More FDA warnings should not be cause for worry.

As reported the other day in the Wall Street Journal, in response to public concern about the safety of medications, the FDA plans to release information to health care professionals and the public earlier and more frequently than in the past. Previously, the FDA would wait until there was clear confirmation that adverse effects reported from drugs were actually true, and caused by that drug. However, due to increasing scrutiny and concern over drugs like Vioxx, the FDA will release information on reported events even earlier.


This sounds like a good thing, and it is. However, my concern has to do with the way the media reports such announcements, patients reactions to this, and sometimes confusing process and terminology of what an FDA warning actually means.


As reported in the WSJ, FDA Commissioner Andrew von Eschenbach stated, "I feel strongly it's important for us to communicate early, but in communicating early we are acting with a much smaller degree of certainty." Translation:many of these "warnings" or "alerts" are meant to be informative, and don't necessarily mean cause for alarm or even that the reported problem is actually true.


Bottom Line: Increasing public awareness about potential adverse reactions is a good thing, but please do not be alarmed every time you hear on the news that there is a new warning about a particular drug.

For those who are interested: (Sorry for such a long post, but this is a complex issue.) For a drug to be approved by the FDA, the company that makes the drug has to prove that it is both safe and effective. Though companies will submit data on thousands of patients taking their drug : 1) the patients enrolled in these studies are usually carefully selected and may not be representative of the entire population and 2) it may takes tens to hundreds of thousands of patients to see an uncommon (but sometimes serious) adverse event.

The current process is that once a drug is approved, two ways to ensure safety are 1) the company commits to doing studies on the drug after its release to the public and 2) patients, physicians and others can report any adverse events to the FDA, who will keep tabs on these regularly, looking for a signal of a problem. The problem is that not all companies have fulfilled their commitments to these post-marketing studies and reporting of adverse events is voluntary.

Chantix, Pfizer's drug for smoking cessation is a great example.

Smoking is the single leading preventable cause of death in the United States. Current guidelines recommedn that every patient interested in quitting smoking be offered some medication (patch, gum, pills) because these agents double the chance at successfully quitting. Chantix is currently the most effective agent for quitting smoking with good studies to back this up. In the initial studies presented to the FDA, with the exception of nausea (about 30% of patients get nausea, though it is usually mild and usually goes away), the side effect profile with Chantix was pretty darn good.

However, the FDA starting getting reports about patients with previous mental health conditions having serious mood and behavior disturbances after starting Chantix. On November 20th, 2007 the FDA released an "early communication" about this, followed by a public health advisory on February 1st, 2008 that "updated the Chantix prescribing information to include warnings about the possibility of severe changes in mood and behavior in patients taking Chantix" as well as an update to the product's label.

That's when the media stories started to run wild. CBS news and other sources reported that Chantix may have lead to a rock musician's suicide. MSNBC stated that "Anti-smoking drug may be tied to suicide risks" which was tame compared to other heavily googled news sites on the web that claimed "Pfizer Anti-Smoking Drug Chantix Worries FDA"

How could such a useful drugs with a pretty good safety profile be found to cause these problems? Some of the initial studies on Chantix compared it the only other drug approved for smoking cessation, bupropion (Chantix was found to be significantly better). However, bupropion is also used for depression. Because of this, people with mental health disorders were excluded from these intial studies. From a research standpoint, this was appropriate. However, persons with mental health disorders are about twice as likely to smoke, and disproportionately represent the population of current smokers. In addition, patients with mental health disorders may use nicotine to treat their illness. Finally, withdrawal from nicotine can itself exacerbate mental health disorders. So was it Chantix that caused these problems, or just that patients with mental health issues (who had not previously been studied) got worse after they stopped smoking? Currently, this is unclear.

Therefore, FDA's repsonse was thus appropriate. Within the label, doctors are now warned about worsening mood and behavior for patients with previous mental health conditions taking Chantix. The FDA added this to the drugs label as a "warning." This does not mean that Chantix is necessarily dangerous or problematic, and thus the media hype about the "dangers" of Chantix was not only unwarranted, but may have been harmful itself since patients who may have been using Chantix stopped taking the drug unnecessarily.

Another issue is the terminology used by the FDA may be confusing to the public (and even some physicians). The information about a drug's use, side effects, interactions, etc. is in a document called the label. On the FDA's web site (though difficult to find) is a Guidance document (posted in draft form) which points out there are muliple levels of warnings in a drug's label.

Some definitions:

Adverse Reaction is "an undesirable effect, reasonably associated with the use of a drug." This is not necessarily soemthing bad or serious.

Adverse Event is "any untoward medical event associated with the use of a drug...whether or not considered drug-related."

A Serious Adverse Reaction is something (obviously) serious, that may have lead to death, hospitalization, disability or birth defect.


Based on the type of reaction or event, this can come under several places in the product's label.

WARNINGS AND PRECAUTIONS: Under this section, these recommendations are about adverse reactions, which may not necessarily be serious, but thought to be clinically significant. Warnings also and usually contain serious adverse reactions as well as drug interactions.

CONTRAINDICATIONS: This means that you shouldn't use this medications in these particular circumstances.

BOXED WARNING

This category is the most confusing and media hyped. First, there is no such thing as a "Black Box," which is a term created by the media. Boxed warnings are warning that are thought to be important enough to go at the very top of the label and are highlighted by being surrouned by a box. A product can get a boxed warning for three reasons.

• "an adverse reaction so serious in proportion to the potential benefit from the drug (e.g., a fatal, life-threatening or permanently disabling adverse reaction) that it is essential that it be considered in assessing the risks and benefits of using a drug"



• A serious adverse reaction that can be prevented by appropriate (i.e. avoiding drugs that interact).



• The FDA approved the drug with restrictions.

A boxed warning an appropriate caution to health care providers, but again does not necessarily mean that the drug is unsafe to use. There are many drugs (metformin for diabetes for example) that are commonly used safely and effectively that have a boxed warning. For Chantix, the new information about potential adverse events came under the heading of "warnings."