Letter in JAMA Responding to Article on the Safety of Withdrawn Drugs

This letter, by Health Research Group Researcher Larry Sasich, Pharm. D., MPH and Deputy Director Peter Lurie, M.D., MPH, appeared in the Journal of the American Medical Association (JAMA) on December 2, 1999.

To the Editor: Dr Friedman and colleagues[1] downplayed serious safety questions about dexfenfluramine, mibefradil, and bromfenac sodium, which were approved in 1996-1997 and subsequently removed from the market, that were raised prior to marketing. Furthermore, Friedman et al failed to acknowledge that these drugs did not represent significant advances over the numerous approved drugs in their therapeutic categories.

For example, data from congestive heart failure trials presented at a Food and Drug Administration (FDA) Advisory Committee meeting on mibefradil suggested that more patients treated with mibefradil died than those taking placebo.[2] Several committee members voted against approval. The drug, the ninth calcium channel blocker approved in the United States, has since been removed from the market because of life-threatening arrhythmias from drug interactions.[3]

The FDA medical officer reviewing bromfenac sodium, the 20th nonsteroidal anti-inflammatory drug (NSAID) approved in the United States, unsuccessfully advocated a black box warning label as a condition of approval because, "The review of the 'liver' laboratory data from the submission shows that bromfenac sodium causes hepatocellular damage to a greater degree than other NSAIDs"(R. M. Widmark, unpublished data; FDA medical officer review memo, bromfenac sodium, December 22, 1995). After at least 4 deaths and 8 liver transplants, bromfenac sodium was removed from the market.[4]

Unfortunately, this trend continues. The 10th fluoroquinolone antibiotic trovafloxacin was approved by the FDA in 1997, despite a premarketing clinical trial for prostatitis in which 10% of patients had liver function test results greater than 3 times the upper limit of normal (FDA medical officer review, December 1997). Since February 1998, 140 documented cases of serious hepatic events have been reported, including 9 patients who died or required liver transplants.[5]

Similarly, troglitazone, the 11th drug for diabetes in the United States, was approved even though 1.9% of patients in the premarketing trials, 54% of whom had taken the drug for at least 6 months, had liver function test results greater than 3 times the upper limit of normal, and 0.4% and 0.2% had 10-fold and 20-fold elevations, respectively.[6] Troglitazone has now been associated with a minimum of 43 cases of liver failure, including 28 deaths (D. J. Graham, L. Green Epidemiology of hepatotoxicity with troglitazone. Presented at: the Endocrinologic and Metabolic Drugs Advisory Committee; March 26, 1999; Washington, DC).

The pharmaceutical industry has actively campaigned to lower drug approval standards, resulting in the Prescription Drug User Fee Act (PDUFA) of 1992, its reauthorization in 1997, and the 1997 Food and Drug Administration Modernization Act (FDAMA). PDUFA allows the FDA to collect fees from manufacturers to review new drug applications, transforming the pharmaceutical industry from a regulated industry into an FDA client. FDAMA also allows new drug approval based on 1 clinical trial (instead of 2), codifies and expands the use of "accelerated approval" reviews, and establishes the use of surrogate end points in clinical trials. These laws, together with the FDA's efforts to forestall even worse legislation by preemptively lowering standards, have created the current dangerous situation.

Peter Lurie, M.D., M.P.H.
Larry D. Sasich, PharmD, M.P.H.

Public Citizen's Health Research Group
Washington, DC

[1] Friedman MA, Woodcock J, Lumpkin MM, Shuren JE, Hass AE, Thompson LJ. The safety of newly approved medicines: do recent market removals mean there is a problem? JAMA. 1999;281:1728-1734. ABSTRACT | FULL TEXT | PDF | MEDLINE

[2] Roche Posicor first-line hypertension/angina use clears FDA advisory committee, with precautions about ECG changes. F-D-C Reports "The Pink Sheet." March 10, 1997:6-7.

[3] Roche Laboratories announces withdrawal of Posicor from the market FDA Talk Paper. June 8, 1998.

[4] Food and Drug Administration. Questions and answers for withdrawal of Duract. June 22, 1998. Available at: http://www.fda.gov/cder/news/duract/qa.htm. Accessed: December 1, 1999.

[5] The European Agency for the Evaluation of Medicinal Products. Public statement on Trovan/Trovan IV/Turvel/Turvel IV (trovafloxacin/alatrofloxacin), serious, severe, and unpredictable liver injuries. May 25, 1999. Available at: http://www.eudra.org/humandocs/humans/ps.htm. Accessed November 1999.

[6] Watkins PB, Whitcomb RW. Hepatic dysfunction associated with troglitazone. N Engl J Med. 1998;338:916-917. MEDLINE