Avandia – The Fallout

Avandia – The Fallout

Over the weekend the Senate Committee on Finance released a report that looks to put the final nail in the Avandia coffin. According to a letter attached to this report by senators Max Baucus Chairman of the committee and Charles E. Grassley Ranking Member of the committee; “The totality of evidence suggests that GSK was aware of the possible cardiac risks associated with Avandia years before such evidence became public.… Based on this knowledge, GSK had a duty to sufficiently warn patients and the FDA of its concerns in a timely manner. Instead, GSK executives intimidated independent physicians, focused on strategies to minimize findings that Avandia may increase cardiovascular risk, and sought ways to downplay findings that the rival drug ACTOS (pioglitazone) might reduce cardiovascular risk.”

GlaxoSmithKline (NYSE:GSK), the company behind Avandia, responded to this report with a letter of their own which stated;   The Staff Report of the Senate Committee on Finance draws conclusions on the safety of Avandia (rosiglitazone) that are based on analyses that are not consistent with the rigorous scientific evidence supporting the safety of the drug. In addition, the report cherry-picks information from documents, which mischaracterizes GlaxoSmithKline’s comprehensive efforts to research Avandia and communicate those findings to regulators, physicians and patients. In fact, the safety and effectiveness of Avandia is well characterized in the label approved by the FDA.”

Before we examine the fallout from this battle between GSK, the FDA and the United States Senate it’s worth noting a few facts. In 2006 worldwide sales of Avandia peaked at $2.6 billion, in 2009 worldwide sales of Avandia had fallen to $721 million. For all practical purposes Avandia is dead in the eyes of physicians who, as the sales numbers indicate, have been switching patients on Avandia to other medications.

Agree or disagree with the findings of the now famous meta-analysis by Dr. Nissen, the Avandia controversy has forever changed the way the FDA examines medications for patients with type 2 diabetes. As a direct result of this controversy the FDA changed the requirements for new drug applications, requiring companies to provide detailed cardiovascular data. The controversy has also changed the mindset of the FDA who now appears to be looking for reasons NOT to approve new drug applications.

In typical Washington fashion these distinguished Senators are looking for their fifteen minutes of fame as they try and position themselves as crusaders of the public good, protecting the public from the big, bad pharmaceutical companies while at the same time chastising the FDA for not doing their job. In their letter that accompanies the report the Senators state; “As senior members of the United States Senate and Chairman and Ranking Member of the Committee on Finance (Committee), we have a duty under the Constitution to conduct oversight into the actions of executive branch agencies, including the Food and Drug Administration (FDA). In this capacity, we must ensure that FDA properly fulfill their mission to advance the public’s welfare, safeguard the nation’s drug supply, and protect patients participating in clinical trials.”  

While Diabetic Investor has taken issue with how the FDA conducts their affairs this is one instance where we actually feel sorry for the agency. From the very beginning of this whole controversy the FDA has been in a no win situation. The agency was ambushed when the meta-analysis was “leaked” to the media and basically racked over the coals by members of the Senate when they conducted their public meetings on the subject.

As Diabetic Investor said back when this controversy first became public, all the Senators really wanted was their moment in front of the TV cameras and that nothing substantial would come of their pathetic attempts to look like they actually cared about patients with diabetes.  Caught in the crosshairs was the FDA who must feel they’re damned no matter what they do. The reality is these Senators are completely clueless when it comes to the complexities of drug approvals and are absolutely brain dead when it comes to understanding the complexities of diabetes. The fact is there is no such thing as an absolutely safe drug and even after surviving the rigorous and expensive approval process there are no guarantees that once on the market drugs won’t develop adverse events that did not reveal themselves during the approval process. Something we experienced with both Avandia and Actos when we learned nearly seven years after their approval of the increased incidence of bone fractures.

It’s no wonder the FDA has become so conservative in their approach to new drug applications. The fact is the agency can only make decisions based on all available data and as we have seen time and time again problems can arise years after a drug is on the market. The agency at the same time must also walk a delicate tightrope. They see diabetes growing at epidemic rates and they are acutely aware of the many co-morbidities associated with diabetes. They know all too well that nearly two-thirds of all patients with diabetes are not adequately controlling their diabetes. Finally the agency knows diabetes is not just a healthcare issue but an economic issue as well. Given this set of circumstances the FDA must make a decision delicately balancing a drug’s potential benefits with what can an unknown set of risk factors. 

This scenario is difficult by itself but when you add in the fact that heaven forbid a mistake is made or an unexpected problem arises, that you will be put in front of a Senate committee who cares only about looking like they are doing something and be publicly humiliated, it’s understandable that you just might be a little gun shy while looking at the next new drug application.

Perhaps this is the reason for the article that recently appeared in the New England Journal of Medicine by Mary Parks, M.D. director, Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research and Curtis Rosebraugh, M.D., M.P.H. director of the FDA’s Office of Drug Evaluation as to why in spite of several concerns over its safety profile the FDA approved Victoza®. (The Senate report on Avandia includes two memos written to Dr. Parks.) The fact is no one is really quite sure if Victoza® causes thyroid cancer. It’s also true that for all practical purposes there is no study that can be done that would conclusively prove of a link between Victoza and thyroid cancer. As Dr. Park points out in the article; “The incidence of medullary thyroid cancer in the United States is approximately 600 cases per year — making it infeasible to conduct a clinical trial to detect an increased risk of this type of cancer associated with liraglutide exposure.”

Understanding they are caught between a rock and a hard place, the FDA took the conservative path and approved Victoza while putting a black box warning on the drug’s label. The FDA knows that in the real world physicians are unlikely to widely prescribe a new drug that comes to market with a black box warning.  While Novo Nordisk (NYSE:NVO) would disagree the FDA has effectively made Victoza DOA in the eyes of physicians, who must balance helping their patients with the concern that one day they could be sued for prescribing a drug that carries a black box warning. Considering that physicians have other options why take the chance.

Sitting around and watching all this are the folks at Amylin (NASDAQ:AMLN) and Lilly (NYSE:LLY) who are anxiously waiting for March 5th, the PUDFA date for their once-weekly GLP-1 Byetta LAR. As Diabetic Investor has previously reported based on all available public data there is no reason for the FDA not to approve LAR. Unlike Victoza, LAR is basically a line extension of Byetta, a twice daily GLP-1, which has been on the market for nearly five years and is being used by over one million patients. Again based on all available data there is no reason to believe that the FDA will approve LAR with any label warnings. While Novo claims the thyroid cancer issue is a class effect, there is no credible evidence to support this claim.   

The wildcard, which surly has the folks at Amylin and Lilly nervous, is will the FDA take extra precautions with LAR given the current environment in Washington. As we have noted before there is no publicly available data that would lead Diabetic Investor to believe that LAR will not be approved. However, with March 5th just days away and the Avandia story making headlines it wouldn’t surprise Diabetic Investor IF the FDA delayed their decision on LAR. TO BE CLEAR HERE DIABETIC INVESTOR HAS NO DIRECT KNOWELDGE THAT THE FDA WILL DELAY THEIR DECISION ON LAR AND WE BELIEVE LAR WILL RECEIVE APPROVAL WITH NO BOXED WARNINGS. Still we are cognizant that drug approvals are not always based on the facts and that the FDA, for good reasons, is sensitive to the convoluted environment they must work in.

The fact is these Senators in their zest to look like they are actually doing something have created more problems and provided no true answers. As H. L. Mencken noted; “The typical politician is not only a rascal but also a jackass, so he greatly values the puerile notoriety and adulation that sensible men try to avoid.” Or as Boies Penrose, a former Senator from Pennsylvania eloquently stated “Public office… is the last refuge of the incompetent.”

That being said Diabetic Investor questions how GSK has responded to the Senate report. The company has seen the sales numbers and understands that thanks to the Senate class action attorneys have a wide grin on their faces. They also understand they will soon have new drug applications in front of the FDA. As screwed up as things may be in Washington Diabetic Investor does not see the value in going to war with the agency that controls your future. You can call the folks at the FDA many things but stupid is not one of them.

Finally Diabetic Investor is beginning to wonder when the FDA and everyone else for that matter will take a closer look at the use of meta-analysis. As Diabetic Investor reported last week when a report came out that indicated that patients taking statins were at increased risk of developing diabetes, a report that was conducted using meta-analysis.  According to this meta-analysis statin therapy was associated with a 9% increased risk for developing diabetes. Never mind that statin therapy has numerous well documented benefits or that patients using statins would likely be predisposed to developing diabetes nor should we consider that statins have a long and established track record. Nope, let’s ignore all these facts and release a study that gives patients another reason not trust the drugs they are taking, drugs that could well save their lives.

The bottom line here is that as hard as it may be to accept every drug, prescription or over the counter, carries with it some degree of risk. That no matter how many studies are conducted there are no guarantees that a drug that looks safe when it’s approved may not develop issues later on. As Edmund Burke once said; “You can never plan the future by the past.”

It would one thing if the Senators instead of looking for face time on TV, actually offered some constructive ideas on how we can balance the needs of the public against the uncertainties of science. Instead of railing against the failings of the FDA, why not provide some clear guidance as to what is and is not an acceptable level of risk. Frankly any idiot can criticize after the fact, it takes true leadership to get past placing blame and offer solutions to the problem. But the sad fact leadership is what’s missing in Washington.

So just what have these Senators accomplished? They have created an environment that’s next to impossible to operate in. As Diabetic Investor also pointed out last week when we wrote about the upcoming FDA panel meeting on insulin pumps, the agency sensitive to criticism they are not doing their job wants to show they are protecting the public. As we noted Medtronic (NYSE:MDT) may be deserving of criticism, the FDA wanting to show how tough they can be is likely to go hard at the company.  If nothing else the company is guilty of bad timing. As Sidney Hook once wrote; “Without [“the sense of timing”], great intelligence can be ineffective. Coupled with strong will, it can carry the mediocre mind to the heights.”

Lastly this report is just another hurdle facing the big, bad pharmaceutical industry. Already viewed as villains in the eyes of the public and easy prey for politicians, they must somehow navigate through the complex maze we call the FDA. No wonder when asked about the agency and the prospects of a particular drug going through the approval process that executives from the company offer nothing more than the customary; “We don’t comment on what the FDA will or will not do.” How could they as anything they would say, even it was based on actual discussions with the agency, could turn out to be a misstatement. Keep in mind this is an agency that has history of changing the rules of the game while the game is being played. As has been said before; “Better to be thought a fool, than to open your mouth and remove all doubt.”

So we ask again; just what have these Senators accomplished?