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Testimony on CDER’s Risk Communication Failures

Sidney Wolfe, M.D.
Public Hearing on CDER’s Current Risk Communication Strategies for Human Drugs

Although the other topics from the list of six questions are important in the context of how well a given amount of information is communicated to patients and health professionals, the main question that I will focus on, question three, asks about the adequacy (and, implicity, timeliness) of the content of the communication rather than the success of the communication process:

“Do these tools provide the right kind and amount of risk and other information that health care professionals need to make informed decisions about whether to prescribe drug products, and that the public needs to make informed decisions about whether to use those products?”

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

A critical part of risk management/communication is remembering 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.

Categories of Failed FDA Risk Information Programs

a) Approving drugs whose pre-approval risks clearly outweigh benefits

When this mistake is made, the misleading message communicated to the public is that the benefits outweigh the risks (the opposite of the above).

Trovan (trovafloxacin-antibiotic) Like another drug also approved in 1997, the painkiller Duract (bromfenac), now off the market because of liver toxicity, 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.

b) Failing to promptly ban drugs when  there is post-approval evidence that risks clearly outweigh benefits 

Rezulin (troglitazone-diabetes drug)
1. March, 1997: U.S. Rezulin marketing begins
2. Dec, 1997: drug withdrawn in UK after 130 cases of liver damage including six deaths, mainly in the US
3. July, 1998: Health Research Group petitions FDA to ban Rezulin after 560 cases of liver damage, including 26 liver deaths
4. March, 1999: FDA advisory committee meeting: now 43 liver deaths
5. Early, 2000: Some FDA physicians state drug should be banned
6. March, 2000: Rezulin is withdrawn in the US; by then, 63 liver deaths, seven liver transplants

Baycol (cerivastatin-cholesterol lowering drug)  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 (an often-fatal destruction of muscle) 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.

c) Failing to promptly warn the public with black box warnings  when there is new risk information of sufficient concern to merit black box warnings

Vioxx (rofecoxib-NSAID) A randomized, controlled study published more than five years ago found  a four to five-fold increase in heart attacks in people using Vioxx compared to those using naproxen. There was then and is now no credible evidence that this enormous difference in risk can be explained by a protective effect of naproxen rather than by the heart attack risk of Vioxx. As a result of this study, we asked FDA for a black box warning almost five years ago (February, 2001). Although such a box warning would have greatly reduced the toll of tens of thousands of heart attacks occurring between then and Vioxx’s withdrawal, the agency, to the pleasure of Merck, rejected a black box and chose not to adequately warn the public. Many lives were thus lost.

Erectile Dysfunction Drugs: Fifty reports of ischemic optic neuropathy (ION), usually resulting in irreversible unilateral blindness, in men using the erectile dysfunction (ED) drugs Viagra, Cialis, or Levitra had been received by the US Food and Drug Administration (FDA) by March 2005. But the FDA and the companies have downplayed the link between these drugs and ION, stating, correctly, that the disease also occurs in men with cardiovascular risk factors who do not take erectile dysfunction drugs, but implying that the cause is cardiovascular risk, not the drugs. To test this, we compared the rate of reports of ION, per million prescriptions filled, in those using ED drugs with the rate in those using Lipitor — both groups having presumed increased cardiovascular risk.

For Viagra, there were 18 times more reports of ION per million prescriptions than for Lipitor and, for Cialis, 25 times more reports. Thus, it is very likely that the drugs can actually cause blindness in some people. Further evidence of causation can be seen in a case report in which one patient using Cialis suffered reversible visual field defects each time within 2 hours after taking 4 sequential doses of Cialis and suffered permanent partial loss of vision shortly after the fifth dose.[1] Our organization has thus petitioned the Food and Drug Administration to immediately require a black box warning on the labels for all three drugs, to require an FDA-approved Medication Guide for patients that contains the black box warning, and to begin a registry of all cases of ION following the taking of ED drugs. The full petition is at www.worstpills.org. Dr. Howard Pomeranz, the neuro-ophthalmologist who first published a report of ION in a man using an ED drug,[2] and has added seven additional cases, has joined us in the petition.[3]  The FDA has thus far failed to respond to our petition and order a black box warning and FDA-approved medication guides for patients.

d) Failing to require FDA-approved medication guides for all drugs, even failing to provide them for all drugs with black box

Twenty-four years ago, in 1981, the carefully researched regulation requiring FDA-approved patient information leaflets to be dispensed with prescriptions was cancelled by the Reagan administration just before it was to have gone into effect. This abrupt reversal was at the behest of drug companies, pharmacy organizations and some physician groups, and private sector-designed leaflets, not approved by the FDA, thereby continued to be the norm.

The Food and Drug Administration (FDA) has the regulatory authority to require pharmaceutical manufactures to prepare a Medication Guide if the agency determines that one or more of the following circumstances exists:

  1. The drug product is one for which patient labeling could help prevent serious adverse effects.
  2. The drug product is one that has serious risk(s) (relative to benefits) of which patients should be made aware because information concerning the risk(s) could affect patients’ decision to use, or to continue to use, the product.
  3. The drug product is important to health and patient adherence to directions for use is crucial to the drug’s effectiveness.[4]

The regulations also require that for drug products for which a Medication Guide is required that pharmacists provide the Medication Guide directly to each patient, or to the patient’s agent, at the time of prescription dispensing.[5]

Shortly after Dr. Mark B. McClellan became FDA commissioner, he listed, as one of his top five priorities, helping consumers to get truthful information about products they use so they can make informed decisions.   This was several years ago and the FDA could now go a long way in achieving this priority by immediately moving forward with a long-overdue initiative to require the mandatory distribution of FDA approved written drug information (Medication Guides) with each new and refill prescription. At present, for only 75 prescription drugs, out of thousands on the market, are Medication Guides required. It is time to end the double standard wherein doctors and other health professionals use and are informed by FDA-approved labeling but patients, like second-class citizens, get whatever the out-of-control purveyors of patient information leaflets choose to have dispensed to them with their prescription drugs.

In a study conducted several years ago by the University of Wisconsin for the FDA, although 89 percent of consumers were are receiving some sort of information when a prescription was filled (patient information leaflets-the content not regulated by the FDA), none of the approximately 1,300 leaflets studied for four common drugs achieved minimum goals for useful, scientifically accurate drug information. As measured by eight objective criteria, the overall usefulness of information was about 50 percent. According to the authors, “a majority of leaflets did not include adequate information about contraindications, precautions, and how to avoid harm.” The notion that consumer drug information can be 50 percent useful is unfathomable. Drug information that communicates only half of what it should is misleading, and misleading drug information is potentially dangerous.

e) Failure of the FDA to enforce the requirement that medication guides, once ordered by the agency, must be distributed by pharmacists to patients when drugs requiring the medication guides are dispensed

On June 15th of this year, the FDA announced the requirement for all prescription NSAIDs to be accompanied by an FDA-approved Medication Guide that included information such as:

NSAID medicines may increase the chance of a heart attack or stroke that can lead to death.  This chance increases:

  • With longer use of NSAID medicines
  • In people who have heart disease

Because of previous concerns that such information, even when FDA has ordered Medication Guides, is not being routinely dispensed with prescriptions for these drugs, our colleague, pharmacist Larry Sasich, Pharm. D., M.P.H, did a study of pharmacies in Erie, Pennsylvania to determine compliance with the NSAID Medication Guide requirement.

During the past ten days, pharmacists in thirteen Erie pharmacies were presented with prescriptions for celecoxib (Celebrex) to determine whether the NSAID medication guide was being dispensed.

The preliminary results for the thirteen pharmacies surveyed are summarized in the following Table: 

Table 1 – Compliance of 13 Pharmacies with the Regulatory Requirements To Distribute a Medication Guide for Celecoxib

Pharmacies Distributing a Medication Guide

1 (8%)

Pharmacies Explaining a Medication Guide


Pharmacies Distributing Written Drug Information Other Than a Medication Guide (non FDA-approved patient information leaflets

13 (100%)

Ironically, the unregulated drug information produced by one vendor contained the statement “Read the Medication Guide provided by your pharmacist before you start using celecoxib and each time you get a refill”, yet no Medication Guide was distributed and no information concerning the existence of a Medication Guide was communicated to the celecoxib purchaser. 

In summary, the answer to question three (“Do these tools provide the right kind and amount of risk and other information that health care professionals need to make informed decisions about whether to prescribe drug products, and that the public needs to make informed decisions about whether to use those products?”) is, in many situations, no, unless adequate communication of too-often inadequate information is viewed as a success.

[1] Bollinger K, Lee MS. Recurrent visual field defect and ischemic optic neuropathy associated with tadalafil rechallenge. Arch Ophthalmol. 2005;123:400-401.

[2] Egan R, Pomeranz H. Sildenafil (Viagra) associated anterior ischemic optic neuropathy. Arch Ophthalmol. 2000;118:291-292.

[3] Pomeranz HD, Bhavsar AR. Nonarteritic iscemic optic neuropathy developing soon after use of sildenafil (Viagra): a report of seven new cases. J Neuroophthalmol. 2005;25:9-13.

[4] 21 CFR 208.1

[5] 21 CFR 208.24