Accuracy, Completeness, and Transparency: lessons from Tamiflu experience
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Accuracy, Completeness, and
Transparency: lessons from
Tamiflu experience
Peter Doshi, PhD (pnd@jhu.edu)
Postdoctoral fellow in Comparative Effectiveness Research
Johns Hopkins University School of Medicine
October 12, 2012
ACT Now EQUATOR Conference, Freiburg, Germany
T. Jefferson :: R. Hama :: C. Heneghan :: C. Del Mar :: P. Doshi :: M Jones :: M Thompson
CHAPTER 1: Conclusions of great benefit
The Tamiflu Success Story 2005 2006
CDC/ACIP Influenza Rec. (2006)
• “Among influenza virus infected
participants in 10 clinical trials, the
risk for pneumonia among those
participants receiving oseltamivir
was approximately 50% lower than
among those persons receiving a
placebo (339). A similar significant
reduction was also found for hospital
admissions; a 50% reduction was
observed in the small subset of high-
risk participants, although this
reduction was not statistically
significant.”
Kaiser 2003
Smith NM, Bresee JS, Shay DK, Uyeki TM, Cox NJ, Strikas RA. Prevention and Control of Influenza:
recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm 4
Rep. 2006 Jul 28;55(RR-10):1–42.
HHS Pandemic Influenza Plan (2005) “Critical assumptions. Treatment with a neuraminidase inhibitor (oseltamivir [Tamiflu®] or zanamivir [Relenza®]) will be effective in decreasing risk of pneumonia, will decrease hospitalization by about half (as shown for interpandemic influenza), and will also decrease mortality.” (p.D-20) U.S. Department of Health and Human Services. HHS Pandemic Influenza Plan [Internet]. 2005 [cited 2009 Jun 9]. http://www.hhs.gov/pandemicflu/plan/pdf/HHSPandemicInfluenzaPlan.pdf 5
HHS 2004 draft pandemic plan • “The impacts of oseltamivir therapy on lower respiratory tract complications (LRTCs) of influenza and on influenza hospitalizations were calculated in a pooled analysis of 10 randomized placebo-controlled studies that included 3,591 adults and adolescents. Overall, 4.6 percent of oseltamivir treated persons had an LRTC of influenza infection compared with 10.3 percent of persons who received placebo – a 55 percent reduction (P
CHAPTER 1: Conclusions of great benefit CHAPTER 2: Conclusions challenged
The Tamiflu Story
2005 2006
April July
---------- 2009 ----------
Hayashi’s criticism
Kaiser 2003 is a…
• Roche authored paper
• Pooled analysis of 10
Roche funded RCTs
from the late 1990s
– 2/10 published (1397
pts)
– 8/10 never published
(2691 pts)
“Conclusion: Oseltamivir
treatment of influenza illness
reduces LRTCs, antibiotic use,
and hospitalization in both
healthy and “at-risk” adults.”
Kaiser et al. Archives of Internal Medicine. 2003; 163:1667-1672 9
CHAPTER 1: Conclusions of great benefit CHAPTER 2: Conclusions challenged CHAPTER 3: Evidence is missing
Profs Kaiser and Hayden
“I suggest to contact Roche directly to
get access to the files.” Email from
Kaiser August 17, 2009
“I have searched but cannot find the original files related
to this 2003 publication. Before and again after my 2+
years at WHO in Geneva, I was obliged to move offices at
the University several times and downsize. The files appear
to have been discarded. My co-author Laurent Kaiser, now
professor at the University of Geneva, is copied on this
reply, as he may have his own sources. The questions
posed by the inquirer are not clear to me, but if original
data or unpublished study reports are required, they will
likely need to come from Roche, the sponsor of these
studies”. Email from Hayden August 14, 2009
Slide courtesy Tom JeffersonProfessor John Treanor Treanor JJ, Hayden FG, Vrooman PS, Barbarash R, Bettis R, Riff D, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA. 2000 Feb 23;283(8):1016-1024.
Professor Karl Nicholson Nicholson KG, Aoki FY, Osterhaus AD, Trottier S, Carewicz O, Mercier CH, et al. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group. Lancet. 2000 May 27;355(9218):1845–50.
“I did not perform an independent
analysis of the primary data, which was
not required or requested by JAMA at
the time of submission, and I do not
have access to the primary data, which
I also never requested.”
“When asked a similar question,
Nicholson said he did not recall seeing
the primary data. He said that the
statistical analysis had been conducted
by Roche and he analysed the
summary data”.
Quotes from Cohen D. Complications: tracking down the data on oseltamivir.
BMJ. 2009 Dec 8;339(dec08_3):b5387.Largest treatment trial – abstract only Source: Cohen D. Complications: tracking down the data on oseltamivir. BMJ. 2009;339:b5387.
Issues to consider • What is the role of trust in the scientific publication and evidence synthesis process? • Do named authors have a responsibility to provide data that allows for independent verification of claims? • What is one to conclude in the absence of obtaining data for trials that are known to exist?
Dec. 2009
Cochrane review, Dec 2009
Roche:
Full study report?
• “very happy to have its
data reviewed by
appropriate authorities
or individuals”
• “full study reports will
also be made available
on a password-protected
site within the coming
days to physicians and
scientists undertaking
legitimate analyses.”Doshi P, Jones M, Jefferson T. Rethinking credible evidence synthesis. BMJ. 2012;344:d7898.
New Methods
Discussed new methods Group decision
Identify all trials (trial programme) Agree
No more published papers! Agree
Identify and retrieve all Clinical Study Reports and Agree
regulatory material
Table of Contents of the Evidence (TOCE) Agree
Weave evidence of trial programmes together Disagree
Assess – if reliable, analyse What does reliable mean?
Complete?
Trustworthy?
(Both?)
(Original slide courtesy Tom Jefferson)CHAPTER 1: Conclusions of great benefit
CHAPTER 2: Conclusions challenged
CHAPTER 3: Evidence is missing
CHAPTER 4: Some (20,000 pages) evidence
retrievedEMA’s “sea-change in attitude”
November 30, 2010What we obtained from EMA
Trial(s) No of Pages Trial(s) No of Pages
patients obtained patients obtained
JV15823 316 32 WV15673/15697 1562 804
JV15824 308 19 WV15707 27 458
M76001 1459 1514 WV15708 385 661
ML16369 478 0 WV15730 60 525
ML20542 534 0 WV15758 698 1126
MV21879 862 0 WV15759/15871 335 1121
NP15757 59 445 WV15799 962 900
NV16871 329 614 WV15812/15872 404 683
NV25118 9 0 WV15825 572 875
WP16263 400 8545 WV15876/15819/15978 741 973
WV15670 726 1032 WV16193 808 894
WV15671 629 1018 WV16277 451 0
Total 13 114 22 239Paper needed to print Clinical Study Report
for oseltamivir trial WP16263
8545 pages
8000
7000
6000
5000
4000
3000
2000
1000Unexpected findings
CERTIFICATE OF ANALYSIS
CHAPTER 1: Conclusions of great benefit
CHAPTER 2: Conclusions challenged
CHAPTER 3: Evidence is missing
CHAPTER 4: Some (20,000 pages) evidence
retrieved
CHAPTER 5: Conclusions of little benefitLatest Cochrane Review (2012)
Conclusions:
• ~1 day reduction in time
to first alleviation of
influenza symptoms
• No decrease in risk of
hospitalization
• No evidence it can stop
the spread of virus
• Suggestive evidence
Tamiflu interferes with
natural influenza antibody
production
January 2012Roche: Tamiflu “reduces incidence
of secondary complications (ie
bacterial infections) by 45%”
FDA: Claim “not supported by
substantial evidence.”
Roche promotional material FDA Warning Letter
31Tamiflu label
“Serious bacterial infections may begin with
influenza-like symptoms or may coexist with or
occur as complications during the course of
influenza. TAMIFLU has not been shown to
prevent such complications.”
Tamiflu Product Labeling
(Nov 17, 2000 to present)
Before 2009, CHF 7.6 billion worth stockpiled by
governments worldwide. Why?
32CHAPTER 1: Conclusions of great benefit
CHAPTER 2: Conclusions challenged
CHAPTER 3: Evidence is missing
CHAPTER 4: Some (20,000 pages) evidence
retrieved
CHAPTER 5: Conclusions of little benefitYou can also read
