Correspondence

Misleading data
analyses in salmeterol
(SMART) study
In 1996, due to reports of paradoxical
bronchospasm associated with the use
of GlaxoSmithKline’s (GSK’s) newly
approved, long-acting inhaled   agonist salmeterol, and previous epidemics of asthma-related deaths in
patients taking other long-acting
  agonists,1 the company initiated a
randomised trial comparing salmeterol
(Serevent, known as Advair when
combined with the steroid fluticasone)
to placebo. The results have never
been published.
We only know the detailed results of
this crucial study because the drug
came before the US Food and Drug
Administration’s (FDA’s) PulmonaryAllergy Drugs Advisory Committee on
July 13, 2005, and because the FDA
now provides the Advisory Committee
briefing materials, including reviews by
its own medical officers, on its website
before the meeting.2 These documents provide insight into the manner
in which the company manipulated
the data it submitted to the FDA in an
apparent attempt to convince the
agency that the drug’s risks were
smaller.
The Salmeterol Multicenter Asthma
Research Trial (SMART) was designed
to randomise 60 000 asthma patients
to either salmeterol 42  g twice daily
or placebo. The study duration was 28
weeks, with patients examined about
every 4 weeks. Investigators were also
asked to report (but not actively seek
out) any serious adverse event that
occurred within 6 months after the
patient completed the trial. The primary outcome was combined respiratory-related
deaths
and
lifethreatening experiences; secondary
outcomes included asthma-related
deaths, asthma-related deaths or lifethreatening experiences, and all-cause
deaths.
In September, 2002, the SMART
Data Safety Monitoring Board (DSMB)
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Relative risk (95% CI)

Respiratory-related deaths and
life-threatening experiences
Asthma-related deaths
Asthma-related deaths or
life-threatening experiences
All-cause deaths

28-week study

28-week study plus 6 months

1·39 (0·91–2·13)

1·16 (0·78–1·72)

4·33 (1·24–15·21)
1·68 (0·99–2·85)

2·50 (0·97–6·44)
1·52 (0·92–2·52)

1·31 (0·83–2·08)

1·04 (0·70–1·55)

Table: Relative risks of primary outcome and major secondary outcomes in SMART study with and
without inclusion of post-trial data

met to review the data on the
25 858 patients who had been
enrolled to date. Based on nearly significant treatment-related increases
in both the primary outcome variable
and asthma-related deaths, the
DSMB offered two alternatives: either
increase the target sample size by at
least 10 000 patients or terminate
the study “with dissemination of
findings as quickly as possible”. GSK
selected the latter option.
GSK presented the interim analysis
of the SMART data at the 2003 meeting of the American College of Chest
Physicians, claiming that “The interim
analysis was inconclusive”.3 Based on
the interim data, on Aug 11, 2003, the
FDA modified the labelling for both
Serevent and Advair to include a black
box warning of a “small but significant
increase in asthma-related deaths”.
With the interim results in hand, the
company finalised a statistical methods appendix, which it submitted to
the agency for the first time on
Aug 29, 2003, along with the final
study data. In a significant deviation
from the original protocol, the appendix permitted including in the study
dataset adverse events that were
reported in the 6 months after the termination of the trial.
The table presents the results of
the SMART study according to
whether or not the post-trial results
are included. For the primary outcome variable, as well as for each of
the three major secondary outcome
variables, the inclusion of the posttrial data produces an apparent
diminution of the dangers associated
with salmeterol.

GSK did not specify to the FDA which
dataset it had submitted. Only on
April 26, 2004, after the FDA specifically enquired as to which dataset had
been provided, did the agency learn
that the company had provided only
the dataset that included the 6-month
data. The medical officers state that
“The Division presumed the data represented [only] the 28-week period as
the 28-week period is clinically the
period of interest”. The FDA recommended that any further labelling
changes be based on the protocolspecified 28-week study, which it
forced the company to provide.
At the July 13, 2005, Advisory
Committee meeting, the committee
recommended strengthening the
labels for both Serevent and Advair to
encourage concomitant inhaled corticosteroid use.4 The agency has not
made a final decision on the label.
It is now approaching 3 years since
the SMART study was terminated. The
results have still not found their way
into print (GSK told the Advisory
Committee that they have been
accepted for publication in Chest) and
the drugs’ labels have still not been
finalised. Instead, the company, seemingly under little pressure from the
FDA, has succeeded in drawing out the
process and initially misleading the
agency, physicians, and patients with
not-per-protocol analyses that diminished the drug’s apparent risks. In the
absence of the transparency associated with Advisory Committee meetings, these deceptions would never
have come to public attention. In
2001, however, only 21% of new drug
approvals were preceded by Advisory
1261

 Correspondence

Committee meetings, allowing most
drugs to avoid similar public scrutiny.5
We declare that we have no conflict of interest.

*Peter Lurie, Sidney M Wolfe
plurie@citizen.org
Public Citizen’s Health Research Group, 1600 20th
Street NW, Washington, DC 20009, USA
1

2

3

4

5

Stolley PD. Why the United States was
spared an epidemic of deaths due to asthma.
Am Rev Respir Dis 1972; 105: 883–90.
US Food and Drug Administration. Medical
officer review. Provided for: Meeting of
Pulmonary-Allergy Drugs Advisory
Committee, July 13, 2005. http://www.
fda.gov/ohrms/dockets/ac/05/briefing/20054148B1_03_02-FDA-Smart-Study.pdf
(accessed July 20, 2005).
Knobil K, Yancey S, Kral K, Rickard K.
Salmeterol Multi-center Asthma Research
Trial (SMART): results from an interim
analysis. Meeting of American College of
Chest Physicians, Orlando, FL, USA; Oct 27,
2003.
Anon. Serevent, Foradil use with steroids
should be strongly urged in labeling.
The Pink Sheet July 18, 2005: 12–13.
Office of the Inspector General. FDA’s review
process for new drug applications: a
management review. Washington, DC:
Department of Health and Human Services,
2003.

GlaxoSmithKline’s reply
Contrary to the assertions posed by
Peter Lurie and Sidney Wolfe, GSK
has acted responsibly and transparently and communicated with a
sense of urgency to ensure that
health-care
professionals
and
patients had access to the results of
SMART.
SMART was a 28-week, randomised, double-blind safety surveillance study consisting of a single
clinic visit at which patients
( 12 years) received seven canisters
(120 doses per canister) of salmeterol or placebo, added to their usual
asthma therapy. Patients were not
required to return for clinic visits, but
were contacted every 4 weeks by
phone to collect information about
serious adverse events.
Respiratory-related deaths or lifethreatening experiences was the primary endpoint, which required an
estimated sample size of 30 000.
However, after 15 000 patients were
enrolled, the actual rate of primary
1262

events was about half that expected,
and the sample size was increased to
60 000. The protocol specified collection of reported events during the
28-week study period and a 6-month
follow-up, since patients might have
had access to, and used, study medication during this period. Study data
were collected and analysed by a clinical research organisation.
The only dataset analysed for the
interim analysis included events from
the 28-week plus 6-month period
and were provided to an independent
DSMB, not to GSK. The interim analysis suggested worse outcomes in salmeterol-treated patients, mainly
African-Americans, and the DSMB
recommended that, ideally, the study
be completed within 2 years, or if
that was not possible, the study
should be terminated and the results
disseminated. After discussions with
the DSMB, GSK was provided with
unmasked results of the interim
analysis and subsequently terminated the study due to difficulties in
enrolment and findings in AfricanAmericans.
In collaboration with the FDA,
numerous activities were undertaken
to immediately communicate SMART
results to health-care professionals.
On the day SMART was stopped
(Jan 23, 2003), a Dear Healthcare
Professional letter was delivered by
overnight mail to all US health-care
professionals who had prescribed salmeterol or salmeterol-containing
products within the previous year.
Simultaneously, notices on both the
FDA and GSK websites were posted.
A second letter was sent when the
prescribing information for Serevent
and Advair was changed to include a
boxed warning with the results of the
interim analysis (Aug 11, 2003).
Results of the interim analysis were
presented at the American College of
Chest Physicians meeting as a latebreaking abstract on Oct 27, 2003,
which was the first national meeting
with high attendance of respiratory
physicians.

There were non-reviewed cases present when SMART was terminated.
Furthermore, because outstanding
deaths from patients lost to follow-up
might have altered the results, two
searches of the National Death Index
database were done, which resulted in
a final dataset (December, 2003). This
final dataset was analysed and
reported to the FDA in February, 2004.
Subsequently, the FDA requested that
GSK further refine the analysis to
include data from the 28-week treatment period because the power calculations were based on 28 weeks of
study treatment. These data were
reported to the FDA in May, 2004.
There were no substantive differences
between the final data for SMART and
those for the interim analysis. The
labelling for Serevent and Advair were
again updated in September, 2004, to
reflect this final analysis for SMART.
SMART results have also been
posted on the GSK Clinical Trial
Registry1 and contain both the
28-week and 28-week plus 6-month
analyses. In addition, the SMART
paper,2 submitted in November, 2004,
to Chest, contains both analyses, and
has been accepted for publication.
In summary, GSK has acted responsibly, transparently, and has communicated rapidly through multiple
channels to ensure that the findings
from SMART were available to healthcare professionals and patients.

Kathy A Rickard
kathy.a.rickard@gsk.com
Vice President, Clinical—North America,
Respiratory Medicine Development Center,
GlaxoSmithKline, 5 Moore Drive, Research Triangle
Park, NC 27709, USA.
1

2

SLGA5011: a double-blind, randomized,
placebo-controlled surveillance study of
asthma event outcomes in subjects receiving
either usual pharmacotherapy of asthma or
usual pharmacotherapy plus salmeterol
42 mcg twice daily. http://ctr.gsk.co.uk/
Summary/salmeterol/studylist.asp (accessed
Sept 20, 2005).
Nelson HS, Weiss ST, Bleecker ER, Yancey SW,
Dorinsky PM, and the SMART Study Group.
The Salmeterol Multicenter Asthma Research
Trial (SMART): a comparison of usual
pharmacotherapy for asthma or usual
pharmacotherapy plus salmeterol. Chest
(in press).

www.thelancet.com Vol 366 October 8, 2005