A new observational study comparing the controversial Avandia diabetes pill found an increased risk of various cardiovascular problems compared with Actos, a similar drug but one that hasn’t raised as many concerns. Yet one co-author, FDA reviewer David Graham, recently wrote top FDA officials over concerns that agency supervisors hadn’t given clearance for the study to be submitted for publication. (You can see Graham’s email to FDA commish Margaret Hamburg further down).

The May 28 manuscript indicates the authors reviewed records of 227,571 Medicare patients with an average age of 74.4 years who were followed for up to three years after starting either of the two pills. The results - GlaxoSmithKline’s Avandia increased the risk of stroke by 27 percent; heart failure by 25 percent; death by 13 percent; acute myocardial infarction or death by 11 percent; AMI, stroke, or death by 14 percent and AMI, stroke, heart failure or death by 17 percent.

The authors write the number needed to harm was 59 patients treated with Avandia for one year to produce one excess case “of any of our outcomes.” They added this translates to 48,000 excess events attributable to Avandia among patients 65 years or older between 1999 and June 2009. And since 62 percent of Avandia use has been among people younger than 65, they estimate the national impact is probably 100,000 or more.

Their conclusion: The impact of risks is “substantial.” And they estimate those 48,000 patients experienced serious cardiovascular harm or death as a result of using Avandia instead of Actos. “The national impact has been undoubtedly much greater because our estimate does not account for (Avandia) use among patients under the age of 65 years, where an estimated 61.6 percent of (Avandia) use occurred through mid-2009. This would place (Avandia) in the same category as (Vioxx)with respect to magnitude and severity of population harm.”

The timing is interesting. Next month, an FDA advisory panel will meet to review Avandia safety and the agency is struggling over the validity of allowing Glaxo to conduct a long-term study (see this). Graham has been saying for years Avandia should be withdrawn and a Senate Finance Committee report released earlier this year revealed bickering inside the FDA over his contention (go here to find the report).

UPDATE: An FDA spokeswoman tells us “we didn’t suppress this.” Graham’s supervisor, she says, indicated the manuscript could be submitted and provided authorization in time for a June 4 deadline, although she couldn’t say when exactly. She also denied the supervisor was afraid to do so. Graham, by the way, is the same reviewer who estimated Vioxx caused more than 27,000 CV events just before the painkiller was withdrawn, and harshly criticized the FDA at a Congressional hearing for not moving faster to push Merck to act and protecting the public (background). Graham has not responded to messages. Several other co-authors declined to comment on the delay. We are awaiting word from the FDA.

UPDATE: Glaxo writes that “it is unclear whether this study has been peer reviewed, and until then, it would be premature to comment. However, it is important to note that there are inherent limitations with retrospective observational studies…Randomized clinical trials remain the gold standard…Results from six randomized clinical trials…show that Avandia does not increase the overall risk of heart attack, stroke or death.”

From: Graham, David J [mailto:David.Graham1@fda.hhs.gov]
Sent: Friday, May 28, 2010 3:31 PM
To: Hamburg, Margaret; Sharfstein, JM
Cc: Graham, David J
Subject: TZD study update

Dear Drs. Hamburg and Sharfstein,

Except for a few minor details, we have completed our study comparing
the cardiovascular risks of rosiglitazone vs. pioglitazone in Medicare elderly.

With over 227,000 exposed patients, we found that
rosiglitazone increases the risk of stroke by 27% (11-44), heart
failure by 25% (16-34), death by 13% (4-23), AMI or death by 11%
(3-18), AMI, stroke, or death by 14% (7-21), and AMI, stroke, heart
failure or death by 17% (12-23). The risk of AMI surviving to
hospitalization was increased by 6% (-5 to +17), but not statistically
significantly so. We suspect that fewer elderly patients survive
their AMI long enough to reach hospital so that AMI/death is a better
measure.

The number needed to harm was 59 patients treated with rosiglitazone
for one year to produce one excess case of any of our outcomes. This
translates to 48,000 excess events attributable to rosiglitazone among
patients age 65 years or older between 1999 and June 2009. Given that
62% of rosiglitazone use has been in patients below age 65, the actual
national impact is probably 100,000 or more.

JAMA is very interested in our manuscript and we would like to submit
it before next Friday, June 4. Gerald Dal Pan, my supervisor is
prepared to sign the clearance form (the paper has a disclaimer and
does not represent an official FDA position) but won’t unless Dr.
Woodcock and Dr. Jenkins approve. He is afraid to act, even though he
is the “clearing official.”

My CMS co-authors are also anxious to submit the manuscript and feel
that they have a duty to their customers, Medicare patients, to bring
these results to public notice in a scientific journal as soon as
possible. The idea of being blocked from doing this by a sister
Agency is a source of concern to them and to me.

In late 2004, CDER management suppressed the publication of a study I
conducted using data from Kaiser California that showed increased AMI
risk with rofecoxib. This was done in an effort to downplay the
seriousness of their prior poor decision-making in leaving rofecoxib
on the market. So you can understand that I am very sensitive to
anything that remotely smells like suppression or censorship.
I am asking for your assistance in ensuring that we are able to submit
our manuscript to JAMA before June 4.

Best regards,
David

[Editor's note: We changed the headline - which first read: 'Is The FDA Suppressing An Avandia Study?' - after the FDA eventually responded to our request for a comment].