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Joseph D. Piorkowski, Jr, DO, JD, MPH

JAMA. 2004;292:2655-2657. Published online November 22, 2004 (doi:10.1001/jama.292.21.2655)

INTRODUCTION
JAMA has invited this response from Bayer Corporation to the article authored by Psaty et al (the "Article"), which appears on page 2622 in this issue. Although the Article is presented as a scientific review of facts, sections are copied verbatim from a report submitted by the lead author in a US lawsuit in which he served as a paid expert for the plaintiff. Moreover, the Article’s conclusions are based upon selected exhibits from another lawsuit in which another author (Dr Ray) submitted a report for plaintiffs. Bayer won that court case (as well as the only other cerivastatin cases that have gone to trial). At least 2 of the authors continue to participate in lawsuits against Bayer.

This response presents a more complete picture of the information available in the public record. It is submitted on Bayer’s behalf by one of its outside counsel because Bayer views the Article as the publication of a disputed position taken in ongoing litigation.

Background

Jump to Section  • Top  • Introduction  • Background  • Errors of the article  • Conclusion  • Author information  • References

Cerivastatin was an HMG-CoA reductase inhibitor shown to be highly effective in lowering serum LDL cholesterol. After extensive preclinical and clinical testing,^1-5 the FDA determined that cerivastatin was safe and effective and approved cerivastatin for sale in the United States.⁶ Regulatory authorities in over 80 countries approved cerivastatin as safe and effective.⁷

At the time of cerivastatin’s US launch in January 1998, rhabdomyolysis was a well-known side effect of the statin class. All statin labeling carried rhabdomyolysis warnings. The medical literature was replete with reports of statin-associated rhabdomyolysis.^8-9 Moreover, the scientific community recognized that coadministration of fibrates with statins increased the risk of myotoxicity.^10-12

Based on this class-wide experience, the original FDA-approved cerivastatin labeling warned of rhabdomyolysis and of a potential fibrate interaction, even though neither the independent clinical investigators nor the FDA reviewers ever characterized any event in the cerivastatin premarketing clinical trials as rhabdomyolysis.¹³ The Article uses a definition of rhabdomyolysis—"combination of CK elevations greater than 10 times the ULN with symptoms"—much broader than the proposed ACC/AHA Advisory definition (which requires renal impairment).¹⁴ But even using that definition, the original cerivastatin labeling specifically disclosed that such cases had occurred in <0.2% of clinical trial patients.¹¹ When higher doses became available, the labeling reflected that 0.4% of clinical trial patients developed this condition.¹⁵ No scientific evidence suggests that the risk of myopathy in cerivastatin patients was higher than that disclosed in the label. Thus, at all times that cerivastatin was marketed, both the nature and the magnitude of the myopathy risk were accurately set forth in the labeling.

Postmarketing, Bayer actively monitored the safety of cerivastatin through phase 4 clinical trials and by collecting and analyzing spontaneous adverse event reports (SAERs). Neither FDA nor the Article criticized Bayer’s diligence and good faith in reporting SAERs. Indeed, FDA has audited Bayer’s compliance with adverse event reporting covering the period of cerivastatin’s marketing and found no deficiencies.¹⁶

After receiving SAERs of rhabdomyolysis, Bayer—without FDA prompting—amended the labeled warnings regarding myopathy 5 times.¹⁷ The December 1999 label change specifically contraindicated coadministration with gemfibrozil in the United States.¹⁸ Another label change in May 2001 emphasized that untitrated use of the highest cerivastatin dose could lead to increased risk of rhabdomyolysis.¹⁹

By August 2001, Bayer and FDA agreed that SAERs of rhabdomyolysis continued, particularly with gemfibrozil coprescription and untitrated use, despite the label changes.²⁰ Accordingly, Bayer voluntarily suspended marketing cerivastatin.²¹

Errors of the Article

Jump to Section  • Top  • Introduction  • Background  • Errors of the article  • Conclusion  • Author information  • References

FDA Effectively Monitors the Safety of Medicines Postmarketing. Using cerivastatin as a supposed example, the Article’s central thesis is that FDA lacks the resources to monitor medicines effectively postmarketing.

This Article’s premise, however, is demonstrably untrue. FDA, in fact, did carefully monitor the safety of cerivastatin. In June 2000, FDA completed a detailed comparison of SAER reporting rates for statin drugs with respect to rhabdomyolysis.²² FDA found that cerivastatin had the highest reporting rate for rhabdomyolysis of any of the statins on the market. To understand this observation, FDA considered these data from several different perspectives.²³ FDA noted the high rate of rhabdomyolysis when cerivastatin was combined with gemfibrozil, commenting that "the voluntary upgrade of the labeling by the manufacturer for cerivastatin from a Warning to a Contraindication regarding combination use with gemfibrozil is consistent with our findings in the AERS database."²³

FDA observed that "reporting of adverse events to FDA’s spontaneous reporting system is highest in the first few years after a new drug is approved."²³ Given this known bias, "reporting rates were also calculated for only the first two years of marketing for each statin, so as to make comparison with cerivastatin (the newest statin) more balanced."²³ Although reporting rates for monotherapy were much more comparable to other statins, the reporting rate for combination use remained higher for cerivastatin.²³

FDA acknowledged that "several major limitations . . . must be borne in mind when examining and interpreting reporting rates. . . . "²³ FDA stated that "perhaps most importantly, the reporting rates presented in this document are NOT incidence rates and are in no way reflective of the actual occurrence of rhabdomyolysis among users of statins and/or fibrates out in the ‘real world’ of clinical practice."²³

Although the Article apparently disagrees with FDA’s experts on the limitations of reporting rates, the contention that FDA lacked resources to adequately evaluate the postmarketing data on cerivastatin is specious. FDA’s internal memorandum reflects a careful analysis that is consistent with positions of other scientists experienced in interpreting SAER data²⁴ and with Bayer’s conduct.

FDA’s analysis was not limited to fatal rhabdomyolysis cases, as the Article suggests, since no fatal rhabdomyolysis cases were reported in the United States during cerivastatin’s first 2 years of marketing.

The Gemfibrozil Interaction. The Article’s criticism of Bayer for not contraindicating gemfibrozil in the United States until December 1999 and for not undertaking an earlier pharmacokinetic interaction study with gemfibrozil employs hindsight analysis.

Statin-fibrate drug interactions had been known to the scientific community for several years prior to cerivastatin’s launch.^{10, 25-29} Numerous studies attempting to elucidate the interaction between statins and fibrates consistently showed the absence of a pharmacokinetic interaction.^30-31

Thus Bayer, like other researchers,³² hypothesized a possible pharmacodynamic mechanism and tested that hypothesis in vitro. Ultimately, this testing showed no pharmacodynamic interaction between Baycol and gemfibrozil.⁷

A pharmacokinetic interaction between any statin and gemfibrozil first was demonstrated in August 2000 with simvastatin.³³ Based on this research, Bayer undertook its own clinical interaction study, which similarly revealed a pharmacokinetic interaction when cerivastatin was coadministered with gemfibrozil.³⁴ Later studies in 2001 with lovastatin demonstrated that pharmacokinetic interactions with gemfibrozil were not unique to cerivastatin among the statin class.³⁵

Bayer Responded to the Postmarketing Data. The Article quotes out-of-context an internal company document discussing postmarketing data. That memorandum actually documents the scientific unreliability of such data and recommended that Bayer undertake a reliable epidemiological study.³⁶

Thereafter, Bayer retained the former chief FDA pharmacoepidemiologist and undertook a comprehensive search for a viable epidemiological database.³⁷ A retrospective study was completed that confirmed an increased myopathy risk with gemfibrozil combination therapy but no difference in the monotherapy myopathy rate.³⁸

Bayer Complied With Its Disclosure Obligations. The Article implies that Bayer should have provided physicians with comparative SAER reporting rates. However, FDA regulations prohibit manufacturers from making comparisons to other medicines based on anything other than data from well-controlled clinical trials.³⁹ Indeed, even when placebo-controlled clinical trials are available for each medication individually, FDA practice precludes comparative statements unless such statements are based on head-to-head comparisons, based upon FDA’s long-standing belief that well-controlled head-to-head clinical trials provide the only reliable basis upon which to base drug comparisons.

Conclusion

Jump to Section  • Top  • Introduction  • Background  • Errors of the article  • Conclusion  • Author information  • References

It always is possible to second guess decision-making after the fact. However, when judged fairly by all the facts in their proper context, Bayer’s conduct in the marketing of cerivastatin from 1997 until its voluntary withdrawal from the market in August 2001 was responsible, appropriate, and consistently motivated by concern about the safety and welfare of patients.

AUTHOR INFORMATION

Jump to Section  • Top  • Introduction  • Background  • Errors of the article  • Conclusion  • Author information  • References

Corresponding Author: Joseph D. Piorkowski, Jr, DO, JD, MPH, 910 17th St NW, Suite 800, Washington, DC 20006 (JPiorkowski{at}lawdoc1.com).

Financial Disclosure: Joseph D. Piorkowski, Jr, DO, JD, MPH, is a physician and attorney who has served, and continues to serve, as outside counsel to Bayer Corporation in connection with its defense of the Baycol litigation. In his capacity as Head of the National Expert Team, the author has taken the deposition of Dr Bruce Psaty and has attended the depositions of Dr Curt Furberg and Dr Wayne Ray. The author assisted with the defense of the Haltom trial, the Texas case upon which Psaty et al purport to base their observations, which resulted in a unanimous verdict in favor of Bayer Corporation. (The only other cerivastatin cases that have gone to trial in the United States have similarly resulted in verdicts in favor of Bayer Corporation.)
The vast majority of claims involving alleged injuries resulting from Baycol use have been dismissed by plaintiffs without settlement by Bayer Corporation. The author received compensation from Bayer Corporation for his work in the Baycol litigation and his time involved in preparing this response. The author has no other financial interest in Bayer Corporation

Acknowledgment: The author gratefully acknowledges the substantial contribution of Tarek Ismail in the preparation of the manuscript.

REFERENCES

Jump to Section  • Top  • Introduction  • Background  • Errors of the article  • Conclusion  • Author information  • References

1. Von Keutz E, Schluter G. Preclinical safety evaluation of cerivastatin, a novel HMG-CoA reductase inhibitor. Am J Cardiol. 1998;82:11J-17J. FULL TEXT | WEB OF SCIENCE | PUBMED 2. Bischoff H, Angerbauer R, Bender J, et al. Preclinical review of cerivastatin sodium—a step forward in HMG-CoA reductase inhibition. Atherosclerosis. 1998;139(suppl 1):S7-S13. PUBMED 3. Kuhlmann J, Mück W, Bischoff H, et al. Cerivastatin (BAY w 6228): a novel HMG-CoA reductase inhibitor. Cardiovasc Drug Rev. 1998;16:236-263. 4. Davignon J, Hanefeld M, Nakaya N, et al. Clinical efficacy and safety of cerivastatin: summary of pivotal phase IIb/III studies. Am J Cardiol. 1998;82:32J-39J. FULL TEXT | WEB OF SCIENCE | PUBMED 5. Hunninghake D, Dujovne C, Stein E, et al. The 0.4 mg dose of cerivastatin: comparative safety and efficacy of cerivastatin 0.3 mg versus fluvastatin 40 mg. Pharmacotherapy. 1999;19:1194. 6. Bayer Exhibit 9, Hollis N. Haltom v Bayer Corporation, et al, Trial Court Cause No. 02-60165-2, Nueces County, Texas [FDA’s June 26, 1997, approval of the cerivastatin NDA]. 7. Plaintiff Exhibit 1826, Hollis N. Haltom v Bayer Corporation, et al, Trial Court Cause No. 02-60165-2, Nueces County, Texas [CIOMS IV Report]. 8. Deslypere JP, Vermeulen A. Rhabdomyolysis and simvastatin. Ann Intern Med. 1991;114:342. FULL TEXT | WEB OF SCIENCE | PUBMED 9. Corpier CL, Jones PH, Suke WN, et al. Rhabdomyolysis and renal injury with lovastatin use: report of two cases in cardiac transplant recipients. JAMA. 1988;260:239-241. FREE FULL TEXT 10. Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA. 1990;264:71-75. FREE FULL TEXT 11. Cerivastatin for hypercholesterolemia. Med Lett Drugs Ther. 1998;40:13-14. WEB OF SCIENCE | PUBMED 12. Hsu I, Spinler SA, Johnson NE. Comparative evaluation of the safety and efficacy of the HMG-CoA reductase inhibitor monotherapy in the treatment of primary hypercholesterolemia. Ann Pharmacother. 1995;29:743-759. ABSTRACT 13. Bayer Exhibit 1596, Hollis N. Haltom v Bayer Corporation, et al, Trial Court Cause No. 02-60165-2, Nueces County, Texas [original cerivastatin label]. 14. Pasternak RC, Smith SC, Bairey-Merz CN, Grundy SM, Cleeman JL, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol. 2002;40:567-572. FREE FULL TEXT 15. Bayer Exhibit 1600, Hollis N. Haltom v Bayer Corporation, et al, Trial Court Cause No. 02-60165-2, Nueces County, Texas [July 2000 cerivastatin label]. 16. Bayer Exhibit 130, Hollis N. Haltom v Bayer Corporation, et al, Trial Court Cause No. 02-60165-2, Nueces County, Texas [FDA August 26, 2002; Establishment Inspection Report for Bayer Drug Safety]. 17. Bayer Exhibits 1597, 1598, 1599, 1600, 1602, Hollis N. Haltom v Bayer Corporation, et al, Trial Court Cause No. 02-60165-2, Nueces County, Texas [cerivastatin labels amended as of July 1998, May 1999, December 1999, July 2000, and May 2001]. 18. Bayer Exhibit 1599, Hollis N. Haltom v Bayer Corporation, et al, Trial Court Cause No. 02-60165-2, Nueces County, Texas [cerivastatin label amended as of December 1999]. 19. Bayer Exhibit 1602, Hollis N. Haltom v Bayer Corporation, et al, Trial Court Cause No. 02-60165-2, Nueces County, Texas [cerivastatin label amended as May 2001]. 20. Plaintiff Exhibit 416, Hollis N. Haltom v Bayer Corporation, et al, Trial Court Cause No. 02-60165-2, Nueces County, Texas [Bayer August 8, 2001; Dear Health Care Professional letter]. 21. Bayer Exhibit 2586, Hollis N. Haltom v Bayer Corporation, et al, Trial Court Cause No. 02-60165-2, Nueces County, Texas [FDA Talk Paper August 8, 2001]. 22. Bayer Exhibit 170, Hardy v Bayer Corporation, et al, No. 25-01-6900COV, Hinds County, Mississippi [FDA internal SAER analysis]. 23. Bayer Exhibit 36, Slaughter v Bayer Corporation, et al, Civil Cause No. 2002-41-CV8, Jones County, Mississippi [FDA June 8, 2000, memorandum]. 24. Jones JK. Spontaneous reports cannot serve as a basis for comparison of two drugs. Am J Cardiol. 2003;92:1141-1142. WEB OF SCIENCE | PUBMED 25. Tal A, Rajeshawari M, Isley W. Rhabdomyolysis associated with simvastatin-gemfibrozil therapy. South Med J. 1997;90:546-547. WEB OF SCIENCE | PUBMED 26. Van Puijenbroek EP, Du Buf-Vereijken PW, Spooren PF, et al. Possible increased risk of rhabdomyolysis during concomitant use of simvastatin and gemfibrozil. J Intern Med. 1996;240:403-404. FULL TEXT | WEB OF SCIENCE | PUBMED 27. Abdul-Ghaffar NU, el-Sonbaty MR. Pancreatitis and rhabdomyolysis associated with lovastatin-gemfibrozil therapy. J Clin Gastroenterol. 1995;21:340-341. WEB OF SCIENCE | PUBMED 28. Knoll RW, Ciafone R, Galen M. Rhabdomyolysis and renal failure secondary to combination therapy of hyperlipidemia with lovastatin and gemfibrozil. Conn Med. 1993;57:593-594. PUBMED 29. Marais GE, Larson KK. Rhabdomyolysis and acute renal failure induced by combination lovastatin and gemfibrozil therapy. Ann Intern Med. 1990;112:228-230. FREE FULL TEXT 30. Pan HY. Clinical pharmacology of pravastatin, a selective inhibitor of HMG-CoA reductase. Eur J Clin Pharmacol. 1991;40(suppl 1):S15-S18. FULL TEXT | PUBMED 31. Spence JD, Munoz CE, Hendricks L, et al. Pharmacokinetics of the combination of fluvastatin and gemfibrozil. Am J Cardiol. 1995;76:80A-83A. FULL TEXT | PUBMED 32. Prueksaritanont T, Zhao JJ, Ma B, et al. Mechanistic studies on metabolic interactions between gemfibrozil and statins. J Pharmacol Exp Ther. 2002;301:1042-1051. FREE FULL TEXT 33. Backman JT, Kyrklund C, Kivistö KT, et al. Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin Pharmacol Ther. 2000;68:122-129. FULL TEXT | WEB OF SCIENCE | PUBMED 34. Bayer Exhibit 1627, Hollis N. Haltom v Bayer Corporation, et al, Trial Court Cause No. 02-60165-2, Nueces County, Texas [Communication Plan]. 35. Kyrklund C, Backman JT, Kivistö KT, et al. Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not bezafibrate. Clin Pharmacol Ther. 2001;69:340-345. FULL TEXT | WEB OF SCIENCE | PUBMED 36. Plaintiff Exhibit 515, Hollis N. Haltom v. Bayer Corporation, et al, Trial Court Cause No. 02-60165-2, Nueces County, Texas [memo dated March 10, 2000, attaching Excerpt from "Statement by Joseph A. Levitt, Director, Center for Food Safety and Applied Nutrition, Food and Drug Administration, Department of Health and Human Services, before the Committee on Government Reform, US House of Representatives, May 27, 1999"]. 37. Plaintiff Exhibit 147, Hollis N. Haltom v Bayer Corporation, et al, Trial Court Cause No. 02-60165-2, Nueces County, Texas [July 7, 2000, memo]. 38. Bayer Exhibit 131, Hollis N. Haltom v Bayer Corporation, et al, Trial Court Cause No. 02-60165-2, Nueces County, Texas ["The Risk of Myopathy Subsequent to HMG Use in a Managed Care Organization"; February 14, 2002]. 39. 21 CFR 201.57(g)(4) (2003).

Controversies Section Editor: Phil B. Fontanarosa, MD, Executive Deputy Editor.

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