Past Experiences

My experience with Vioxx is typical of how CDER responds to serious drug safety issues in general. This is similar to what Dr. Mosholder went through earlier this year when he reached his conclusion that most SSRIs should not be used by children.

I could bore you with a long list of prominent and not-so-prominent safety issues where CDER and its Office of New Drugs proved to be extremely resistant to full and open disclosure of safety information, especially when it called into question an existing regulatory position. In these situations, the new drug reviewing division that approved the drug in the first place and that regards it as its own child, typically proves to be the single greatest obstacle to effectively dealing with serious drug safety issues.

The second greatest obstacle is often the senior management within the Office of Drug Safety, who either actively or tacitly go along with what the Office of New Drugs wants. Examples are numerous so I'll mention just a few. With Lotronex, even though there was strong evidence in the pre-approval clinical trials of a problem with ischemic colitis, OND approved it.

When cases of severe constipation and ischemic colitis began pouring into FDA's MedWatch program, the reaction was one of denial. When CDER decided to bring Lotronex back on the market, ODS safety reviewers were instructed to help make this happen.

Later, when CDER held an advisory committee meeting to get support for bringing Lotronex back on the market, the presentation on ways to manage its reintroduction was carefully shaped and controlled by OND. When it came to presenting the range of possible options for how Lotronex could be made available, the list of options was censored by OND.

The day before the advisory meeting, I was told by the ODS reviewer who gave this presentation that the director of the reviewing office within OND that approved Lotronex in the first place came to her office and removed material from her talk. An OND manager was managing an ODS employee. When informed of this, ODS senior management ignored it. I guess they knew who was calling the shots.

Rezulin was a drug used to treat diabetes. It also caused acute liver failure, which was usually fatal unless a liver transplant was performed. The pre-approval clinical trials showed strong evidence of liver toxicity. The drug was withdrawn from the market in the United Kingdom in December 1997. With CDER and the Office of New Drugs, withdrawal didn't occur until March 2000.

Between these dates, CDER relied on risk management strategies that were utterly ineffective and it persisted in relying on these strategies long after the evidence was clear that they didn't work. The continued marketing of Rezulin probably led to thousands of Americans being severely injured or killed by the drug. And note, there were many other safer diabetes drugs available.

During this time, I understand that Rezulin's manufacturer continued to make about $2 million per day in sales.

The Big Picture

The problem you are confronting today is immense in scope. Vioxx is a terrible tragedy and a profound regulatory failure. I would argue that the FDA, as currently configured, is incapable of protecting America against another Vioxx. We are virtually defenseless.

It is important that this Committee and the American people understand that what has happened with Vioxx is really a symptom of something far more dangerous to the safety of the American people. Simply put, FDA and its Center for Drug Evaluation and Research are broken.

Now, I'm sure you have read the recent proposal to have the Institute of Medicine perform a review of CDER and its drug safety program and make recommendations for fixing things up. Don't expect anything meaningful or effective from this exercise. Over the history of CDER's drug safety program, a number of similar reviews have been done.

In the late 1970's, I believe that a blue ribbon panel recommended that there be an entirely separate drug safety operation in FDA with full regulatory authority. It wasn't implemented. During the 1980's and early 1990's, CDER organized its own program reviews of drug safety.

The basic premise underlying each of these reviews was that the problem was with the drug safety group; it didn't fit into the Center. So, the charge given to the review panel members was always framed as "figure out what's wrong with drug safety, and tell us what to do to get it to fit in."

There was and is an implicit expectation that the status quo will remain unaltered. The organizational structure within CDER is entirely geared towards the review and approval of new drugs. When a CDER new drug reviewing division approves a new drug, it is also saying the drug is safe and effective.

When a serious safety issue arises post-marketing, their immediate reaction is almost always one of denial, rejection and heat. They approved the drug so there can't possibly be anything wrong with it. The same group that approved the drug is also responsible for taking regulatory action against it post-marketing. This is an inherent conflict of interest.

At the same time, the Office of Drug Safety has no regulatory power and must first convince the new drug reviewing division that a problem exists before anything beneficial to the public can be done. Often, the new drug reviewing division is the single greatest obstacle to effectively protecting the public against drug safety risks.

A close second in my opinion, is an ODS management that sees its mission as pleasing the Office of New Drugs. The corporate culture within CDER is also a barrier to effectively protecting the American people from unnecessary harm due to prescription and OTC drugs.

The culture is dominated by a world-view that believes only randomized clinical trials provide useful and actionable information and that postmarketing safety is an afterthought. This culture also views the pharmaceutical industry it is supposed to regulate as its client, over-values the benefits of the drugs it approves and seriously under-values, disregards and disrespects drug safety.

Finally, the scientific standards CDER applies to drug safety guarantee that unsafe and deadly drugs will remain on the US market.

When an OND reviewing division reviews a drug to decide whether to approve it, great reliance is placed on statistical tests. Usually, a drug is only approved if there is a 95% or greater probability that the drug actually works. From a safety perspective, this is also a very protective standard because it protects patients against drugs that don't work.

The real problem is how CDER applies statistics to post-marketing safety. We see from the structural and cultural problems in CDER, that everything revolves around OND and the drug approval process. When it comes to safety, the OND paradigm of 95% certainty prevails. Under this paradigm, a drug is safe until you can show with 95% or greater certainty that it is not safe.

This is an incredibly high, almost insurmountable barrier to overcome. It's the equivalent of "beyond a shadow of a doubt." And here's an added kicker. In order to demonstrate a safety problem with 95% certainty, extremely large studies are often needed. And guess what? Those large studies can't be done.

There are 2 analogies I want to leave you with to illustrate the unreasonableness of CDER's standard of evidence as applied to safety, both pre- and post-approval. If the weather-man says there is an 80% chance of rain, most people would bring an umbrella. Using CDER s standard, you wouldn t bring an umbrella until there was a 95% or greater chance of rain.

The second analogy is more graphic, but I think it brings home the point more clearly. Imagine for a moment that you have a pistol with a barrel having 100 chambers. Now, randomly place 95 bullets into those chambers. The gun represents a drug and the bullets represent a serious safety problem. Using CDER's standard, only when you have 95 bullets or more in the gun will you agree that the gun is loaded and a safety problem exists.

Let's remove 5 bullets at random. We now have 90 bullets distributed across 100 chambers. Because there is only a 90% chance that a bullet will fire when I pull the trigger, CDER would conclude that the gun is not loaded and that the drug is safe.