decided as amended august 24 1973.: August 8, 1973.
D.C. Civil Action No. 68-391. APPEALS FROM THE UNITED STATES DISTRICT COURT FOR THE MIDDLE DISTRICT OF PENNSYLVANIA.
Biggs, Hastie and Hunter, Circuit Judges. Hastie, Circuit Judge, concurring in part and dissenting in part.
In this diversity action*fn1 Hoffman, plaintiff-appellee cross-appellant, sought to recover damages for serious and permanent injuries allegedly sustained as the result of ingesting the drug chloroquine phosphate, which was manufactured by Sterling Drug, Inc. and Winthrop Laboratories, Inc., and marketed under the trade name of Aralen. Count I of the complaint charged that the defendants were negligent insofar as they failed to properly test the drug prior to placing it on the market, failed to adequately warn users or the medical profession of the dangers inherent in their product, and violated Sections 301, 501, and 502 of the Federal Food, Drug and Cosmetic Act, 21 U.S.C. §§ 331, 351, 352. Count III alleged that the defendants were strictly liable in tort,*fn2 and Count IV charged the defendants with fraudulently, falsely and deceitfully misrepresenting and concealing the true state of knowledge about the safety of the drug, or, in the alternative, making such misrepresentations in reckless disregard of reports to them of the harmful nature of the product.*fn3
After a lengthy trial, the jury returned a verdict in the plaintiff's favor in the amount of $437,000, and judgment was entered on the verdict. The defendants' motion for a new trial was denied by the district court,*fn4 and the plaintiff's motion for a retrial on the issue of punitive damages was also denied. These appeals followed.
The plaintiff's relevant medical history dates back to the early 1950's, when, while seeing a Dr. Kammer for a gastric condition and arthritic pains, Dr. Kammer recommended that plaintiff see a dermatologist about a rash on his face. The plaintiff was referred to Dr. Ernest Markey, an osteopath specializing in dermatology, who diagnosed the plaintiff's condition as lupus erythematosus and in May of 1957, prescribed Aralen as treatment. Dr. Markey treated the plaintiff for 13 months, from April, 1957 to May, 1958, until Dr. Kammer referred plaintiff to Dr. Milton Cohen, a medical doctor and dermatologist. Dr. Cohen treated the plaintiff from June, 1958 until March, 1964, and he too prescribed Aralen. Dr. Cohen testified*fn5 that he was aware of and informed the plaintiff of the possibility of eye damage from the prolonged use of chloroquine, that he questioned the plaintiff about his sight on each visit, and on several occasions suggested to the plaintiff that he see an eye doctor for a slit-lamp examination, but that he did not know that eye damage would be irreversible.*fn6 The plaintiff stopped seeing Dr. Cohen in March, 1964, and continued taking Aralen under a refillable prescription from Dr. Cohen until June, 1965, when Dr. Ludwig, another doctor consulted by the plaintiff concerning his arthritic type of pain, advised him to stop taking the drug.
It was in 1965 or 1966 that the plaintiff began to experience problems with his eyesight. Plaintiff's optometrist, Dr. Cruse, testified that prior to 1966, plaintiff's vision was correctable to normal or what is termed 20/20 vision. Dr. Cruse stated that in June, 1966, plaintiff's vision had deteriorated to approximately 20/30 in each eye, and plaintiff's eyesight continually worsened.*fn7 Dr. McHenry, an ophthalmologist, examined the plaintiff in December, 1965, at which time he found that plaintiff's vision was 20/30 in each eye and could not be corrected to 20/20. In 1970, Dr. McHenry concluded that the plaintiff suffered from chloroquine retinopathy, and in 1971, he found his vision to be 10/200 in each eye, which rendered him legally blind under Pennsylvania law.*fn8
Chloroquine retinopathy is a damaged condition of the retina which can result from the long continuous use of chloroquine drugs. That permanent retinal damage might result from the use of such drugs was not suspected when the defendants first started marketing Aralen in 1946. Aralen had been approved by the Food and Drug Administration for the treatment of malaria. Commonly observed side effects noted in the 1940's and early 1950's included nausea, abdominal cramps, and some instances of blurring of vision. Visual disturbances disappeared when chloroquine treatment was discontinued, leading investigators to conclude that the condition was transitory. By 1953, reports of the successful use of Aralen in the treatment of rheumatoid arthritis and lupus erythematosus, the skin disease which the plaintiff suffered from, began to appear. In 1955, defendant Winthrop Laboratories, Inc., published and distributed a pamphlet which discussed Aralen treatment for lupus erythematosus.*fn9 In the same year, Winthrop submitted for publication in the Physician's Desk Reference*fn10 information concerning Aralen's use in the treatment of lupus erythematosus. Finally, on July 25, 1957, defendants filed a supplemental new drug application with the FDA seeking approval to advertise and sell Aralen for use in the treatment of rheumatoid arthritis and purportedly for lupus erythematosus as well.*fn11 Conditional FDA approval was obtained three weeks later, with final approval following on October 2, 1957.
Suspicion that chloroquine use might permanently damage the retina began to arise circa 1957. An article by Dr. Goldman and Dr. Preston, entitled "Reactions to Chloroquine Observed During Treatment of Various Dermatologic Disorders,"*fn12 stated that chloroquine was suspected of severe fundal (retinal) changes but this could not be proved. In 1959, the suspicion was strengthened by an article entitled "Retinopathy Following Chloroquine Therapy" by Hobbs, Sorsby, and Freedman.*fn13 This report explained that "in the doses used to suppress or treat malaria, the toxic effects of chloroquine and its derivatives are only minor. . . . Since in both lupus erythematosus and rheumatoid arthritis the effective dose commonly exceeds that used for malaria, and the drug is administered for much longer periods, it is not surprising that toxic effects have been reported. . . .
"Recently we have seen changes of a much graver character, with visual damage which, in some cases at least, is evidently irreversible. These patients . . . were under treatment with chloroquine compounds for lupus erythematosus and rheumatoid arthritis."*fn14
The article concluded, after a discussion of certain case reports, "On present evidence, the retinopathy here described results from treatment with chloroquine compounds. . . ."*fn15 Defendants' witness, Dr. Rice, testified that this article made "it very likely, or quite likely, that chloroquine might be involved in the production of retinopathy. This I say 'likely' because the drug that they used was not Chloroquine Phosphate as sold by Winthrop but was Chloroquine Sulfate and which might have an entirely different toxity than Chloroquine Phosphate."*fn16 Numerous letters were also received by defendants from physicians during this period (1956-1960) reporting loss of vision, field changes, and fundus changes in patients being treated with Aralen and inquiring into the possibility that Aralen might be the cause. Defendants made reference to the Hobbs, Sorsby, and Freedman article in their 1960 product literature, and, after numerous reports in medical literature of irreversible retinal damage following chloroquine treatment, defendants included in their 1962 product literature a warning that retinal changes "have been reported as rarely occurring within several months to several years of chloroquine therapy" and pointed out "the necessity of periodic visual field examinations in order to detect early changes during prolonged treatment with the drug."*fn17 In February, 1963, defendants sent out letters to physicians, 248,000 in all, warning of occular complications from the use of the drug and of the need for initial and periodic ophthalmologic examinations of the patient.*fn18
Defendants have appealed the judgment of the district court at our No. 72-1259, asserting that the trial court committed reversible error (1) in submitting to the jury the issue of whether the defendants violated the Federal Food, Drug and Cosmetic Act, (2) in admitting certain evidence relevant to alleged withholding from the FDA of letters of inquiry and reports from physicians, (3) in submitting to the jury the issue of whether the defendants sold Aralen without adequately testing it to discover harmful side effects, and (4) in charging the jury that the defendants were under a duty to warn treating as well as prescribing physicians about the danger of retinal damage. The defendants also contend that (5) the jury's award in the amount of $437,000 is excessive. Plaintiff has appealed at our Nos. 72-1257 and 72-1258 insofar as the district judge refused to permit the jury to consider the issue of punitive damages and refused to tax as costs certain of the plaintiff's expenses.
Defendants maintain that there was no evidence of a violation of the Federal Food, Drug and Cosmetic Act or the regulations thereunder and that, even if there was such evidence, any violation was not the proximate cause of the plaintiff's injuries. Therefore they assert error in the submission of this issue to the jury.
Section 301 of the Act, as amended, 21 U.S.C. § 331, provides: "The following acts and the causing thereof are prohibited: * * * (d) The introduction or delivery for introduction into interstate commerce of any article in violation of section 404 or 505." Section 505, as amended, 21 U.S.C. § 355, states: "(a) No person shall introduce or deliver for introduction into interstate commerce any new drug, unless an application filed pursuant to subsection (b) is effective with respect to such drug. * * *"
As hereinbefore mentioned, a new drug application had been approved by the FDA in 1946 for the marketing of Aralen for use in the treatment of malaria. The newness of a drug within the meaning of the Act,*fn19 however, may arise by reason of a new or different recommended use for the drug even though the same drug may not be a new drug when used for another disease. Merritt Corporation v. Folsom, 165 F. Supp. 418 (D.D.C. 1958). See also 21 C.F.R. § 1.109(d) (1955) and 21 C.F.R. § 130.1(h)(4) (1972); Developments in the Law, The Federal Food, Drug and Cosmetic Act, 67 Harv. L. Rev. 632, 679 (1954). The plaintiff thus attempted to show that offering Aralen to the public for use in the treatment of lupus erythematosus rendered it a "new drug" and required prior approval of the FDA. The FDA regulations then in effect, 21 C.F.R. § 1.110(d) (1955), provided for FDA approval of "any proposed change in the conditions under which such drug is to be used."*fn20
The evidence presented plainly warranted the trial judge in submitting this issue to the jury. Defendants' witness, Dr. Rice, testified on cross-examination that prior to 1957 the sole authorized use of Aralen was for the treatment of malaria and amebiasis and that any change in the authorized use would require the filing of a supplemental application. It was also brought out that Defendants' Exhibit 134, a letter dated August 15, 1946 from the FDA to Winthrop, advised Winthrop that "the application is effective with respect to the use of this drug [Aralen] only under the conditions prescribed, recommended and suggested in the application. Should you decide to alter the composition, or dosage, or method or duration of administration or application, or other condition of use, an appropriate amendment to the application should be submitted for consideration."*fn21 There was also evidence that as early as 1955, defendants recommended Aralen for use in the treatment of lupus erythematosus. We think that the jury was entitled to consider this evidence and that it could properly find that, contrary to law, the defendants offered Aralen to the public for use in the treatment of lupus erythematosus without first securing approval of the FDA.
Nor do we agree with the defendants' contention that the alleged violation of the Act or FDA regulations was in no way connected with the plaintiff's injury. The record discloses that Dr. Markey prescribed Aralen for the plaintiff's lupus erythematosus several months before the FDA approved such use. Viewing the evidence in the light most favorable to the plaintiff and giving him the benefit of every favorable inference, as we are required to do. O'Neill v. Reading Co., 306 F.2d 204 (3 Cir. 1962), we think that a jury question was presented as to whether Dr. Markey was influenced to prescribe Aralen by the defendants' recommendations of the drug for use in the treatment of lupus erythematosus made prior to FDA approval of the supplemental new drug application, and whether these allegedly unlawful recommendations were therefore a substantial factor in causing the plaintiff's injury.
Defendants also contend that the district court's charge failed to state the applicable provisions of the Act or FDA regulations, thereby permitting the jury to speculate as to what the law required and what facts would constitute a violation thereof. It is the general rule, however, that an appellate court will not consider trial errors to which no objection was made. F.R. Civ. P. 51 states that "no party may assign as error the giving or the failure to give an instruction unless he objects thereto before the jury retires . . ., stating distinctly the matter to which he objects and the grounds of his objection." This rule is not inexorable, and in rare instances, where the error is fundamental and results in a miscarriage of justice, this court will notice such error despite counsel's failure to comply with Rule 51. Pritchard v. Liggett and Myers Tobacco Co., 350 F.2d 479 (3 Cir. 1965), cert. denied, 382 U.S. 987, 15 L. Ed. 2d 475, 86 S. Ct. 549 (1966); Paluch v. Erie Lackawanna Railroad Co., 387 F.2d 996 (3 Cir. 1968); McNello v. John B. Kelly, Inc., 283 F.2d 96 (3 Cir. 1960).
In the case at bar, counsel for the defendants neither requested instructions in this regard nor objected to the asserted inadequacies in the charge.*fn22 Assuming arguendo that the instructions given were inadequate, we think that the circumstances do not justify a departure from Rule 51, especially where, as here, the jury was informed as to the substance of what FDA required.*fn23
The defendants next assert that the testimony of Mr. Jordan concerning the "Bagnall letter" was inadmissible and highly prejudicial. In October, 1958, Dr. Bagnall wrote a letter to Dr. Rice, the Director of Medical Research for the defendants, in which he referred to two patients who were on long-term Aralen therapy and who had developed eye complications. "The first of these was a recurring corneal ulceration every time that Aralen was resumed and the decision of everyone concerned was that Aralen was to blame for this unfortunate, but not serious side effect. The second case was . . . a woman who had been on long term therapy for rheumatoid arthritis. . . . [The patient] noticed diminution of vision in one eye and the opthalmologist described macular degeneration of this eye and a central scotoma. This has only recently been observed and whether it continues with withdrawal of Aralen therapy is still to be discovered."
Mr. Jordan, the official court reporter in an Aralen case which had been tried in the United States District Court for the Southern District of Mississippi, testified that a photostat of the Bagnall letter and a photostat of a handwritten note had been introduced as a single exhibit in the Mississippi case. The note, dated March 25, 1960, stated as follows: "Do not advise FDA now. Send lit. when reprinted including corneal changes and say it is modified version of what we subm. several months and which they passed on. Discussed w/Dr. Foley & Dr. Rice." Mr. Jordan brought with him a sealed box containing all the exhibits from that earlier trial and, after opening the box in the jury's presence, removed this one exhibit in which the note was attached to the Bagnall letter. Based on this evidence, plaintiff's attorney, in his closing argument to the jury, submitted that "it shows . . . that they [the defendants] were holding back information to make their buck" and "did they not intentionally . . . attempt to conceal this information from the FDA."*fn24
The defendants attack the admission of Mr. Jordan's testimony apparently for its lack of probative value, arguing that since Mr. Jordan did not know how the photostats of the letter and the note came to be attached or who attached them, the jury could not properly infer any connection between them.*fn25 Although we find the connection between the letter and the note extremely remote, we believe that the error in admitting this evidence was harmless. F.R.Civ.P. 61. The evidence was relevant to the allegations of fraud and concealment contained in Count IV of the complaint. But the district court judge submitted the case to the jury only on the theories of negligence and strict liability (alleged in Counts I and III of the complaint), and the evidence with regard to these issues was such that the jury's findings on these issues could not have been significantly influenced by admission of evidence on the fraud count.*fn26
Defendants contend that the evidence was not sufficient to permit the trial court to submit to the jury the issue whether Aralen was sold for use in the treatment of lupus erythematosus without adequate testing to determine possible harmful side effects.*fn27 A review of the record more than satisfies us of the sufficiency of evidence in this regard.
Dr. Dennis, the man who conducted the testing on behalf of the defendants, testified that only three of the tests concerning the side effects of chloroquine on animals were long-term,*fn28 i.e., extended longer than one year. The first was a two year test on rats, conducted in 1953 or 1954, and Dr. Dennis disclosed that this test paid no particular attention to and made no special examination of retina.*fn29 The second study, that of monkeys, was 74 weeks in duration, from March, 1958, to August, 1959. Plaintiff's expert, Dr. Shelanski, testified that this test was inadequate for it was based upon an evaluation of Aralen and aspirin "and in no wise can this be interpreted to mean or to be considered effective as a basis for the evaluation of Aralen alone."*fn30 The third test of the side effects from long-term use of Aralen, conducted on cats, was not until 1968-1969, well after it was known that Aralen could cause retinopathy and well beyond the period of concern in the case at bar, which extends up to 1965. Dr. Dennis stated that the rest of the tests made by defendants, 12-15 in number, were short-term and "were general tests not specifically directed at the eye or the retina."*fn31
Another of plaintiff's witnesses, Dr. Carr, testified that one study he made in 1964-1965, while at the International Institutes of Health, produced retinal degeneration in rats and that studies made by others from 1963 to 1968 also succeeded in producing retinal changes and retinal damage in animals following ingestion of chloroquine. The point made by Dr. Carr was that such studies were not technologically infeasible ten years earlier.*fn32
It thus appears to this court that whether adequate testing would have disclosed potentially harmful side effects from the long-term use of Aralen and whether the studies made by defendants were in fact adequate were properly questions for the jury. Defendants' argument that they cannot be accused of negligently failing "to conduct animal studies to show the connection between Aralen and chloroquine retinopathy at a time when the causal connection was not even suspected in the long term use by humans of the drug" is without merit. As was stated by Justice Jackson, dissenting in Dalehite v. United States, 346 U.S. 15, 51-52, 97 L. Ed. 1427, 73 S. Ct. 956 (1953): "This is a day of synthetic living, when to an ever- increasing extent our population is dependent upon mass producers for its food and drink, its cures and complexions, its apparel and gadgets. These no longer are natural or simple products but complex ones whose composition and qualities are often secret. Such a dependent society must exact greater care than in more simple days and must require from manufacturers or producers increased integrity and caution as the only protection of its safety and well-being. Purchasers cannot try out drugs to determine whether they kill or cure . . . Where experiment or research is necessary to determine the presence or the degree of danger, the product must not be tried out on the public, nor must the public be expected to possess the facilities or the technical knowledge to learn for itself of inherent but latent dangers. The claim that a hazard was not foreseen is not available to one who did not use foresight appropriate to his enterprise." In view of the number of letters, beginning in 1956, from physicians reporting visual disturbances and retinal changes in patients using Aralen, and medical literature appearing in the late 1950's and early 1960's, we think it at least open to question whether defendants used "foresight appropriate to [their] enterprise."
It is next asserted by the defendants that the trial judge improperly instructed the jury that they had a duty to warn both the prescribing and the treating physicians, and that this was prejudicial because the prescribing physician, Dr. Cohen, was already aware of the danger to the eye.*fn33 Citing Incollingo v. Ewing, 444 Pa. 263, 282 A.2d 206, 444 Pa. 299 (1971), they maintain that Pennsylvania law requires warning only to the prescribing doctor. We disagree.
The Court in Incollingo, 444 Pa. at 288, 282 A.2d at 220, stated: "Since the drug was available only upon prescription of a duly licensed physician, the warning required is not to the general public or to the patient, but to the prescribing doctor. See Stottlemire v. Cawood, 213 F. Supp. 897, 899 (D.C. 1963)." But the Court was not faced with the question now before us, for there was no treating physician in Incollingo, and the plaintiff's doctors in that case were both prescribing physicians. We think that the Court was not attempting to establish a class of doctors to whom a warning must be given, but rather sought to establish the most effective means by which a warning could reach the patient, i.e., by a warning to the patient's doctors instead of communication to the general public. "A warning . . . given . . . to those doctors might . . . have avoided the tragedy which occurred in this case." 444 Pa. at 293, 282 A.2d at 222. The use of the Stottlemire case as authority supports this view, for Stottlemire held only that warning need not be given to the public. We conclude that in defining the scope of a drug company's duty to warn, Pennsylvania would view it as insignificant whether the doctor is a prescribing or treating physician, the important consideration being that the warning best reach the patient. Indeed, this is the policy behind the rule stated not only in Incollingo, but in numerous other cases as well.*fn34 "In the [use] of prescription drugs . . . it is difficult . . . for the manufacturer, by label or direct communication, to reach the consumer with a warning. A warning to the medical profession is in such cases the only effective means by which a warning could help the patient." Davis v. Wyeth Laboratories, Inc., 399 F.2d 121, 130 (9 Cir. 1968). (Emphasis added). Certainly in the case at bar, a warning given to Dr. Kammer, the treating physician, might have avoided the tragedy which occurred.
Our interpretation of Incollingo is buttressed by the general rule in Pennsylvania that, in defining the extent of the seller's duty to inform the consumer of dangers in a product, " every reasonable precaution suggested by experience and the . . . dangers of the subject ought to be taken." See Thomas v. Arvon Products Company, 424 Pa. 365, 370, 227 A.2d 897, 900 (1967). (Emphasis added). A warning to treating as well as prescribing physicians is within this guideline. In short, Incollingo ...