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Testimony on the U.S. Drug Safety System

Sidney M. Wolfe, M.D.
Director, Public Citizen’s Health Research Group
Before the IOM Committee Assessing the U.S. Drug Safety System


The desired outcome of increased safety of drugs for patients can be viewed as a multiple regression equation with many predictor variables including the (1) adequacy and timeliness of the data submitted by drug companies before and after approval, (2) the adequacy and conclusions of FDA’s pre-approval review and ongoing post-approval reviews, (3) labeling, (4) other kinds of risk communication and (5) advertising.

The FDA currently lacks any statutory authority to impose civil monetary penalties on drug companies for any violation of FDA laws or regulations (it has, on rare occasions, but not often enough, brought successful criminal prosecution against companies for withholding safety data). Thus I will not discuss (1) above but will focus most of my comments on (2), the adequacy and conclusions of FDA’s pre-approval review and ongoing post-approval reviews and briefly comment on labeling and advertising.

Following are 13 cases in which serious mistakes have been made by the FDA, leading to large numbers of avoidable deaths and injuries.

Pre-Approval Mistakes:

Duract (bromfenac): 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shows that   bromfenac sodium causes hepatocellular damage to a greater degree  than other NSAIDs”(R. M. Widmark, unpublished data; FDA medical   officer review memo, bromfenac sodium, December 22, 1995).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.  

Posicor (mibefradil): Data from congestive heart failure trials presented at a Food and Drug Administration (FDA) Advisory Committee meeting on whether or not to approve mibefradil suggested that more patients treated with the drug died of sudden deaths than those taking placebo. 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. j

Rezulin: (troglitazone), the 11th drug for diabetes in the United States, was approved even though 1.9% of patients in the pre-marketing 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. Well before it was removed from the market, troglitazone had already been associated with a minimum of 43 cases of liver failure, including 28 deaths.

Trovan (trovafloxacin): Trovafloxacin was approved by the FDA   in 1997. Like (bromfenac), there was also clear evidence of liver damage caused by Trovan in animals and in humans before the drug was approved in December 1997. In one pre- approval study in which the drug was used to treat prostatitis, 10% of the men (14 out of 140) given the drug developed evidence of liver toxicity. With eight other drugs in this fluoroquinolone antibiotic family available in the U.S, as well as dozens of other safer and equally or more effective drugs for infections, the removal of Trovan from the market by the FDA would not have deprived doctors or patients of a drug that could possibly be considered indispensable. Instead of banning Trovan in 1999, as was done everywhere else in the world, the FDA chose to “limit” its use in the   United States to patients who were either hospitalized or in nursing homes. At the time of our petition in 1999 to ban the drug, there were eight cases of liver failure, including five deaths and three liver transplants. There were, as of December 31, 2004, a total of 58 cases of liver failure, including 29 deaths and nine people requiring liver transplants. This is especially alarming since for the past several years there were a total of only 350,000 prescriptions filled in the U.S.(from April 2002 through Feb 2005). As sales waned following the 1999 market withdrawal in Europe but more and more cases of liver failure and death occurred, Pfizer quietly discontinued making the drug in 2002. However, during the latest year for which U.S. sales data are available, there were still 18,000 prescriptions filled in the U.S (March 2004 through February 2005), long after Pfizer quietly stopped manufacturing the drug.

Lotronex (alosetron): Seven cases of life-threatening ischemic colitis occurred in clinical trials for this drug with marginal benefits in treating the diarrhea variety of irritable bowel syndrome. Within six months of marketing an additional 16 cases had occurred. We petitioned the FDA to remove it from the market but, after its removal, it was approved with very limited distribution.

Crestor (rosuvastatin): Seven cases of rhabdomyolysis (an often-fatal destruction of muscle) occurred in clinical trials prior to approval (none had occurred in clinical trials for any other statin including Baycol, eventually banned because an increased rate of rhabdomyolysis reports/million prescriptions. In addition, according to the FDA reviewer, there were cases of dose-related proteinuria and hematuria, with some patients having documented creatinine elevations.He stated that ““in contrast to currently approved statins, rosuvastatin was also associated with renal findings not previously reported with other statins”.

Post-Approval Mistakes: All six of the above drugs, based on data described above, also represent post-approval mistakes in that it took an inordinate amount of time with further preventable post-marketing deaths or injuries, all   predicted by the pre-market data, for the drugs to be taken off the market. Additional examples, focus primarily on post-marketing mistakes, include the following:

Seldane (terfenadine), Hismanal (astemizole) These two antihistamines as well as Propulsid (cisapride), a gastrointestinal drug, and Raxar (grepafloxicin) a fluoroqinolone antibiotic, were all found after approval to cause cardiac arrhythmias, often in combination with other drugs. For each, years of delay occurred between the discovery of this life-threatening adverse reaction and the removal of the drug from the market.  

PPA (phenylpropanolamine): Clear evidence from case reports of hemorrhagic stroke and other adverse cardiovascular events caused by this drug were unfortunately not enough for the FDA to ban PPA. Instead, additional years elapsed during which a case control study further confirmed that which was already well documented, costing many additional lives.

Baycol (cerivastatin):Approximately one year before Baycol was removed from the market in August 2001, its manufacturer Bayer, using FDA data on other statins, found that Baycol had 20 times more reports of rhabdomyolysis per million prescriptions than Lipitor.   An FDA official, feebly excusing FDA’s belated ban, stated that “We weren’t aware at that point of the difference between Baycol, and the other similar [drugs]. Our expectation is when a company becomes aware of a specific problem with their drug, they come to us”. By the time Baycol was banned, there were 1,899 cases of rhabdomyolysis; a significant number having occurred between the time there was unequivocal evidence that FDA should have banned the drug and when it was actually banned a year later.

Accutane (isotretinoin): Our organization has been trying for more than 20 years to get the FDA to significantly restrict the overall use and reduce, if not eliminate, pregnancy exposures which confer a more than 20% risk of a major birth defect. More than five years ago, an FDA advisory committee asked for much stronger restrictions than Roche or the FDA was willing to implement. Now, and just in the past year, almost 25 years after initial marketing and the knowledge of teratogenicity, there are more restrictions than ever before, but these are probably still not adequate.


In the case of drugs for which the problems became clear only after approval, the receipt and prompt evaluation of post-marketing adverse reaction reports (ADRs) are critical. But the concept of generating a warning signal from ADRs is useful only if the signal is taken seriously and the action taken is prompt and proportional to the strength of the signal. This is especially important when the signal confirms earlier, pre-approval evidence of dangers seen in randomized controlled trials, as in the six drugs cited above. There has been an historic split and an imbalance of power between FDA drug review divisions and the postmarket surveillance (Office of Drug Safety) division. In too many instances, serious post-marketing safety problems identified by the Office of Drug Safety have not been acted upon because of resistance from FDA management and from the review division that originally approved the drug.

Another reason the morale in the Center for Drug Evaluation and Research (CDER) appears to be lower than in 30 years has to do with what CDER Director Dr. Woodcock has aptly described as the “sweat shop environment” created in the wake of the Prescription Drug User Fee Act (PDUFA).

In addition to this dangerous imbalance of power between the FDA drug review divisions and the post-market surveillance (Office of Drug Safety) division, and the pro-industry environment,   enhanced by PDUFA, other causes of pathology at the FDA can be seen in three different surveys/studies of FDA medical officers done by our organization (1998), the FDA itself (2001) and the HHS Inspector General (2003).

Public Citizen Survey: We received responses from 53 FDA CDER physicians, which included 27 instances in which the FDA medical officer thought a drug was too dangerous to be approved but approval occurred over their objection.  Seventeen medical officers described the current standards of FDA review for safety and efficacy as “lower” or “much lower” compared to those in existence prior to 1995. Several medical officers said they had been instructed by their superiors to censor their reports or presentations.

FDA Survey: Precipitated by high turnover rates among scientists and physicians in the agency, this study showed that: “About one third of respondents did not feel comfortable expressing their differing scientific opinions…over one third felt that decisions such as holds, refuse-to-file actions, and non-approvals are stigmatized in the agency. Over one third felt that their work has more impact on a product’s labeling and marketability than it does on public health. A number of reviewers added comments stating that decisions should be based more on science and less on corporate wishes.” One of the 13 recommendations in the report is to “Encourage freedom of expression of scientific opinion.”

Inspector General Study: Confirmed that decisions concerning drug safety and effectiveness were being overturned. Eighteen percent of surveyed FDA physicians and scientists felt pressure to recommend that drugs be approved for sale despite their reservations about the drug’s safety, efficacy or quality. The report concluded: “Overall, these findings present a significant warning signal.”

Labeling and other Risk Communication: For too many of the drugs cited above—for most of those eventually taken off the market—there was a futile, dangerous interval before withdrawal during which there were attempts, through labeling changes, to solve a problem of an unacceptably dangerous drug, mainly ones for which there were safer alternatives.

However, much better, well organized and prioritized labeling for physicians as finalized yesterday is a good step but puts even more emphasis on the pitiful state of patient information leaflets dispensed when prescriptions are filled. These unregulated sheets, that “achieved” a failing score of 50 out of 100 in a recent FDA-funded study of their accuracy and completeness, need to be put on the trash heap and replaced by FDA-approved Medication Guides for all, not just 75 out of the thousands of drugs for which they are currently required.

Dangerous Decline in FDA Enforcement of Advertising Laws and Regulations:
From a peak number of enforcement actions against illegal prescription drug ads of 157 ads in 1998, despite an increase in such as and no evidence in an improvement in their legality, there was an 85% decrease in enforcement actions, dropping to 24 in both 2003 and 2004.


George Santayana is frequently remembered for his statement that “Those who cannot remember the past are condemned to repeat it.”

A critical part of improving the system for drug safety is remembering, admitting and learning from past mistakes. The FDA, because it appears largely incapable of doing so, will inevitably continue to repeat the kind of mistakes that a careful “post-mortem” examination and course correction would have prevented. Along with the FDA, however, the public winds up being “condemned” by the inadequate actions of this agency of the Public Health Service. This is certain to continue unless some fundamental changes take place. The most important of these include:

A. Repeal PDUFA

B. Separate the Office of Drug Safety from under the dangerous thumb of CDER but having it remain in the FDA, with the independence to make decisions.

C. Give the FDA the legal authority to impose massive civil penalties on drug companies in addition to the very limited current authority to initiate criminal prosecution.

D. Authorize FDA to require post-market studies of situations not anticipated at the time of approval.

E. Encourage much more Congressional oversight of the FDA. It is now 14 months since the highly-publicized hearing on the COX-2 drugs and other FDA problems chaired by Senator Grassley. There are enough specific problems to elucidate to have dozens of more days of hearings in the near future. There has been a deadly silence from the Congress, aided by Senator Enzi’s love for the pharmaceutical industry.

All of the first four changes I have proposed above are among the options suggested in the thoughtful Congressional Research Service report on this topic. The Ganslow summary incorporates 3 ½   of these first four changes in that it still calls for user fees. It is of interest, but not  very surprising, that none of the first four changes are even suggested as options in the FDA Report to the Commissioner of its Task Force on Risk Management, confirming the urgent need for the fifth change I have suggested, much more congressional oversight.

There are other proposed changes in some of documents we have been asked to review but, in the absence of all of the five above reforms, they will not succeed. Some are more sensible than others, such as the issues of expedited public access to data from clinical trials.