. September 1978 — small white spot developing following subconjunctival injections of Depo-Medrol; spot remained for a long time at the injection site in the mucosal. November 1978 — temporary blindness accompanied by severe pain, following the injection of Depo-Medrol into the nose. November 1979 — intense swelling around the eyes and nose; blockage of the ears following injection of Depo-Medrol subconjunctivally. September 1980 — diminished vision in one eye following an injection of Depo-Medrol in the turbinates after nasal surgery. May 1983 — conjunctival necrosis overlying the area of the injection 17 days after a conjunctival injection of Depo-Medrol. July 1983 — blindness and eye damage following an implant into the eye with subconjunctival injection of Depo-Medrol. September 1983 — inadvertent injection of Depo-Medrol into the vitreous of the eye instead of the retrobulbar space; vitrectomy performed and patient regained partial vision.  Dr. Samuel Stubbs, one of Upjohn’s Depo-Medrol overseers, testified that the book "Drug Induced Ocular Side Effects and Drug Inter-reactions” by Fraunfelder was in Upjohn’s medical library in Kalamazoo. In the 1976 edition, it states "inadvertent intraocular steroid injections have caused blindness probably as a result of direct drug toxicity to the retina or optic nerve.” (Emphasis added.) Dr. Stubbs admitted that it was part of his duties and responsibilities to be aware of this kind of information. Dr. Stubbs also knew that there had been several articles reporting the accidental injection of Depo-Medrol into the eye itself. Dr. Stubbs admitted that prior to the incident, he knew that if Depo-Medrol got into the eye, its white substance might obscure a physician’s ability to identify any damage from the injection. He was aware of articles which reported that the substance remained in the eye. None of this information was contained in Upjohn’s labels or inserts. Another writing concluded that Depo-Medrol remains active as long as it is visible. This text was dated 1978. Neither the package nor the label insert for Depo-Medrol stated, to November 7, 1983, how long the drug remained active around the eye.   On March 8, 1961, Dr. Crawford wrote another letter to this same doctor about his use of subconjunctival injections of Depo-Medrol, stating: "The F.D.A. has not approved this use for Depo-Medrol because we have had no clinical work to show to them.” (Emphasis added.)   Meanwhile, on January 9,1962, Bob Fuoto, one of Upjohn’s salesmen in Manhattan, sent an inquiry to Upjohn’s medical department, asking why the eye became "very red,” and whether that condition could be prevented, following subconjunctival injections in cataract surgery patients. Dr. Gerard, from Upjohn, responded to this inquiry in a letter dated February 14, 1962: "I know of no way of giving a definite answer *** as to why the eye becomes red after the subconjunctival use of Depo-Medrol. I do think that it should be pointed out, however, that it has never been recommended that Depo-Medrol be used this way. Our recommendations for Depo-Medrol is that the injection be given deep intramuscularly or if used for intralesional treatment of the skin, that the injections be kept as small as possible. It seems to me that 1 cc. of Depo-Medrol subconjunctivally is a rather large dose to place in this area. When this amount is given subcutaneously in other areas of the body, it can occasionally cause tissue atrophy. I would think that our best recommendation *** would be that at this dosage level of Depo-Medrol, *** the medication [should be given] intramuscularly, as probably the predominant steroid effect is going to be a systemic effect anyway. This preparation is a suspension and not a solution, and it may well be that the crystalline material in the area of such a sensitive tissue as a subconjunctiva is the cause in itself for the redness.” (Emphasis added.)    Plaintiff’s expert, Dr. Philip Walson, testified, however, that so few cases did not constitute sufficient experience with the drug. Further, the material received from these doctors did not provide complete data for purposes of making any scientific use according to accepted principles. No double blind studies were done, for example, making it difficult to evaluate whether the patient had improved spontaneously or because of the therapy or treatment received, although that scientific methodology was available to do these kinds of studies.   Dr. Walson also testified that those papers could not be used to justify the statement, because they were merely anecdotal, not scientific studies, and there was no proof for the claim that the procedure they employed was "simple and effective in those inflammatory ocular processes for which steroids are indicated.”   Dr. Stubbs knew what was needed, but what he did not get, from these reports, writing on September 19, 1963: "I would be most happy to pay your secretary a little bit extra for these case reports if she would be willing to re-work them, perhaps with an occasional word from you to cover the following points: patient’s identification; age; sex; diagnosis; duration of illness; therapy used, and in this instance Depo-Medrol; the strength of the Depo-Medrol, in other words how many milligrams per cc; the amount given; the frequency of injection, with dates as you have done to a certain extent; the results of therapy; and finally any side effects. This information is what the F.D.A. requires as a minimum and is certainly not my idea, although I think that their requirements are a minimal particularly for a type of therapy which is not completely accepted in a general way as yet.” (Emphasis added.)    One such article, published in 1964, stated: "Maximum local response may be expected with only minimal or no systemic steroid effects. 'A voluminous mass of reports testifies to the efficacy and safety of this report in general medicine and in surgery.’ ” The article went on to state: "Similarly, an ophthalmologist has recently reviewed indications for and the fine results to be expected from some subconjunctivally injected steroids. This experience has been confirmed by others.” (Emphasis added.) Dr. Stubbs admitted that this article did not mention the need to conduct double-blind studies to assess the effectiveness of subconjunctival injections with Depo-Medrol; that the article, which had been written by Upjohn staff writers and submitted by Upjohn for publication, was already stating to the ophthalmic community that the use of this drug for subconjunctival injections was "safe, simple and effective,” without performing double-blind or animal studies by Upjohn for the subconjunctival use of Depo-Medrol.