Transcript Center for Drug Evaluation and Research

Journal Club
Graham DJ, Ouellet-Hellstrom R, Macurdy TE, Ali F, Sholley C, Worrall C,
Kelman JA.
Risk of Acute Myocardial Infarction, Stroke, Heart Failure, and Death in Elderly
Medicare Patients Treated With Rosiglitazone or Pioglitazone.
JAMA. 2010 Jun 28. [Epub ahead of print]
Bergenstal RM, Tamborlane WV, Ahmann A, Buse JB, Dailey G, Davis SN, Joyce
C, Peoples T, Perkins BA, Welsh JB, Willi SM, Wood MA; the STAR 3 Study
Group.
Effectiveness of Sensor-Augmented Insulin-Pump Therapy in Type 1 Diabetes.
N Engl J Med. 2010 Jun 29. [Epub ahead of print]
2010年７月15日 8:30-8:55
８階 医局
埼玉医科大学 総合医療センター 内分泌・糖尿病内科
Department of Endocrinology and Diabetes,
Saitama Medical Center, Saitama Medical University
松田 昌文
Matsuda, Masafumi
Leading the News
July 14, 2010
FDA Panelists Divided Over Safety Of Avandia.
ABC World News (7/13, story 3, 1:50, Sawyer) reported, "Government advisors began debating the safety of the diabetes drug Avandia
[rosiglitazone]. The medication once enjoyed blockbuster sales, but it's been dogged by questions on whether it can cause heart attacks."
The Washington Post (7/14, Stein) reports that the panelists "disagreed sharply Tuesday about whether" Avandia "is unsafe and should be
removed from the market." During the hearing, "the FDA's Thomas A. Marciniak presented a detailed critique of a study GlaxoSmithKline
sponsored and has held up as the best evidence of the drug's safety." However, "in an unusual display of conflict within the agency, other FDA
researchers challenged Marciniak's analysis of the pivotal study, known as Record. Ellis F. Unger, for example, questioned Marciniak's
interpretations of how the data were selected, and agreed with the company's argument that the study showed the drug was safe."
The AP (7/14, Perrone) notes, "FDA Commissioner Margaret Hamburg opened the meeting by advising panelists to 'follow the science
wherever it leads and the rest will fall into place.' But it quickly became clear that the FDA's own staff have reached vastly different conclusions
from the same science."
USA Today (7/14, Rubin) reports, "Only one randomized controlled trial -- considered the gold standard for testing medications -- has been
completed since 2007, and even FDA reviewers were divided on its value."
The New York Times (7/14, A16, Harris) points out that five "of the experts who gave presentations were largely supportive of the drug,
saying the clinical trial did not make Avandia appear as risky as some other officials have claimed." Meanwhile, on Wednesday, the panel will
vote "to advise the Food and Drug Administration on whether the drug...should remain on the market."
The CBS Evening News (7/13, story 4, 2:30, Couric) reported that "the credibility of [Glaxo] was called into question when investigators
released documents showing the company knew about problems 11 years ago but didn't make them public." Still, "GlaxoSmithKline released a
statement saying that the documents were taken out of context," and the company accused "the Senate committee of cherry-picking a handful of
document which distorts its record and is misleading" The Wall Street Journal (7/14, Mundy, Dooren), CNN (7/14) and CQ Today (7/14) also
cover the story.
Unconfirmed Report Says GlaxoSmithKline Agreed To Pay $460 Million To Settle Avandia Lawsuits. NBC Nightly News (7/13, story 4,
2:30, Williams) reported, "There's a report circulating tonight that the drugmaker GlaxoSmithKline has agreed to pay $460 million to settle most of
the lawsuits connected to its one-time blockbuster diabetes drug Avandia [rosiglitazone]. The company isn't commenting on that report...but it
comes on the very same day an FDA advisory committee started hearing evidence on whether Avandia is so unsafe, it should be pulled off the
market all together."
Bloomberg News (7/14, Feeley, Kelley) reports, "GlaxoSmithKline Plc agreed to pay about $460 million to resolve a majority of lawsuits
alleging the company's Avandia diabetes drug can cause heart attacks and strokes, people familiar with the accords said." According to these
unnamed sources, Glaxo has "agreed to settle about 10,000 suits for an average of at least $46,000 apiece." The drugmaker "had been facing
more than 13,000 suits alleging" that it "hid the drug's heart-attack risk, according to a UBS AG analyst."
According to Reuters (7/14, Richwine), this week's FDA panel review of Avandia's safety may have played a role in Glaxo's decision to
begin negotiations with attorneys representing patients who used to use the drug. The Philadelphia Business Journal (7/13, George) also
covered the story.
From Bloomberg TV July 13, 2010 1min 46sec
チアゾリジン系薬剤
Assessment of the cardiovascular risks
and health benefits of rosiglitazone
David J. Graham, MD, MPH
Office of Surveillance and Epidemiology
Food and Drug Administration
July 30, 2007
Center for Drug Evaluation and Research
Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the
Drug Safety and Risk Management Advisory Committee
July 30, 2007
Does CV risk with RSG differ from that with PIO?
• Yes
•
From DREAM, relatively low-risk population:
RSG increased risk by ~40% c/w PBO
•
From PROactive, high risk population:
PIO decreased risk by ~15% c/w PBO
•
From RSG meta-analysis:
RSG increased risk of serious IHD by ~40% c/w all
comparators & by ~70% c/w PBO
•
From PIO meta-analysis:
PIO decreased risk by ~25% c/w all comparators
•
From head-to-head GLAI:
RSG increased risk 3.5-fold c/w PIO
Center for Drug Evaluation and Research
Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the
Drug Safety and Risk Management Advisory Committee
July 30, 2007
Office of Surveillance and Epidemiology, Center
for Drug Evaluation and Research, US Food and
Drug Administration, Silver Spring, Maryland
(Drs Graham and Ouellet-Hellstrom); Stanford
University, Stanford, California (Dr MaCurdy);
Acumen LLC, Burlingame, California (Dr
MaCurdy, Ms Ali, and Mr Sholley); and Centers
for Medicare & Medicaid Services, Washington,
DC (Mr Worrall and Dr Kelman).
JAMA. 2010;304(4):(doi:10.1001/jama.2010.920) www.jama
Background
Context Studies have suggested that the
use of rosiglitazone may be associated
with an increased risk of serious
cardiovascular events compared with
other treatments for type 2 diabetes.
Objective To determine if the risk of
serious cardiovascular harm is increased
by rosiglitazone compared with
pioglitazone, the other thiazolidinedione
marketed in the United States.
Methods
Design, Setting, and Patients Nationwide, observational,
retrospective, inception cohort of 227 571 Medicare beneficiaries
aged 65 years or older (mean age, 74.4 years) who initiated
treatment with rosiglitazone or pioglitazone through a Medicare
Part D prescription drug plan from July 2006-June 2009 and who
underwent follow- up for up to 3 years after thiazolidinedione
initiation.
Main Outcome Measures Individual end points of acute
myocardial infarction (AMI), stroke, heart failure, and all-cause
mortality (death), and composite end point of AMI, stroke, heart
failure, or death, assessed using incidence rates by
thiazolidinedione, attributable risk, number needed to harm,
Kaplan-Meier plots of time to event, and Cox proportional hazard
ratios for time to event, adjusted for potential confounding factors,
with pioglitazone as reference.
Medicare is a social insurance program administered by the United
States government, providing health insurance coverage to people
who are aged 65 and over, or who meet other special criteria.
They are 65 years or older and U.S. citizens or have been permanent legal residents for 5
continuous years, and they or their spouse has paid Medicare taxes for at least 10 years.
or
They are under 65, disabled, and have been receiving either Social Security benefits or the
Railroad Retirement Board disability benefits for at least 24 months from date of entitlement
(first disability payment).
or
They get continuing dialysis for end stage renal disease or need a kidney transplant.
or
They are eligible for Social Security Disability Insurance and have amyotrophic lateral
sclerosis (known as ALS or Lou Gehrig's disease).
Part A: Hospital Insurance
Part B: Medical Insurance
Part C: Medicare Advantage plans
Part D: Prescription Drug plans
Results
A total of 8667 end points were observed during the
study period. The adjusted hazard ratio for
rosiglitazone compared with pioglitazone was 1.06
(95% confidence interval [CI], 0.96-1.18) for AMI; 1.27
(95% CI, 1.12-1.45) for stroke; 1.25 (95% CI, 1.161.34) for heart failure; 1.14 (95% CI, 1.05-1.24) for
death; and 1.18 (95% CI, 1.12-1.23) for the composite
of AMI, stroke, heart failure, or death. The attributable
risk for this composite end point was 1.68 (95% CI,
1.27-2.08) excess events per 100 personyears of
treatment with rosiglitazone compared with
pioglitazone. The corresponding number needed to
harm was 60 (95% CI, 48-79) treated for 1 year.
Conclusion
Compared with prescription of
pioglitazone, prescription of
rosiglitazone was associated with
an increased risk of stroke, heart
failure, and all-cause mortality and
an increased risk of the composite
of AMI, stroke, heart failure, or allcause mortality in patients 65 years
or older.
Message
アバンディア®(ロジグリタゾン)を販売し
ていたGlaxoSmithKline社はアクトス®より
心血管障害を惹起しやすいことを1999年に
知っていた。これを隠していたことで今大
騒ぎ！！！
この騒ぎの訴訟でGlaxoSmithKline社は
$460million[620億円]支払うことを決めて
いると報道されている。
the International Diabetes Center at Park Nicollet, Minneapolis (R.M.B.); Yale University, New
Haven, CT (W.V.T.); Oregon Health and Science University, Portland (A.A.); University of North
Carolina School of Medicine, Chapel Hill ( J.B.B.); Scripps Institute, La Jolla (G.D.), and
Medtronic, Northridge (T.P., J.B.W.) — both in California; University of Maryland School of
Medicine, Baltimore (S.N.D.); Memorial University of Newfoundland, Health Science Centre, St.
John’s, NL, Canada (C.J.); Toronto General Hospital, Toronto (B.A.P.); Children’s Hospital of
Philadelphia, Philadelphia (S.M.W.); and Helen DeVos Children’s Hospital, Grand Rapids, MI
(M.A.W.).
10.1056/nejmoa1002853 nejm.org
Background
Recently developed technologies
for the treatment of type 1
diabetes mellitus include a variety
of pumps and pumps with glucose
sensors.
Methods
In this 1-year, multicenter, randomized,
controlled trial, we compared the efficacy of
sensor-augmented pump therapy (pump
therapy) with that of a regimen of multiple daily
insulin injections (injection therapy) in 485
patients (329 adults and 156 children) with
inadequately controlled type 1 diabetes. Patients
received recombinant insulin analogues and
were supervised by expert clinical teams. The
primary end point was the change from the
baseline glycated hemoglobin level.
The MiniMed Paradigm REAL-Time System is comprised of six components: 1) the
Paradigm® 722 insulin pump (MMT-722), 2) the MiniLink™ REAL-Time transmitter
(MMT- 7703) with charger (MMT-7705), 3) the glucose sensor (MMT-7002/7003), 4)
the Paradigm® Link glucose meter, 5) the ComLink (MMT-7304), and 6) a Personal
Computer (PC).
 722 Arm: MiniMed Paradigm REAL-Time System using
NovoLog®/NovoRapid® for 1 year;
 MDI Arm: MDI (Lantus® and NovoLog®/NovoRapid®) for 1 year.
* Plus–minus values are means ±SD. Percentages may not total 100 because of rounding.
† Race or ethnic group was self-reported.
‡ Patients could select more than one answer in this category.
§ P<0.05 for the comparison between the pump-therapy group and the injection-therapy group.
¶ The body-mass index is the weight in kilograms divided by the square of the height in meters.
Results
At 1 year, the baseline mean glycated hemoglobin level
(8.3% in the two study groups) had decreased to 7.5% in
the pump-therapy group, as compared with 8.1% in the
injection-therapy group (P<0.001). The proportion of
patients who reached the glycated hemoglobin target
(<7%) was greater in the pump-therapy group than in
the injection-therapy group. The rate of severe
hypoglycemia in the pump-therapy group (13.31 cases
per 100 person-years) did not differ significantly from
that in the injection- therapy group (13.48 per 100
person-years, P = 0.58). There was no significant weight
gain in either group.
Conclusion
In both adults and children with inadequately
controlled type 1 diabetes, sensoraugmented
pump therapy resulted in significant
improvement in glycated hemoglobin levels, as
compared with injection therapy. A significantly
greater proportion of both adults and children in
the pump-therapy group than in the injectiontherapy group reached the target glycated
hemoglobin level.
(ClinicalTrials.gov number, NCT00417989.)
Editorial Comments
Continuous Glucose Monitoring — Coming of Age
Howard A. Wolpert, M.D.
The STAR 3 study and other randomized trials
have shown that continuous glucose monitoring
can take the management of type 1 diabetes to
a new level: improved glycemic control without
an associated increase in hypoglycemia.
Message
Real time CGM を行うCSIIは１型糖尿病患者に
とって低血糖が少ない良好な血糖管理に近づく
大きな進歩で、子供にも大人にも良いようであ
る。
しかし、課題（装着，コストなど）もある。