INTERNATIONAL DRUG INFORMATION NOTES
Larry D. Sasich* and Sana R.. Sukkari
U.S. DRUG APPROVAL PROCESS IN QUESTION
Bromfenac was the third new drug withdrawn from the market in the U.S in the nine month period between September 1997 and June 1998 for safety reasons. The other two products were the diet drug dexfenfluramine (Redux) and the antihypertensive-antianginal agent, mibefradil (Posicor). These three drugs are among a flood of new drugs approved in the U.S since the pharmaceutical industry, through the U.S.
Congress, has been pressuring the FDA to set records for new drug approvals. This unprecedented number of withdrawals places in serious question the quality of the drug approval process in the U.S once among the most respected in the world.
Documents obtained from the FDA through the Freedom of Information Act, clearly show that the Agency's medical reviewers were concerned about bromfenac's liver toxicity before the drug was approved. The medical officer noted that bromfenac's liver toxicity was greater than other NSAIDs and wrote: The review of liver laboratory data from the submission show that bromfenac sodium causes hepato-cellular damage to a greater degree than other NSAIDs, even diclofenac [Voltaren in the U.S]. Although the repair process seems to occur in almost all cases when the drug is discontinued, it should not be forgotten that patients in clinical trials are closely monitored, which is difficult to achieve in the practice of medicine.
Although the medical officer had serious reservations about the drug's safety, the FDA's upper management was apparently more interested in setting new records for approvals rather than protecting the public's safety. Bromfenac was the 20th NSAID licensed in the U.S and there is no sound medical explanation as to why this drug was approved when multiple, equally or no more effective, and safer treatment options were available to physicians and patients.
There were also serious safety questions raised about miberfradil and dexfenfluramine before their approvals, questions that could have and should have been answered before they were cleared for marketing. Mibefradil was the ninth calcium blocker approved in the U.S and this class of drugs can only be considered as third or forth line therapy for hypertension and there are numerous treatment options available for hypertension and angina. A long-term clinical trial was underway when the application for mibefradil was being reviewed by the FDA that raised safety questions about the drug. A number of sudden deaths were reported during an interim analysis of this trial and the trial's completion would have answered the question about the sudden deaths.
Rather than erring on the side of public safety and waiting for the completion of the long-term trial the FDA approved mibefradil.
Dexfenfluramine was an old European diet drug claimed by many as the cure for obesity. No diet drug has ever been shown that it can be taken safely for a long enough period of time to reduce the morbidity and mortality associated with obesity.
Dexfenfluramine was known to cause neurotoxicity in laboratory animals and was associated with primary pulmonary hypertension and adverse drug reaction with a fatality rate of 50 percent. The FDA's original advisory committee recommended against approval of this drug for safety just mentioned. In a highly irregular move the FDA convinced a second advisory committee that, on a split vote, recommended to approve the drug. Public Citizen's Health Research Group wrote the FDA in support of the opinion of 21 neuroscientists asking the drug's approval be delayed until the safety question could be answered, but dexfenfluramine was approved.
The approvals and subsequent withdrawals of bromfenac, mibefradil, and dexfenfluramine point to serious systemic problems in the FDA's drug approval process. None of these drugs were used to treat serious or life-threatening diseases for which there are no effective treatments available. There were multiple options available to physicians and patients, both drug and non-drug treatments, that were equally or more effective and safer for the conditions for which these drugs were licensed.
We may never known why these drugs were allowed on the market. There is no mandatory requirement in the U.S for independent review of drug safety withdrawals.
Some observers have suggested that a system of review, similar to the investigations done in detail after airline disasters to ascertain causes or to recommended procedures to prevent future injury and deaths should exist for drugs. Congress has this authority, but at this point in time has shown little interest in investigating the withdrawals of these three drugs or in preventing the licensing of more drugs with serious safety problems when multiple treatment options exist.
The pharmaceutical industry, using the United States Congress, has systematically weakened the FDA during 1990s culminating in passage of FDA. Modernization Act of 1997. This special interest law has placed the economic well-being of multi-national pharmaceutical manufactures above the health and safety of patients and marks a law point in U.S drug regulatory history by weakening, rather than strengthening, laws meant to protect the public from drug induced injury.
The weakening of the FDA has important implications for drug approval in developing countries that have used FDA approval as the basis for licensing new drugs. The FDA as the world standard for drug regulation, can no longer be blindly accepted as sufficient evidence to approve new drugs. The risks both economically, and in terms of needless drug induced injuries to the public are too high. Developing countries must find the resources to strengthen their own drug regulatory authorities so that they can conduct high quality, independent evaluations of new drug applications.
This can be done by investing in an adequate drug information service, with access to a high quality medical library, and in the education and training of its own health professionals in the sciences necessary to conduct drug evaluations.
References
1. United States Department of Health and Human Services. Food and Drug Administration. FDA Talk Paper: Wyeth-Ayerst Laboratories Announces The Withdrawal of Duract from the Market. June 22, 1998.
2. United States Department of Health and Human Services. Food and Drug Administration. FDA Press Release: FDA Announces Withdrawal of Fenfluramine and Dexfenfluramine. September 15, 1997.
3. United States Department of Health and Human Services. Food and Drug Administration. FDA Talk Paper: Roche Laboratories Announces Withdrawal of Posicor from the Market. June 8, 1998.
4. Food and Drug Administration. Medical Officer Review. Bromfenac sodium. Rudolph M. Widmark, December 22, 1995.
From Saudi Pharmaceutical Journal, Vol. 6, No. 3-4, July-October 1998