Avandia, Heart Attacks & An Internal FDA Battle
22 CommentsBy Ed Silverman // February 20th, 2010 // 1:03 am
Avandia is needlessly causing hundreds of cases of heart attacks and heart failure each month, according to confidential government reports, The New York Times writes. Moreover, if every diabetic taking Avandia were given Actos instead, about 500 heart attacks and 300 cases of heart failure would be avoided each month. The pill was linked to 304 deaths during the third quarter of 2009, and a report by the FDA’s David Graham and Kate Gelperin concludes the pill should be yanked (Graham said this in 2007 - look).
Some FDA officials want Avandia withdrawn because they believe a safer alternative exists, the Times adds, noting others insist studies offer contradictory info and Avandia should remain an option. GlaxoSmithKline, which makes the pill, says it studied Avandia extensively and “scientific evidence simply does not establish that Avandia increases” risk of heart attacks. The debate, which began with a meta-analysis in The New England Journal of Medicine (see here and here) is intensifying thanks to disagreement over a new clinical trial (see the FDA report on the trial here) and a Senate probe concluding Glaxo should have warned of risks earlier (press release).
READ THE 342-PAGE SENATE REPORT RIGHT HERE
In a December 2009 internal memo, FDA official Janet Woodcock, wrote “there are multiple conflicting opinions” about Avandia within the agency (see here), and she ordered an advisory committee, expected to meet this summer, to reconsider whether the drug should be sold. FDA commish Margaret Hamburg tells the Times she’ll wait for the committee recommendations but is reviewing the Senate findings, which are expected to be released on Monday. The investigation criticizes Glaxo for failing to warn patients years ago that Avandia was potentially deadly.
“Instead, GSK executives attempted to intimidate independent physicians (see here), focused on strategies to minimize or misrepresent findings that Avandia may increase cardiovascular risk, and sought ways to downplay findings that a competing drug might reduce cardiovascular risk,” according to the report from Max Baucus, a Montana Democrat, and Chuck Grassley, an Iowa Republican, which the Times obtained.
Graham and Gelperin argued in separate internal reports that a new Glaxo study called TIDE is “unethical and exploitative” because patients given Avandia face greater risks than those given Actos, with no promise of added benefit. The trial may include patients who had heart attacks or chest pains even though foreign drug regulators warned against Avandia’s use by such patients. “The safety of the study itself cannot be assured and is not acceptable,” one report concludes.
The internal reports, which were dated October 2008 and not made public until now, were later overruled by other FDA officials, and Glaxo is currently enrolling patients in the TIDE trial, which isn’t expected to be completed until 2020, although the company is hoping to report some results to the FDA by 2014. But by 2012, the Times notes, the Avandia patent expires.
Grassley said the internal agency battle shows the FDA needs to be reorganized to give more power to safety officials over their counterparts who approve drugs and deal more directly with industry. “It doesn’t make any sense to have these experts who study drugs after they have been on the market for several years under the thumb of the officials who approved the drug in the first place and have a natural interest in defending that decision,” Grassley tells the Times. “The Avandia case may be the most alarming example of the problem with this setup.”
Glaxo issued a statement saying the report “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.” Here is the complete statement.
patrons99
Yes, I suspect that there is ALSO an internal battle within the FDA with respect to use of the LABA’s (long acting beta agonists) in treatment of asthma. Yet, they still remain in the marketplace. Waves of dangerous drugs (and biologicals) remain in the marketplace, even after significant safety signals are identified.
http://articles.latimes.com/2010/feb/19/nation/la-na-fda-asthma19-2010feb19
http://www.opednews.com/populum/print_friendly.php?p=Was-Asthma-Clinical-Resear-by-Robert-Davidson-091126-883.html
Sometimes risk-benefit is a very close call. A relevant question to ask might be: whether there are SAFER and effective alternatives to treating a particular disease condition.
Matthew Holford
I remember reading the SFC’s report, shortly after it was published. I laughed!! How I laughed - it was brilliantly written, and contained the quotation of the millenium, thus far, when it described GSK’s behaviour as
“…less than stellar.”
Ouch! It also revealed Garnier to be a liar, when he denied in print knowing anything about the Buse affair, only for emails to come to light later on which he was included in the circulation list (the infamous “Avandia Renegade” thread, which I think was initiated by Tacky Yamada).
Finally, the Report expressed a belief that this sort of intimidation of academics is widespread, not limited to a few, isolated cases, and the Buse affair could actually be a case study for a pattern of behaviour.
Like I wrote: Ouch!
Matt
Matthew Holford
Oh, incidentally, I wrote to the Gates Foundation, asking if they knew about Yamada’s conduct. I can’t really remember whether it stonewalled me, or came back with some legally-drafted bollox to the effect that “that’s somebody else’s problem, not ours”. Either way, that tells me all I need to know about the Gates Foundation.
Matt
pharmavet
Ed, could you please send the congressional report as a compressed file. It’s taking a long time to open it up.
Thanks.
elmore
This is especially interesting–and scary–in light of the Supreme Court ruling about corporate political donations.
Justice in MI
Hi Elmore–How are you linking this case to the Supreme Court ruling? Meaning, is there something you’re seeing about it that goes beyond what we know from other cases?
elmore
I was thinking about the potential for a company to spend virtually unlimited amounts of money on candidates who did not push for close scrutiny of pharma claims, and negative advertising on those who did.
Justice in MI
That would be a lot of companies, not to mention the Chamber of Commerce, National Alliance of Manufacturers, Big Tobacco, and the like!
Indeed, I think we’ll see more lobbying money focused on policy issues than on specific candidates. So I think we can anticipate lobbying toward:
1. FDA preemption, next act (Dan Troy is Glaxo #2).
2. Rolling back the very small (some would say, infinitesimal) positive changes at FDA.
3. Unlimited off-label promotion will itself be promoted.
4. Meaningful health care reform will be buried even deeper than it already is.
5. DOJ will fold up shop on FCA cases.
6. Whistleblower protection will be further eroded and whistleblowing will be further de-incentivized.
For starters…
Condor
JiM — I’d love to say that I think you are wrong about your six “for starters” items (in view of the recent Supreme Court corporate spending on political campaigns ruling) — but I sincerely fear that you are (mostly) right.
Great stuff as ever, Ed! Thanks for hostin’ such a comprehensive joint — and, on a weekend too.
Namaste
David
Wow, as if Troglitazone wasn’t bad enough.
To be honest, I’ve been concerned about the increased risk of heart issues shown in some studies for use of Actos as well…
http://healthlifeandstuff.com/2009/09/actos-side-effects-problems/
Is there a problem with the whole class of medications?
patrons99
Excellent point, David. Similarly, I’ve had concerns as to Celebrex, after nearly 200,000 Vioxx-related deaths. Is it drug-specific or class-specific?
belmont
Avandia- wow this news has been all over- lot of people looking to get off this.
Elaine
So many travesties so little time. Where are the prescribers in all of this? Surely they don’t just trust FDA’s approvals …or do they?
The issues become redundant for the reading but tragic and life-altering for the citizens who suffer the consequences of the status quo. This said, do FDA approvals kill people or do prescribers?
You can have transparency up the wazzu but the bottom line will always be FDA’s reliance on industry for the “science,” a process seriously flawed at the getgo. Anything after is moot.
Jack Saturday
Look for Celebrex to go where Avandia’s going. Pfizer successfully deployed the same strategy as GSK has used–a long study that would keep the drug alive as long as possible (before patent expires). Hopefully, the plug will be pulled by dmb before too many people are sunk.
JaT
What would we do without Senator Grassley.
Something in the way of Post Marketing Commitments is very wrong. I don’t like the idea of Fast Tracked drugs. Knowing how altered products are approved- I don’t want those either (that about covers…) because they generally have no commitment. It shouldn’t take this many years and so many losses to come to this sort of conclusion.
Side Note:
When discussing Quality by Design with Prabir Basu he used Toyota as one of the gleaming examples. I wasn’t going to mention it- though it’s been almost killing me not to. Mr. Toyoda now having to go and explain himself makes me wonder when some other similar sessions might be warrented.
pharmavet
The Senate report is dated February 18, 2010. Assuming the usual two day leak/embargo routine, the stock price on the LSE was barely dented. This is because declining sales is already “baked” into the share price, and the company’s first obligation, like it or not is to its shareholders. Even with the decline, Avandia is on track for about $4.7 billion in sales worldwide. Not too shabby, I’d say.
JaT
Shouldn’t their first obligation be to consumers?
Sonal Singh
I am glad the truth is finally catching up with the FDA and GSK
We wrote this in 2007
” Regulatory agencies ought to reevaluate whether rosiglitazone should be allowed to remain on the market. Health plans and physicians should not wait for regulatory actions. They should avoid using rosiglitazone in patients with diabetes who are at risk of cardiovascular events, especially since safer treatment alternatives are available. ”
http://jama.ama-assn.org/cgi/content/full/298/10/1189
patrons99
Shouldn’t FDA’s first obligation be to the public?
I blame it on the PDUFA. The system needs to be changed. The current system is broken. With the initial enactment of the PDUFA in 1992, FDA became a client of pharma. Its a “pay-to-play” system. Most economists love it. Who bears the burden? The public. You can’t measure its effect in economic terms. It must be measured with hard clinical endpoints, in terms of hospitalizations and deaths. Numbers of drugs withdrawn by FDA is a totally bogus surrogate endpoint because so many dangerous drugs remain in the marketplace…they are NOT WITHDRAWN. This makes the safety track record under the PDUFA appear to be wonderful. It is fallacious economic arguments like “number of drugs withdrawn” that lead Congress to renew the PDUFA every few years.
http://www.opednews.com/populum/print_friendly.php?p=Are-Big-Pharma-and-the-PDU-by-Robert-Davidson-091126-534.html
Waves of dangerous drugs and biologicals will continue to be “approved” and remain in the marketplace long after significant safety signals are identified. The approvals are expedited under the PDUFA. Illegal off-label marketing begins almost immediately upon market approval. It’s really all about time in the marketplace. Time in the marketplace is literally worth billions to pharma. There is a drug safety crisis in this country.
The drug safety crisis is certain to get much worse. For new biologicals “approved” with the non-inferiority margin as the choice of controls, political expediency has become the new standard for approval. Safety and efficacy have become superfluous. Now all biopharma has to show to obtain expedited approval, is that their new biological is no more acutely toxic than existing biologicals.
Gardasil is a case in point. Instead of a placebo control arm in the pivotal studies for approval, FDA allowed aluminum adjuvants to be the placebo arm. Prevar 13 is another case in point.
http://www.pharmalot.com/2009/11/pfizer-vaccine-missed-some-goals-fda-review/
J.O.
It is ironical that tort reform, something that seemed to make sense, has turned out to be a catalyst for the end of our democracy and a threat to our health and safety. Some politicians want tort reform included in healthcare reform. If that happens, the winners will be those in the pocket of Big Pharma and the insurance industry. The losers will be the rest of us. FDA preemption will be on the agenda. This will happen through state legislatures who sell out to pharma. i.e., Michigan. With protection from product liability, drugs will become even more dangerous, off-label marketing will increase, more people will become ill (causing an increase in the sale of drugs), more people will die. Like Michigan, other states won’t be able to hold drug makers accountable; states will not be able to recover Medicaid cost that rightfully belonged to the wrong-doers. Publicity about bad drugs will get even less attention than they do now, and there will be very little main-stream media reporting of this trend; most Americans won’t know what hit them till it’s too late.
One thing is reassuring. Eighty per cent of Americans polled thought the Supreme Court got it wrong in regards to corporations’ unlimited political advertising. People became aware of that misguided decision because the President mentioned it in his State of the Union address. If he hadn’t, would “the people” know about it? I wonder what the vote would be if the public understood what is happening to their civil liberties with preemption and tort reform?
pharmavet
“Pay-to-play” can benefit the public. Specifically, the FDA is now considering imposing user fees for ANDA’D generic drugs, which will speed up the process of generic approvals. Without user fees, the average approval time for generics has slipped from 16 to 26 months in recent years. The generic industry is generally in favor of this idea. The additional funding will allow FDA to hire more reviewers in the generic drug division. Two other things will help: 1) outlaw “pay-to-delay” contracts, 2) shorten the automatic stay of ANDA approval from 30 to 12 months following an innovator patent infringement suit after a Paragraph IV Certification filing.
Bob Hagstom
This is an interesting article.