After six years of public
debate, an FDA panel put to rest many of the concerns about the
cardiovascular safety of Avandia rosiglitazone using a mix of observational
studies, meta-analyses and controlled trials. The panel's deliberations could
shed light on how to balance and interpret such data as the agency is
increasingly faced with a similar melange of real-world and clinical data to
evaluate the benefit and risks of drugs in the postmarket.
At a joint meeting of the Endocrinologic and Metabolic Drugs
and the Drug Safety and Risk Management advisory committees last week, panel
members voted to relax the REMS on diabetes drug Avandia from GlaxoSmithKline
Among the 26-member panel, 13
voted to modify the REMS, 7 to remove it, 5 to maintain it, and 1 to withdraw
Avandia from the market. Twelve of the 13 who voted to modify the REMS
recommended that it be eased.
The vote is an about-face from
a 2010 recommendation to place restrictions on the drug after the panel
determined results from the RECORD cardiovascular outcomes trial could not be
trusted. While the original RECORD results showed no increased CV risk for
Avandia, FDA's Thomas Marciniak, medical team leader in the Division of
Cardiovascular and Renal products, picked apart the trial at that meeting and
suggested impropriety by GSK in the handling of the data.
At the time, the panel
struggled to balance GSK's reported results with Marciniak's critique of
RECORD, along with previous meta-analyses and observational studies that
suggested an increased risk.
In September 2010, FDA
restricted the use of Avandia and requested that GSK have the RECORD data
readjudicated by a third party (see BioCentury, July 19, 2010).
The game changer at last week's panel was the independent
readjudication of RECORD by Duke
Clinical Research Institute. The readjudicated results found no
increased cardiovascular risk for Avandia, confirming the original analysis.
"What's different now is
that the results of readjudication in RECORD, in my mind, have moved the
needle," said temporary voting member Marvin Konstam.
Konstam, chief physician executive of the Cardiovascular
Center at Tufts
Medical Center, voted to withdraw Avandia in 2010, but last week voted
to relax the drug's REMS.
While Marciniak again attempted
to discredit RECORD along with the readjudication process, senior FDA officials
and staff pushed back, and the committee ultimately devoted little time to
Marciniak's latest critique.
Instead, the panel focused on
weighing the strength of evidence from observational studies and meta-analyses
While most members acknowledged
that randomized, controlled trials with robust clinical data collection
processes remain the gold standard, they said observational studies and
meta-analyses with large effect sizes where the hypothesis is prespecified are
valuable and could be used to make clinical decisions.
The panel's deliberations could
be relevant to FDA's efforts to assess benefit-risk in the postmarket setting
and also could have implications for decisions that payers and clinicians will
be making based on real-world data once a drug is approved.
The debate over Avandia's CV
risk has stretched across six years and three FDA advisory committee meetings.
A firestorm was sparked in 2007, when Steven Nissen and Kathy
Wolski of the Cleveland
Clinic published a meta-analysis of 42 trials that showed an increased
risk of myocardial infarction (MI) and CV mortality for Avandia.
Nissen and Wolski identified a
43% higher risk of MI for Avandia (95% CI: 1.03, 1.98) and an increased
risk of 64% for CV mortality (95% CI: 0.98, 2.74). Results were published
in the June 14, 2007, New England Journal of Medicine.
In August 2007, FDA held its
first panel meeting to discuss the results along with FDA's own meta-analysis
and an interim look at the RECORD data. FDA's meta-analysis showed an increased
risk of 50% for MI (95% CI: 0.9, 2.5) and 70% for cardiovascular death (95% CI:
0.7, 4.0). RECORD did not.
RECORD was an open-label trial
that enrolled 4,447 patients and compared Avandia plus metformin or a
sulfonylurea to metformin plus sulfonylurea. The primary endpoint was the
composite of CV death and CV hospitalizations.
An interim analysis showed
little to no effect for Avandia. The HR for CV mortality was 0.83 (95% CI:
0.51, 1.36; p=0.46), and the HR for MI was 1.16 (95% CI: 0.75, 1.81; p=0.50).
Despite the mixed signals,
members of the 2007 panel concluded the benefits of Avandia outweighed the
risks and voted 22-1 in favor of keeping the drug on the market (see
BioCentury, Aug. 6, 2007).
In July 2010, the panel met to
discuss the complete results from RECORD.
The trial met the primary
endpoint with an HR of 0.99 (95% CI: 0.85, 1.16). Also, the upper bound of the
95% confidence interval was below the 1.3 threshold required under FDA's 2008
guidance for cardiovascular outcomes trials of diabetes drugs.
However, FDA's Marciniak cast
considerable doubt on the results and suggested GSK mishandled the data.
Marciniak reviewed about 12% of
the 4,447 case report forms and found problems with 13% of them. He reported
that the problematic forms were four times more likely to favor Avandia than
the comparator arm and that endpoint problems were twice as likely to favor
He also said GSK was given "unrestricted
access" to unblinded data.
Marciniak readjudicated the
RECORD data with an updated definition of major adverse CV events and exclusion
of cardiovascular hospitalizations, showing a MACE HR of 1.13 (95% CI: 0.85,
1.5). Marciniak's updated definition of MACE included MI, stroke and CV death.
After his analysis, the panel
had little confidence in the RECORD data.
At the time, temporary voting
member Michael Proschan said the imbalance in discrepancies favoring Avandia "scares
the hell out of me." He concluded: "I don't feel comfortable about
the results of RECORD."
Proschan is a mathematical statistician in the Biostatistics
Research Branch at the National
Institute of Allergy and Infectious Diseases (NIAID).
The 2010 committee split into
three almost equal groups that recommended mild, moderate and extreme
regulatory actions: 10 voted to keep Avandia on the market with existing or
updated labeling, 10 advised adding limits on its use, and 12 wanted the drug
In September 2010, FDA decided
to keep Avandia on the market but restricted its use to patients who could not
tolerate or could not maintain adequate glucose control on any other diabetic
agents. The agency also issued a REMS and asked GSK to have an independent
third party readjudicate RECORD.
asked GSK to withdraw Avandia from the European market.
Marciniak played a pivotal role
in the 2010 meeting, but last week he was a sideshow.
Given a 30-minute slot at the
start of the two-day meeting to provide his personal perspective on the
readjudicated RECORD data, Marciniak came out swinging. Just as he had done in
briefing documents ahead of the meeting, Marciniak blasted not only the
integrity of GSK but also that of Duke Clinical Research Institute.
Marciniak went through a
laundry list of issues with DCRI and suggested the institute had mishandled
other trials where it was asked to adjudicate CV outcomes, including the Phase
III PLATO trial of Brilinta ticagrelor vs. clopidogrel, and the Phase III
ARISTOTLE trial of Eliquis apixaban vs. warfarin for atrial fibrillation.
He noted DCRI was paid by GSK
and that the pharma gave the data directly to the researchers.
Marciniak stopped short of
accusing GSK or DCRI of fraud, but said FDA should have been involved in the
data transfer to ensure its completeness and integrity.
Where Marciniak's critique of
RECORD received little pushback from senior agency officials in 2010, last week
was a different story.
Ellis Unger, director of the
Center for Drug Evaluation and Research's Office of Drug Evaluation-I, noted
the data belong to GSK, not FDA.
"The sponsor generated the
data. They own the data and have to protect the confidentiality of the data,"
Mary Parks, director in the
division of Metabolism and Endocrinology Products, echoed Unger's response and
added: "I think the question to ask is do we have evidence that
there has been willful redaction of information or evidence provided that GSK
has not abided by the expectations of FDA."
Later in the meeting, Parks and
other FDA officials said there was no evidence of impropriety on GSK's part.
"We are not aware of any
evidence that [GSK] did not provide DCRI with all of the data," said John
Jenkins, director of the Office of New Drugs.
Also, the shoe was on the other
foot for Marciniak when Karen Murry Mahoney, lead medical officer in the
Division of Metabolism and Endocrinology Products, noted it was Marciniak who
was unblinded to the RECORD results before he did his analysis in 2010 - an
accusation Marciniak had made of GSK.
In briefing materials for last
week's meeting, Mahoney called Marciniak's 2010 review "unacceptable."
"Regrettably, the case
reviews of his original consult were not blinded; although he states that some
type of blinding occurred, it appears that he himself did the redactions, then
followed with his own review," she wrote. "This is not an acceptable
review procedure if one wants to put forth one's review work as blinded."
In last week's proceedings,
panel members asked the agency and GSK a few questions about the selection of
DCRI and the transfer of data, but did not dwell on this or any of Marciniak's
Instead, the panel praised Duke's
review of RECORD, and some members expressed regret about their 2010 decisions.
"I think that the readjudication
by Duke really struck a chord with me in that GSK had done a really good job
with the study," said Ellen Seely, permanent voting member of the
Endocrinologic and Metabolic Drugs Advisory Committee.
Seely is a professor of medicine at Harvard
Medical School and a practicing endocrinologist at Brigham
and Women's Hospital.
"I do think that the DCRI
adjudication process went a long way to help erase events in 2010 vis-à -vis bias
and potential malfeasance on ascertainment of cases. In 2010, I didn't feel
like I could look to RECORD at all. I don't feel this way today," he said.
Patient representative Rebecca
Killion voiced regret over the panel's 2010 decision in light of the Duke
"Based on DCRI's
adjudication, it went a long way for me in validating the sponsor's initial
data. It also tells me that we were jumping the gun in terms of concerns in
2010," she said.
Killion has been the patient
representative on all three panel meetings.
Katherine Flegal, temporary voting member and senior research
scientist at the National Center for Health Statistics at the Centers
for Disease Control and Prevention (CDC), echoed the comment. "I
wonder, if at the 2010 meeting, if there had not been so much uncertainty about
RECORD that our deliberations would have been different," she said.
Nonetheless, panel members
acknowledged that RECORD had weaknesses that could not be overcome by readjudication,
namely the open-label design.
"Because of the lack of a
blind for investigators, I have a lot more uncertainty about whether the
endpoints are being captured completely," said Erica Brittain, permanent
voting member of the Endocrinologic and Metabolic Drugs committee.
Brittain is a mathematical
statistician in NIAID's Biostatistics Research Branch.
Konstam and others also raised
concerns about the "high degree of missingness."
DCRI was able to readjudicate
the mortality endpoint with data from all but 87 of the 4,447 patients. The
missing data were balanced between Avandia and the control group.
However, both FDA and DCRI
noted in their presentations that there were more missing data for the MACE
endpoint. In the Avandia group, 346 (15.6%) patients were not followed for MI
or stroke to the end of study. The rate was similar in the control group, with
398 (17.9%) patients lost to follow-up.
FDA asked the panel to discuss
how the different data sources should be weighed in evaluating the CV risk of
Avandia. Committee members were mixed on how much weight should be placed on
the meta-analyses and observational studies.
Kate Gelperin, medical officer in FDA's Division of
Epidemiology, presented data from 21 observational studies of CV endpoints for
Avandia, including studies that compared Avandia to other antidiabetic agents
such as Actos pioglitazone from Takeda
Pharmaceutical Co. Ltd. Avandia and Actos are both thiazolidinedione
(TZD) peroxisome proliferation activated receptor (PPAR) gamma agonists.
The updated analysis included
seven studies not in FDA's 2010 analysis.
In the 10 trials that tested
Avandia vs. another diabetic agent - excluding Actos - three favored Avandia in
terms of acute MI, with one that was statistically significant. Three were
neutral, and the remaining four favored an alternative agent. One of the four
was statistically significant.
Four out of four studies of
Avandia vs. Actos in patients at least 65 years old favored Actos in terms of
acute MI, but none were statistically significant. However, in another seven
studies, six favored Actos in terms of all-cause mortality, including four that
were statistically significant. One study favored Avandia, but it was not
The panel split on these
Temporary voting member Sanjay
Kaul dismissed most of the observational studies because they lacked a
prespecified hypothesis. "Prespecification is very important in
interpretation of the data. Otherwise, you can go on a fishing expedition and
the data drive the hypothesis."
Kaul is director of the Fellowship Training Program in
Cardiovascular Disease at Cedars
Sinai Heart Institute and professor in the Division of Cardiology at David
Geffen School of Medicine at UCLA.
Only one of the studies
included in FDA's observational analysis had a prespecified hypothesis.
However, Konstam and others
felt the observational studies were valuable.
"Generally speaking, I
would have completely dismissed all of the observational findings that I've
seen, except this series of studies where pioglitazone was better than
rosiglitazone in mortality," he said.
Konstam noted the consistency
of the results across the different studies and the similar backgrounds of the
patients helped to support the findings of the four Actos vs. Avandia studies.
Maria Suarez-Almazor, a professor at MD
Anderson Cancer Center, also argued the consistency of the
observational studies made them equally if not more reliable than RECORD. She
also felt more comfortable with the observational studies because "they
can provide a more real-world experience compared to clinical trials."
Suarez-Almazor is a permanent
voting member of the Drug Safety and Risk Management committee.
The panel also considered
Nissen's 2007 meta-analysis, as well as FDA's meta-analyses of 52 randomized
trials that had been presented at the 2010 panel meeting.
FDA's meta-analysis showed an
odds ratio of 1.38 (95% CI: 0.72, 2.72) for all-cause death, OR of 1.46 (95%
CI: 0.60, 3.77) for CV death, an OR of 1.8 (95% CI: 1.03, 3.25) for MI and an
OR of 1.44 (95% CI: 0.95, 2.20) for MACE. The increase in MI was statistically
A subgroup analysis of the MACE
endpoint in active-controlled trials showed a lower OR of 1.05 (95% CI:0.48,
Kaul noted the results from FDA's
analysis were driven by events in placebo-controlled trials, which accounted
for about 80% of the studies.
"The RECORD results for
MACE are similar to what we get in FDA's meta-analyses when we only look at
active-controlled trials," he said.
Kaul said he thought the
consistency between the subgroup analysis and RECORD was reassuring. Brittain
"Even though the point
estimates are different than in RECORD, there is some consistency, with the
point estimates going in the same direction," she said.
Kaul also called FDA's analysis
"high quality" because "it only included randomized controlled
trials confined to diabetics, and long-term trials were excluded. It also
focused on a clinically relevant endpoint - MACE - and the method used, exact
odds ratio, was appropriate. Other meta-analyses don't do that."
For example, Kaul argued Nissen's
analysis was flawed because, while the majority of trials included were
short-term studies of about six months in duration, it also included two
long-term studies, one of which didn't include actual diabetic patients. DREAM
was a three-year trial in patients at risk of developing diabetes, and ADOPT
was a five-year trial in diabetics.
When these trials were removed
from Nissen's analysis, the odds ratio for MI increased to 1.45 from 1.43, but
the lower bound of the 95% CI decreased to 0.88 from 1.03 and rendered the results
non-significant with a p-value of 0.15 vs. a p-value of 0.03 from the complete
Kaul also said DREAM shouldn't
have been included because it was the hypothesis-generating study.
Indeed, Nissen stated at the
previous advisory meetings that the reason for doing the meta-analysis in the
first place was due to the imbalance in the number of acute MIs in the Avandia
arm of DREAM.
Konstam said the meta-analyses
are valuable but have to be interpreted according to the context of the trials
In this case, "these are
short-term and mostly placebo-controlled trials, so you can draw conclusions
that maybe increasing glycemic control in the short term may drive short-term
events," but the analyses could not be used to interpret long-term outcomes,
Guest speaker Hertzel Gerstein noted observational studies and
meta-analyses should be interpreted with caution. Gerstein is a professor and
director of the Division of Endocrinology and Metabolism in the Population Health
Research Institute at McMaster
University and Hamilton
For example, he pointed to
multiple observational studies that showed benefits of treatments like hormone
replacement therapy in women that were later disproven.
"ERT therapy was touted as
the therapy to give postmenopausal women until the large randomized,
controlled Women's Health Initiative showed that it was harmful," Gerstein
FDA plans to rely more on
real-world data to monitor the benefits and risks of the drugs in the
postmarket setting under its new benefit-risk framework (see BioCentury,
After the meeting, Gerstein
told BioCentury that as more real-world data become available, and regulators
and clinicians are faced with mounds of results from observational studies, the
best way to interpret the results is based on the magnitude of benefit.
"Unless it is a five- or
tenfold swing in either direction, it shouldn't change the treatment decision,"
Gerstein also noted that
regulators like FDA "understand the importance of collecting these data
and are obliging companies to do that postmarket, particularly for drugs that
are meant to be taken for many years."
However, just like clinicians,
regulators must interpret real-world data cautiously and recognize its
limitations, he said.
At the end of the day, panel
members concluded that the DCRI readjudication erased significant ambiguity
about Avandia's safety and that the restrictions on the drug should be eased.
"When you have uncertainty
in data, you should be allowed to exercise your own clinical judgment. These
are judgment calls, and doctors should be allowed to make judgment calls in the
face of uncertainty," Kaul said.
An increased risk for bladder cancer
for Actos also weighed on panelists.
In September 2010, FDA said it
would review the safety of Actos after interim data from a long-term
observational study showed a statistically significant increased risk of
bladder cancer in patients exposed to the diabetes drug for more than 24
In August 2011, FDA updated the
label for Actos-containing products to include dose- and duration-dependent
increased risk of bladder cancer. The label also warns against using Actos in
patients with active bladder cancer and to "use caution" in patients
with a history of bladder cancer.
Harvard's Seely and others
believed Avandia should remain on the market to provide an option to patients.
However, they felt there was still some uncertainty about its safety and thus
the REMS should be eased but remain in place.
The current REMS for Avandia
includes patient and prescriber certification, along with a restricted
Typical were the comments of
temporary voting member Ruth Day: "I think there needs to be a lightening
up of all of this intense monitoring, about the restrictive part of the
program. It is a huge amount of time and energy," for doctors and
Among the 26-member panel, 16
had been present at the 2010 meeting and half of them changed their vote in
favor of Avandia. Two of three who voted in 2010 to withdraw the drug this time
voted to loosen the restrictions; the third voted to keep the REMS as is.
Additionally, panel members
like Day who voted for a REMS in 2010, now concluded it was too strict (see "RECORD
Day and others said the
certification programs and restricted distribution should be replaced with a
communication plan and medication guide.
If FDA follows the panel's
recommendation, it could be easier for doctors and patients to get access to
Avandia. But a look at prescription and sales data trends since 2007 suggest a
major uptick in Avandia use is unlikely.
Prescription data presented by
FDA show declining use since Nissen's 2007 meta-analysis.
According to the agency's
presentation, prescriptions for Avandia from retail pharmacies peaked at 12.7
million in 2006. By the 2007 panel meeting, prescriptions had dropped below 10
million. Similarly, the number of patients who had received an Avandia-containing
prescription in 2008 was 820,000; this dropped to less than 500,000 in 2010.
At last week's meeting, GSK
presented data that showed a steep drop-off in prescriptions in May 2011 when
the restricted distribution system became fully operational.
According to the pharma, the
number of patients taking Avandia dropped 97% to 3,405 from 117,349 patients in
2010. The majority of patients taking the drug now were taking Avandia prior to
the REMS and only 6% are new patients.
GSK reported Avandia sales of
£6 million ($9 million) for 2012, compared to £123 million ($187 million) in
2011 and £440 million ($669 million) in 2010.
and Women's Hospital, Boston, Mass.
Sinai Heart Institute, Los Angeles, Calif.
for Disease Control and Prevention (CDC), Atlanta, Ga.
Clinic, Cleveland, Ohio
Geffen School of Medicine at UCLA, Los Angeles, Calif.
Clinical Research Institute (DCRI), Durham, N.C.
Medicines Agency (EMA), London, U.K.
plc (LSE:GSK; NYSE:GSK), London, U.K.
Health Sciences, Hamilton, Ontario
Medical School, Cambridge, Mass.
University, Hamilton, Ontario
Anderson Cancer Center, Houston, Texas
Institute of Allergy and Infectious Diseases (NIAID), Bethesda, Md.
Pharmaceutical Co. Ltd. (Tokyo:4502), Osaka, Japan
Medical Center, Boston, Mass.
Food and Drug Administration (FDA), Silver Spring, Md.