Publication of Clinical Trials Supporting Successful New Drug Applications: A
Literature Analysis
Background:
The United States (US) Food and Drug Administration (FDA) approves new drugs based on
sponsor-submitted clinical trials. The publication status of these trials in the medical
literature and factors associated with publication have not been evaluated. We sought to
determine the proportion of trials submitted to the FDA in support of newly approved
drugs that are published in biomedical journals that a typical clinician, consumer, or
policy maker living in the US would reasonably search.
Methods and Findings:
We conducted a cohort study of trials supporting new drugs approved between 1998 and
2000, as described in FDA medical and statistical review documents and the FDA approved
drug label. We determined publication status and time from approval to full publication
in the medical literature at 2 and 5 y by searching PubMed and other databases through
01 August 2006. We then evaluated trial characteristics associated with publication. We
identified 909 trials supporting 90 approved drugs in the FDA reviews, of which
43% (394/909) were published. Among the subset of trials described in the
FDA-approved drug label and classified as “pivotal trials” for our
analysis, 76% (257/340) were published. In multivariable logistic regression
for all trials 5 y postapproval, likelihood of publication correlated with statistically
significant results (odds ratio [OR] 3.03, 95% confidence
interval [CI] 1.78–5.17); larger sample sizes (OR 1.33 per
2-fold increase in sample size, 95% CI 1.17–1.52); and pivotal
status (OR 5.31, 95% CI 3.30–8.55). In multivariable logistic
regression for only the pivotal trials 5 y postapproval, likelihood of publication
correlated with statistically significant results (OR 2.96, 95% CI
1. 24–7.06) and larger sample sizes (OR 1.47 per 2-fold increase in sample
size, 95% CI 1.15–1.88). Statistically significant results and
larger sample sizes were also predictive of publication at 2 y postapproval and in
multivariable Cox proportional models for all trials and the subset of pivotal
trials.
Conclusions:
Over half of all supporting trials for FDA-approved drugs remained unpublished ≥
5 y after approval. Pivotal trials and trials with statistically significant results and
larger sample sizes are more likely to be published. Selective reporting of trial
results exists for commonly marketed drugs. Our data provide a baseline for evaluating
publication bias as the new FDA Amendments Act comes into force mandating basic results
reporting of clinical trials.
Vyšlo v časopise:
Publication of Clinical Trials Supporting Successful New Drug Applications: A
Literature Analysis. PLoS Med 5(9): e191. doi:10.1371/journal.pmed.0050191
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pmed.0050191
Souhrn
Background:
The United States (US) Food and Drug Administration (FDA) approves new drugs based on
sponsor-submitted clinical trials. The publication status of these trials in the medical
literature and factors associated with publication have not been evaluated. We sought to
determine the proportion of trials submitted to the FDA in support of newly approved
drugs that are published in biomedical journals that a typical clinician, consumer, or
policy maker living in the US would reasonably search.
Methods and Findings:
We conducted a cohort study of trials supporting new drugs approved between 1998 and
2000, as described in FDA medical and statistical review documents and the FDA approved
drug label. We determined publication status and time from approval to full publication
in the medical literature at 2 and 5 y by searching PubMed and other databases through
01 August 2006. We then evaluated trial characteristics associated with publication. We
identified 909 trials supporting 90 approved drugs in the FDA reviews, of which
43% (394/909) were published. Among the subset of trials described in the
FDA-approved drug label and classified as “pivotal trials” for our
analysis, 76% (257/340) were published. In multivariable logistic regression
for all trials 5 y postapproval, likelihood of publication correlated with statistically
significant results (odds ratio [OR] 3.03, 95% confidence
interval [CI] 1.78–5.17); larger sample sizes (OR 1.33 per
2-fold increase in sample size, 95% CI 1.17–1.52); and pivotal
status (OR 5.31, 95% CI 3.30–8.55). In multivariable logistic
regression for only the pivotal trials 5 y postapproval, likelihood of publication
correlated with statistically significant results (OR 2.96, 95% CI
1. 24–7.06) and larger sample sizes (OR 1.47 per 2-fold increase in sample
size, 95% CI 1.15–1.88). Statistically significant results and
larger sample sizes were also predictive of publication at 2 y postapproval and in
multivariable Cox proportional models for all trials and the subset of pivotal
trials.
Conclusions:
Over half of all supporting trials for FDA-approved drugs remained unpublished ≥
5 y after approval. Pivotal trials and trials with statistically significant results and
larger sample sizes are more likely to be published. Selective reporting of trial
results exists for commonly marketed drugs. Our data provide a baseline for evaluating
publication bias as the new FDA Amendments Act comes into force mandating basic results
reporting of clinical trials.
Zdroje
1. [No author listed]
2006
Content and format of an application.
Code of Federal Regulations (CFR) Title 21, Pt. 314.50
2. [No author listed]
2006
Availability for public disclosure of data and information in an
application or abbreviated application.
CFR Title 21, Pt. 314.430
3. [No author listed]
2006
Freedom of Information Act.
Title 5 US Code 552(b)(4)
4. Simes
RJ
1986
Publication bias: the case for an international registry of clinical
trials.
J Clin Oncol
4
1529
1541
5. Chalmers
I
1990
Underreporting research is scientific misconduct.
JAMA
263
1405
1408
6. Nissen
SE
Wolski
K
2007
Effect of rosiglitazone on the risk of myocardial infarction and death from
cardiovascular causes.
N Engl J Med
356
2457
2471
7. New York State Court
(2
6
2004)
Spitzer v. GlaxoSmithKline PLC
New York Superior Court
No. 04/401707.
8. Topol
EJ
2004
Failing the public health—Rofecoxib, Merck, and the
FDA.
N Engl J Med
351
1707
1709
9. Mathews
A
Martinez
B
(01
11
2004)
E-mails suggest Merck knew Vioxx's dangers at early stage.
Wall Street Journal
1
10. Benjamin
DK
Jr.
Smith
PB
Murphy
MD
Roberts
R
Mathis
L
2006
Peer-reviewed publication of clinical trials completed for pediatric
exclusivity.
JAMA
296
1266
1273
11. Sim
I
Chan
AW
Gülmezoglu
AM
Evans
T
Pang
T
2006
Clinical Trial Registration: Transparency is the Watchword.
The Lancet
367
1631
1633
12. Laine
C
Horton
R
Deangelis
CD
Drazen
JM
Frizelle
FA
2007
Clinical trial registration: Looking back and moving ahead.
N Engl J Med
356
2734
2736
13. Committee on the Assessment of the US Drug Safety System
2007
The future of drug safety: Promoting and protecting the health of the
public.
In:
Baciu
A
Stratton
K
Burke
SP
Washington (D. C.)
National Academies Press
14. Hemminki
E
1980
Study of information submitted by drug companies to licensing
authorities.
BMJ
280
833
836
15. Melander
H
Ahlqvist-Rastad
J
Meijer
G
Beermann
B
2003
Evidence b(i)ased medicine—Selective reporting from studies
sponsored by pharmaceutical industry: review of studies in new drug
applications.
BMJ
326
1171
1173
16. Turner
EH
Matthews
AM
Linardatos
E
Tell
RA
Rosenthal
R
2008
Selective publication of antidepressant trials and its influence on
apparent efficacy.
N Engl J Med
358
252
260
17. MedAdNews
2005
Top 50 companies.
Available: http://www.pharmalive.com/magazines/medad/view.cfm?articleID=3799&f=3797.
Accessed 3 August 2007.
18. Moher
D
Schulz
KF
Altman
DG
2001
The CONSORT statement: revised recommendations for improving the quality of
reports of parallel-group randomized trials.
Ann Intern Med
134
657
662
19. Khan
A
Khan
SR
Leventhal
RM
Krishnan
KR
Gorman
JM
2002
An application of the revised CONSORT standards to FDA summary reports of
recently approved antidepressants and antipsychotics.
Biol Psychiatry
52
62
67
20. [No authors listed]
2007
PhRMA clinical study results database.
Available: http://www.clinicalstudyresults.org/home/. Accessed 14 July
2008.
21. Dickersin
K
Chan
S
Chalmers
TC
Sacks
HS
Smith
H
Jr.
1987
Publication bias and clinical trials.
Control Clin Trials
8
343
353
22. Krzyzanowska
MK
Pintilie
M
Tannock
IF
2003
Factors associated with failure to publish large randomized trials
presented at an oncology meeting.
JAMA
290
495
501
23. Smith
R
2005
Medical journals are an extension of the marketing arm of pharmaceutical
companies.
PLoS Med
2
e138
doi:10.1371/journal.pmed.0020138
24. Lee
KP
Boyd
EA
Holroyd-Leduc
JM
Bacchetti
P
Bero
LA
2006
Predictors of publication: Characteristics of submitted manuscripts
associated with acceptance at major biomedical journals.
Med J Aust
184
621
626
25. Olson
CM
Rennie
D
Cook
D
Dickersin
K
Flanagin
A
2002
Publication bias in editorial decision making.
JAMA
287
2825
2828
26. Moher
D
Jones
A
Lepage
L
2001
Use of the CONSORT statement and quality of reports of randomized trials: A
comparative before-and-after evaluation.
JAMA
285
1992
1995
27. Chan
AW
Hrobjartsson
A
Haahr
MT
Gotzsche
PC
Altman
DG
2004
Empirical evidence for selective reporting of outcomes in randomized
trials: comparison of protocols to published articles.
JAMA
291
2457
2465
28. Groves
T
2008
Mandatory disclosure of trial results for drugs and
devices.
BMJ
336
170
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