GEORGE PAULEY AND SUSAN PAULEY, H/W, Appellants : : : : v. : : BAYER CORPORATION AND BAYER AG GLAXOSMITHKLINE, Appellees IN THE SUPERIOR COURT OF PENNSYLVANIA : : : No. 2681 EDA 2005 Appeal from the Judgment entered September 14, 2005 In the Court of Common Pleas of Philadelphia County Civil, March Term, 2002, No. 002729 BEFORE: KLEIN, GANTMAN, JJ., and McEWEN, P.J.E. DISSENTING MEMORANDUM BY KLEIN, J.: FILED JUNE 12, 2009 It is not disputed that statin drugs, particularly in combination with gemfibrozil, create a risk of rhabdomyolysis. It is also true that Bayer 1 did warn that the combined use of Baycol and gemfibrozil was contraindicated. However, plaintiff Pauley s claim is that the risk from Baycol, either alone or in combination with gemfibrozil, creates a much more significant risk than using any other statin. Pauley s cardiologist, Dr. Peter Caples, did testify that had he been warned of the much greater risk of Baycol, while he might have still prescribed Pauley a statin drug and gemfibrozil, he never would have prescribed Baycol. There is no question that the combination of these specific two drugs caused the injury to Pauley. While some of this testimony was 1 Baycol was produced by Defendant Bayer Corporation, Bayer A.G. and comarked with Glaxosmithkline. The defendants are referred to collectively as Bayer for convenience.
admitted, the jury was not permitted to hear the details of the excessive Baycol risk. By keeping out the relevant information from Adverse Event Reports (AERs), the plaintiff was handcuffed in presenting his case. Therefore, I would reverse. Under the majority s decision a drug manufacturer may produce a drug, collect required anecdotal information indicating that drug is substantially 2 more likely to cause a certain injury than other equivalent drugs, sell more than 2,000,000 prescriptions of that drug, rely on the anecdotal information indicating a higher risk of harm to pull the drug from the market prior to controlled studies, have patients suffer the specific injury indicated by the anecdotal evidence, and suffer no legal consequences for marketing the drug with an inadequate warning because the evidence required to be collected by the government and relied on by the drug company is anecdotal. This is not just one or two reports these are reports collected after millions of prescriptions have been issued. This is far from using junk science to demonstrate a disputed causative connection. In fact, in this case, causation is not an issue. What is at issue is the warning provided to doctors who prescribe the drug and what information is relevant to that warning. It is uncontested that doctors are aware that statin drugs, particularly in combination with gemfibrozil, create a risk of rhabdomyolysis. It is similarly uncontested that doctors are warned of this 2 In one circumstance the drug appeared to be up to 68 (6,800%) times more likely to cause the injury in question. - 2 -
risk. However, when a drug is significantly more likely to cause a certain harm over other drugs, a doctor will be lulled into prescribing a drug that has a significantly higher risk of causing rhabdomyolysis if the warning does not adequately convey that risk. The question at issue here is not whether there is a risk (causation), but rather the nature and extent of that risk. Is a warning that drug may cause a certain reaction a one size fits all warning, no matter that the risk is 1 in 100,000 or 1 in 100. In that light, what would a reasonable doctor want to know about the risks of a drug before writing a prescription for that drug. By analogy, let us suppose that a certain drug carried with it a 2% risk of death. Causation is not at issue, 2% of the patients using the drug will die. This is clearly a serious risk considering the nature of the adverse consequence. As a result of that risk a warning is given to the physicians. However, it comes to light that through AERs that after two years of use, the incidence of fatality rises to 40%. Even though the reports of increased fatalities are anecdotal, is it reasonable to wait for an additional warning until the number can be absolutely linked to the drug through clinical studies or would a reasonably prudent manufacturer be on notice of an additional problem that would require an additional warning. I believe the trial court improperly excluded relevant information regarding the nature of the harm and therefore the nature of the warning for the use of Baycol. Bayer took Baycol off the market, not because of clinical - 3 -
studies but because of a multitude of AERs. I believe Pauley is correct that it was trial error to significantly limit both the use of the AERs and correspondingly the treating physicians testimony as to why he would not have prescribed Baycol had he known what Bayer knew about the drug and was appropriately warned. By excluding this information the jury was not allowed to consider and weigh important and relevant information, information that the manufacturer considered and weighed in making its decisions regarding the drug, when asked to determine the propriety of the Baycol warning. In this case, Pauley s cardiologist, Dr. Peter Caples, was prepared to testify that he was aware of the risk and the warnings were adequate for most statins. However, because of Pauley s significant medical problems, Dr. Caples thought the relatively small risk of rhabdomyolsis was worth taking because of Pauley s risk of death from heart problems. Pauley s severe medical problems included a prior heart attack, diabetes, high cholesterol and high triglycerides. Therefore Dr. Caples prescribed the combination of a statin and gemfibrozil despite the risk. Initially, he used another statin with no significant problems. Dr. Caples switched Pauley to Baycol when Pauley s insurance would not cover the other statin. Dr. Caples would testify that had he known how much greater a risk Baycol created without providing any greater benefit, he would not have prescribed it but would have prescribed a different statin. - 4 -
Bayer had done its own analysis of the AERs in March of 2000, before Dr. Caples prescribed its use for Pauley. The report was prepared by Bayer epidemiologist, Dr. Steve Niemcryk. Bayer found that patients using just Baycol had a hugely elevated risk for rhabdomyolsis, and In combination with gemfibrozil, cerviastatin [Baycol] patients were also found to be at a remarkable disadvantage compared with patients receiving gemfibrozil and another statin. [Emphasis supplied.] All that was admitted from the report was the fact that Bayer was having increased rates of rhabdomyolysis, but not increased relative to what. Pauley wanted to use another Bayer report which would show that the risk of using Baycol was 20 times higher than using another statin, more when in combination with gemfibrozil. The study showed that of 2,287,000 Baycol prescriptions, there were 94 reported confirmed cases of rhadomyolysis or 4.11 cases per 100,000. The rate for another statin, atorvastatin, was only.06 cases per 100,000 prescriptions. The numbers therefore were that viewing these AERs, Baycol used alone was 20 times more likely to cause rhadomyolsis than atorvastatin. If Baycol was used in combination with gemfibrozil, it was 68 times more likely to cause rhadomyolsis than another statin. It is these numbers that were kept from the jury. It is hard to say that if the details of the differential in AERs were given to the jury there would not have been a different result. The charts that could be presented to the jury are as follows: - 5 -
Chart showing all cases of rhabdomyolysis Baycol is the dark bar, the other statin on left Chart showing cases of rhabdomyolysis using just statin Baycol is the dark bar, the other statin on left - 6 -
DISCUSSION Chart showing all cases of rhabdomyolysis by month Baycol is the higher bar, the other statin on the bottom 1. The error in precluding admission of AERs Because of the ruling on the motion in limine, one of Pauley s experts, Sorrel Schwartz, Ph.D., a Professor Emeritus of Pharmacology at Georgetown University School of Medicine, was limited in his testimony. He was precluded from discussing the AERs of Baycol relative to other, safer, statins. Pauley was also was precluded from introducing the Bayer report of Dr. Steve Niemcryk discussed above. Because the testimony of the prescribing physician, Dr. Caples, was videotaped prior to the ruling on the motion in limine precluding the use of the - 7 -
AER comparisons, much of his testimony was redacted. The testimony not read to the jury was Dr. Caples saying that had he known of the increased risk of rhabdomyolysis from Baycol over other statin drugs, he would not have prescribed Baycol. Essentially, Bayer claims that although AERs are required by the Federal Drug Administration (FDA), the limits on their reporting prevent admission in a state court trial. Moreover, it claims they are hearsay and inadmissible. I disagree. A. There is no federal preemption or other reason not to warn of the drastically increased AERs with Baycol. Very recently, after the trial in this matter, the United States Supreme Court ruled that compliance with the FDA requirements as to labeling does not preempt a state from requiring a higher standard. In Wyeth v. Levine, 129 U.S. 1187 (2009), the United States Supreme Court held that if it is discovered that a product is more dangerous than thought, the manufacturer can add a stronger warning without prior FDA approval. Wyeth stated in no uncertain terms: Yet through many amendments to the FDCA and to FDA regulations, it has remained a central premise of federal drug regulation that the manufacturer bears responsibility for the content of its label at all times. It is charged both with crafting an adequate label and with ensuring that its warnings remain adequate as long as the drug is on the market. See e.g., 21 CFR 201.80(e) (requiring a manufacturer to revise its label to include a warning as soon as there is reasonable evidence of an association of a serious hazard with a drug ); 314.80(b) (placing responsibility for postmarketing surveillance on the manufacturer); - 8 -
73 Fed.Reg. 49605 ( Manufacturers continue to have a responsibility under Federal law to maintain their labeling and update the label with new safety information ). 129 U.S. at 1197-98. The court rejected the manufacturer s position that state law requiring a stronger warning would interfere with Congress purpose of having an expert agency make drug labeling decisions and held that it is the manufacturer rather than the FDA that bears the primary responsibility for drug labeling. Therefore, merely complying with an FDA-approved label does not protect a manufacturer from liability if it distributes a dangerous drug when the FDAapproved label is not sufficient. A key factor in the trial judge s ruling was his position that because the label was approved by the FDA, Bayer was unable to change it. If there was ever any doubt about this error, Wyeth puts it to rest. 3 B. The AERs are not being offered to prove causation and are relevant and admissible. Bayer argues that AERs do not necessarily reflect a conclusion that the report information constitutes an admission that the drug caused or 3 Pauley also cites to 44 Fed.Reg. 37337 (June 26, 1979) to support the contention that drug manufacturers need to be proactive in giving warnings even in the absence of proof of causation or advance FDA approval of the warning. The Federal Register and Code of Federal Regulations are a labyrinth that we do not often find ourselves in. Although we note the compelling statements, and agree that in general such ideas are to be found in both the case law and the regulations, we cannot specifically link those comments to current regulations found in the C.F.R., thus we do not rely on this to support our decision. We note as well that Bayer does not specifically deny the applicability of the comments cited to in the Federal Register. - 9 -
contributed to an adverse event. Bayer Brief, 5/15/06 at 17 (citing 21 C.F.R. 314.80(k)). Here, there is no dispute that Pauley s rhabdomyolysis was caused because he took Baycol. Thus, the C.F.R. caution regarding causation is not directly applicable. The plaintiff s position was that his chance of contracting rhabdomyolysis would have been significantly decreased had he taken one of the other statins. As noted, there would have been testimony that Dr. Caples would not have prescribed Baycol had he known the huge differential in AERs between Baycol and other statins. His testimony was further redacted to eliminate Dr. Caples testimony that he would not have prescribed Baycol had he known of the remarkable disadvantage language of the Niemcryk report. Although Dr. Caples testified that he thought Baycol warnings were inappropriate and inaccurate, the jury could not tell why he thought the warnings were inappropriate and inaccurate. Pauley was forced to do the equivalent of the proverbial fighting with one arm tied behind the back. While I agree that AERs are not conclusive, they certainly are not irrelevant. The FDA caveats regarding AERs also state that risk comparisons cannot be made from the data because true incidence rates are not known through this information. Again, that is largely dealing with causation, which is not at issue here. The fact in this matter remains that AERs from all similar drugs indicate that Baycol was up to 68 times more likely to cause the adverse event than other drugs. Perhaps there are benign statistical reasons why - 10 -
Baycol users suffer 68 times the adverse events than other drug users. Let Bayer produce that testimony and explain why the AERs in this case are not reliable. It is my belief that this is information for a jury to sort through and should not have been precluded from their consideration. I note that although Bayer withheld reporting the AERs to the FDA for months and during the period Pauley was given the drug Baycol was pulled from the market a month after the AERs were submitted. It might be argued that AERs are anecdotal and so they have no inherent scientific reliability. That is true to a point. I believe that is a more relevant consideration when causation is at issue. Here, as noted, causation is already admitted. It has already been established that this class of drugs can cause rhabdomyolysis. The AERs in this case are not starting on a blank slate. The underlying cause and effect is known. The AERs indicate in this case that, all other things being equal, when Baycol is introduced into the equation the risk of a known and specific adverse reaction increases by a multiple of 20 to 68 times. If there are unknowns in the equation that bring those multiples into question, then Bayer is likely to be aware of them and can refute the significance of the AERs. I am not suggesting that AERs be used in general to support a claim of causation. I agree that anecdotal reports are not dispositive of causation. However, in limited circumstances where causation is known and the AERs provide for a reasonable conclusion that there is a significant increase in the - 11 -
incidence of a specific adverse reaction, then I believe that a jury is entitled to know what the drug manufacturer knows. Given that the drug manufacturer will produce reasons why the AERs do not provide a reasonable conclusion, I do not believe that the introduction of AERs, in this limited circumstance, will be more prejudicial than probative. Bayer has cited Ackley v. Wyeth Laboratories, Inc., 919 F.2d 397 (6th Cir. 1990), for the proposition that under Ohio law relative risks need not be disclosed. Ackley dealt with DPT inoculations. According to Ackley, at the time the Wyeth drug was developed, it fit the description of an unavoidably unsafe drug meaning at the time of distribution, there existed no alternative design that would have as effectively accomplished the same purpose or result with less risk. Id. at 400. There is no indication that Baycol was determined to be an unavoidably unsafe drug. Also, in Ackley, prior cases had determined that the warning was adequate and the Ackely court determined it was bound by those decisions. Notably, Ackley never describes what the relative risks between the different DPT drugs actually was. It is also unclear if the determination that the warnings were adequate were made in conjunction with the determination that the drug was unavoidably unsafe or if the two determinations were grafted on to each other. It appears to me that if a drug is unavoidably unsafe it would largely preclude a determination that at the time of distribution it was also found to be significantly more hazardous than other similar drugs. Finally, Ackley was decided almost twenty years - 12 -
prior to Wyeth, supra, which allows for greater drug company responsibility in labeling, rather than allowing the drug companies to rely upon FDA approval. Wyeth also states: Failure-to-warn actions, in particular, lend force to the FDCA s premise that manufacturers, not the FDA, bear primary responsibility for their drug labeling at all times. 129 U.S. at 1202. Thus, I do not believe that Ackley is dispositive on the issue of Ohio law and relative risks. The warning that the combination of Baycol and gemfibrozil is contraindicated does not cure the problem. As noted, because of the great risk of a heart attack, Dr. Caples believed the small risk of rhabdomyolysis was worth taking. The warning that should have been given was that Baycol was much more toxic than other statins, especially when given with gemfibrozil. The risk was not in the combination it was in Baycol. I finally note on the issue of relative risks that when there is more than one manufacturer for a type of drug, it would seem likely that one might be safer in some regards than another. This does not mean that I believe that all such differences must be made known to the medical community. A trial court can make a determination, as it would in any case, that as a matter of law the overall risk and/or added risks are not so significant that it constitutes any type of extraordinary danger. In such instances summary judgment must be granted. I am not suggesting that any difference in risk, no matter how small or what the overall risk is, must be noted. I am suggesting that there are - 13 -
some differences in risk that are so great and the overall risk so significant that those risks should not be ignored. That is the case here. 2. The error in admitting the AERs was compounded by precluding the use of toxicology studies on animals. As noted, the AERs were not intended to prove causation, as that was admitted. Also, it is not from the AERs alone that much more stringent warnings should have been given. Other evidence alerted Bayer that this was a dangerous drug. Bayer had conducted animal studies that showed cerebral hemorrhages in animals, indicating that Baycol had a very high toxicity. Those studies were kept out because there was no showing how the animal studies related to humans. I believe this was error. Once again, this is not why they were offered. In determining what warnings should be given for a drug, it is impossible to make the determination with absolute certainty. Various evidence and studies are necessary for an expert to come to a conclusion. Pauley offered such an expert, epidemiologist Sorrel Schwartz, Ph.D. He would have testified, if permitted, that the combination of AERs and the toxicity of Baycol required a warning different from that of all other statins to properly alert physicians. While he was able to give some conclusions, because he was severely limited in stating the reasons for his conclusions, his credibility with the jury was drastically reduced. - 14 -
For all these reasons, I believed Pauley was improperly precluded from showing the overwhelming likelihood that Baycol is much more dangerous than other statins, that this kind of a warning should have been placed on the product, and had Dr. Caples had the benefit of this knowledge and warning, he never would have prescribed Baycol to Pauley and Pauley would not have been so severely disabled with rhabdomyolysis. Therefore, I believe the case should be reversed for a new trial and, accordingly, must dissent. - 15 -