Avelient BioPharm Blog

FDA Balancing Act

The Food and Drug Administration (FDA) has come under a lot of scrutiny lately over safety concerns of approved drugs that were on the market but had to be recalled because of some serious adverse events reported by their customers. We can view mainly Merk’s Vioxx as the catalyst for this interest and examination into the way the FDA does business, and in general I’ve noticed a trend in recent months towards a more conservative approach in dealing with drugs in the midst of the approval process and those that are already on the market. An article I saw today in Pharmaceutical Executive magazine entitled, “FDA’s Approvable Problem,” seemed to support the theory and took me for an in-depth look into one of the aspects of the FDA approval process in the United Sates.

As one might think, the FDA has a process for approving and rejecting drugs sold in the United States. From what I remember from my days working at one of the large pharmaceuticals as a consultant in their regulatory department, few drugs are actually rejected; companies don’t even want to risk rejection, because costs to correct problems and then re-apply for approval can be high, and there’s probably a certain amount of stigma attached to a drug that had been rejected its first time around. Approved drugs, on the other hand, have reached the holy grail of the process, and can start showing returns for the millions of dollars that have been spent to develop and market them. However, there is a recent trend of “approvable” letters that are being sent out in larger numbers from the FDA in response to new drug applications (NDAs). These letters are like purgatory for NDAs — they’re not quite approved for consumer use, yet they’re not quite rejected.

Proof of the increase in the use of this device was substantiated thanks to the effort of Chris Milne of the Tufts Center for Drug Development. As of October 1st, 2007, 36 approvable letters had been issued by the FDA since January 2006. By comparison, 35 similar letters had been issued between 2001 and 2004.(1) The approvable vortex generally appears to put the drug into a suspended animation of sorts until certain issues can be resolved as outlined by the FDA in their response. While the prospect of being an approvable drug sounds encouraging, the reality is that the average time a drug remains approvable is 20 months, and drug makers must expend additional resources in order to bring the necessary evidence to the FDA for the drug to be approved. In some cases, as highlighted by the article, this will cause the drug company to throw out the NDA altogether, claiming the requested data would be impossible to retrieve in a timely fashion. Some examples cited:

• After the FDA issued an “approvable” letter for its diabetes drug, Pargluva (muraglitazar), Bristol-Myers Squibb ended up withdrawing the drug because it claimed it would take 5 years to gather the data requested in the letter.
• Sanofi-Aventis’ Acomplia, intended to fight obesity, got an approvable letter from the FDA in 2006 but then was given an unfavorable review from an FDA advisory committee in June this year prompting the French firm to withdraw its NDA. For more information on this, you can see the 2 articles I wrote about the drug here, before the FDA released its findings and here, after the FDA released its findings.
• The anticipated diabetes blockbuster for Novartis, Galvus (vildagliptin), received its US approvable letter in February 2007, but the additional clinical trials required by the FDA are anticipated to push its launch to 2009, putting it well behind its competition Merk and their drug, Januvia. The projected cost for the delay is $500 million in unmet projections.

There is a question as to whether these delays can be attributed to safety concerns, politics, or a little of both. The article indicates that the trend to send an approvable letter indicates that the FDA is raising the standard for drug safety, a sentiment supported by the fact that most of its letters ask for additional data regarding a specific “safety signal” or more general information around heart and liver toxicity. We can surmise this more conservative approach is probably due to pressure it’s receiving from congress to ensure another Vioxx scandal doesn’t ensue, yet they proclaim a desire to recapture their image of being a guardian of public health, unshackled by the burden of politics.

If I had to choose between one or the other, I would prefer an FDA that didn’t answer to lobbyists or politicians, and wasn’t under the pressure to approve blockbuster drugs without the benefit of time to truly study their effect on human subjects. I think most of the confusion stems from the fact that the FDA had no consistent leadership from about 2001 until last spring, when Andrew von Eschenbach was appointed to head up the organization. With his appointment and an in-depth examination of how the organization is run, I’m confident they can regain some of their luster as the custodian of the food and drug market in the US.

In examining the available data, the organization might not be as bad off as it may initially seem. As Tufts’ Chris Milne states in the article, “Withdrawals of Drugs happen in a cluster — every three to five years. But the actual rate of withdrawals is consistent over time at three percent.” Hence, the FDA doesn’t seem to be approving riskier drugs as a result of changes in the length of its approval process. What does need to be better communicated to the public, perhaps, is that there is a safety-to-benefit ratio that is considered for approval of a drug, and for each patient a drug’s advantages need to be weighed against its risks. Chances are that a change to a length in the approval process in order to appease political forces won’t change this safety-to-benefit ratio, and won’t prevent something like Vioxx from happening again.

I find all these demands for a change to the FDA approval process a little overzealous, and while I think a strong, lean organization is necessary to ensure drug safety for all, even the most efficient of organizations will make mistakes. We have a tendency to point fingers at a government agency to protect us in extreme scenarios, and when something unusual occurs we feel the need to “fix” the problem. We must make changes with the anticipation that we’ll never have a perfect organization because the needs of the public will demand change within even the most established organizations.

We saw an increase in the amount of time it takes for people to get through the airport after 9/11/2001 in the name of safety. We needed someone to make us feel like there was a watchdog, a guardian protecting our interest in the skies. Yet, news agencies continually report how mistakes are made at airports and publicized as a horrific collapse of the organization that is meant to protect us. Which do we want, better safety or a more convenient, quicker airport experience? Is the FDA destined for the same fate? Do we anticipate long, drawn-out approval processes for benign drugs while the occasional toxic drug will slip through the cracks? Must we reexamine the organization every time it will make a mistake in the future and have our politicians demand change and reorganization and simplification?

I don’t know what the answer to any of these questions is, but I do know that things seemed a lot simpler when I was younger and regulations didn’t seem to burden the every move of government agencies that were meant to protect us. We almost seem to want to create a scandal where none exists.

It seems to me that the FDA does need to invite change into its charter, but it needs to become a more lean organization. Its established process for drug approvals seems to be thorough enough, and you can see a basic flowchart of a standard approval process here. Perhaps what needs to be better established is what the FDA can do after a drug gets into a market, and establishing rules for Pharmaceutical companies to better communicate the risk-to-benefit ratio of their drugs to the doctors that prescribe them.

What are your thoughts? How well do you think the FDA works? Do you think it actually needs a change? Do you feel the FDA is largely responsible for the Vioxx issue, or is it more in the hands of its owner, Merk? Can you compare the agency to its counterparts in other countries? Do you feel we could learn a lesson from them?

I’d love to hear what you have to say! And please, I encourage you to check out the full article that I analyzed for this blog in this month’s issue of the Pharmaceutical Executive! You can get the full text of the article online here.

(1) See “FDA’s Approval Problem,” Walter Armstrong, Senior Editor, Pharmaceutical Executive, November 2007, pp 56-64, 118.