Jane Henney, M.D.
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
This letter is to request the opening of a criminal investigation of Warner-Lambert/Parke-Davis for what appears to be illegally delaying the submission of a compilation of data known to the company before marketing had begun – clearly showing troglitazone-induced liver toxicity – until after the drug was marketed.
Prior to the marketing of troglitazone in March 1997, Warner-Lambert/Parke-Davis was aware of a significant number of “treatment-emergent” cases in which liver toxicity evolved in people after they were given the drug. These are highly significant adverse reaction data which were compiled as of February 3, 1997 (before marketing was begun) by the company but not submitted to the FDA as a compilation of what was clearly a pattern of drug-induced liver toxicity until October 21, 1997 (6 months after marketing had begun).
On page two of a November 12, 1997 memo by FDA reviewer Robert Misbin, M.D. commenting on this belated submission of compiled data, he states that: “As of February 3 , (from the submission of October 21, 1997) Parke-Davis reported 21 patients with treatment-emergent elevations of transaminases greater than 3x normal which required troglitazone to be discontinued. The maximum ALT [liver enzyme] exceeded 10x ULN [upper limit of normal] in 13/21 cases and exceeded 1000 in 5/21 cases. There are three cases of biopsy-proven hepatitis with peak transaminase levels of 1000 U/L and jaundice in two cases.”
This delay in reporting the compilation of these findings is highly significant because had the data been submitted promptly, within 15 days, as required by Federal law, it is likely that the drug would, when first marketed, have had a more serious warning about liver toxicity and would clearly have had instructions to have liver monitoring tests done. It is thus likely that many of the estimated 400 patients who have suffered troglitazone-induced liver failure (as of now, with many cases not reported, there have been 89 cases of liver failure including 61 deaths reported) would have been spared had this compilation of cases been sent to the FDA promptly instead of eight months later. When the drug was first approved and marketed, there was no mention of the seriousness of the liver toxicity nor was there any label instruction to have any liver tests done. Upon belatedly learning in the fall of 1997 of the cases of liver toxicity which had occurred prior to marketing, along with other cases of severe toxicity occurring after marketing, the FDA for the first time, in late October 1997 required the label to be changed to request initial liver testing the first two months of treatment and subsequent tests for a total of five tests in the first year. The October 28, 1997 change in the labeling was as follows:
Dear Healthcare Professional Letter – Labeling Changes
RARE CASES OF SEVERE IDIOSYNCRATIC HEPATOCELLULAR INJURY HAVE BEEN REPORTED DURING MARKETED USE.
THE HEPATIC INJURY IS USUALLY REVERSIBLE, BUT VERY RARE CASES OF HEPATIC FAILURE, INCLUDING DEATH, HAVE BEEN REPORTED. INJURY HAS OCCURRED AFTER BOTH SHORT- AND LONG-TERM TREATMENT.
It is recommended that serum transaminase levels be checked within the first one to two months and then every three months during the first year of troglitazone therapy, and periodically thereafter.
In the previous cases of successful criminal prosecution of pharmaceutical companies for temporarily and illegally withholding information from the FDA – Lilly for the arthritis drug Oraflex, SmithKline for the hypertension drug Selacryn and Hoechst for the antidepressant Merital – the drugs were taken off the market. Likewise, troglitazone is a doomed drug and it is only a matter of when, not whether it will come off the market.
I look forward to a prompt response to this request for a criminal prosecution and to this now-third time request to ban this unacceptably dangerous drug.
Sidney M. Wolfe, M.D.
Public Citizen’s Health Research Group