www.thelancet.com Vol 369 June 9, 2007 1909
or practical trials obtain scientifi c evidence for
decisionmaking in health care by measuring eff ectiveness
(“does it work?”) rather than effi cacy (“can it work?”).
Clinically relevant interventions are examined in the full
range of patients (with minimum exclusion criteria),
care besides intervention is according to prevailing
practice, and relevant outcome measures, including
cost-eff ectiveness, are reported.9 Because pragmatic trials
maximise external validity (generalisability), internal
validity (reliability of the results) might be compromised.10
However, Khan avoided possible methodological fl aws
such as patients’ selection, inadequate randomisation,
contamination of intervention, and biased assessment of
outcome. Developing countries see too few studies, such
as Khan’s, that provide scientifi c evidence for decisions in
The primary objective of Khan and colleagues’ study
was to investigate the eff ect of the intervention in
women, because women test smear-positive less often
than men, especially in Asia.11 Gender might aff ect
the diagnosis of tuberculosis. First, health services
might be less accessible to women than to men, or
diagnostic tests of any kind might be less likely to
be done in women than in men. Second, not many
women might know the diff erence between saliva
and sputum, or be comfortable to cough deeply and
expectorate. Third, for biological reasons, women with
tuberculosis might have less infl ammation and a lower
frequency of productive cough than men.12 In Khan’s
study, the response to intervention was sex-dependent.
Instruction by a female health-worker increased
detection by 63% in women versus 18% in men. Simple
sputum-submission instructions increased detection of
tuberculosis substantially, especially in women. There-
fore combination of this intervention with others,
such as education of health professionals or use of
more sensitive diagnostic methods, might further im-
prove the diagnosis of tuberculosis.
*Bachti Alisjahbana, Reinout van Crevel
Internal Medicine Department, Medical Faculty, Padjadjaran
University, Hasan Sadikin Hospital, Bandung, Indonesia (BA); and
Department of Internal Medicine, Radboud University Nijmegen
Medical Center, Nijmegen, Netherlands (RvC)
We declare that we have no confl ict of interest.
1 Khan MS, Dar O, Sismanidis C, Shah K, Godfrey-Faussett P. Improvement of
tuberculosis case detection and reduction of discrepancies between men
and women by simple sputum-submission instructions: a pragmatic
randomised controlled trial. Lancet 2007; 369: 1955–60.
Pai M, Kalantri S, Dheda K. New tools and emerging technologies for the
diagnosis of tuberculosis: part II. Active tuberculosis and drug resistance.
Expert Rev Mol Diagn 2006; 6: 423–32.
Boehme CC, Nabeta P, Henastroza G, et al. Operational feasibility of using
loop-mediated isothermal amplifi cation (LAMP) for the diagnosis of
pulmonary TB in microscopy centers of developing countries.
J Clin Microbiol 2007; published online March 28. DOI:JCM.02352-06v1.
Fairall LR, Zwarenstein M, Bateman ED, et al. Eff ect of educational outreach to
nurses on tuberculosis case detection and primary care of respiratory illness:
pragmatic cluster randomised controlled trial. BMJ 2005; 331: 750–54.
Steingart KR, Ng V, Henry M, et al. Sputum processing methods to improve
the sensitivity of smear microscopy for tuberculosis: a systematic review.
Lancet Infect Dis 2006; 6: 664–74.
Steingart KR, Henry M, Ng V, et al. Fluorescence versus conventional
sputum smear microscopy for tuberculosis: a systematic review.
Lancet Infect Dis 2006; 6: 570–81.
Nguyen VH, Dinh NS, Anthony RM, Cobelens FG, van Soolingen D.
Fluorescence microscopy for tuberculosis diagnosis. Lancet Infect Dis 2007;
Alisjahbana B, van Crevel R, Danusantoso H, et al. Better patient instruction
for sputum sampling can improve microscopic tuberculosis diagnosis.
Int J Tuberc Lung Dis 2005; 9: 814–17.
Tunis SR, Stryer DB, Clancy CM. Practical clinical trials: increasing the value
of clinical research for decision making in clinical and health policy.
JAMA 2003; 290: 1624–32.
10 Godwin M, Ruhland L, Casson I, et al. Pragmatic controlled clinical trials in
primary care: the struggle between external and internal validity.
BMC Med Res Methodol 2003; 3: 28.
11 Borgdorff MW, Nagelkerke NJ, Dye C, Nunn P. Gender and tuberculosis:
a comparison of prevalence surveys with notifi cation data to explore sex
diff erences in case detection. Int J Tuberc Lung Dis 2000; 4: 123–32.
12 Long NH, Diwan VK, Winkvist A. Diff erence in symptoms suggesting
pulmonary tuberculosis among men and women. J Clin Epidemiol 2002;
In 2005, the International Committee of Medical Journal
Editors (ICMJE) initiated a policy requiring investigators
to deposit information about trial design into an
accepted clinical trials registry before the onset of patient
enrolment.1 This policy aimed to ensure that information
about the existence and design of clinically directive
trials was publicly available, an ideal that leaders in
evidence-based medicine have advocated for decades.2
The policy precipitated much angst among research
investigators and sponsors, who feared that registration
would be burdensome and would stifl e competition.
Yet, the response to this policy has been overwhelming.
The ICMJE promised to re-evaluate the policy 2 years
after implementation. Here, we summarise that re-
evaluation, specifi cally commenting on registries that
meet the policy requirements, the types of studies that
Clinical trial registration: looking back and moving ahead
For the ICMJE see
www.thelancet.com Vol 369 June 9, 2007
require registration, and the registration of trial results.
As is always the case, the ICMJE establishes policy only for
the 12 member journals, but many other journals have
adopted our initial trial registration recommendations,
and we hope that they will also adopt the modifi cations
discussed in this update.
The research community has embraced trial
registration. Before the ICMJE policy, ClinicalTrials.
gov, the largest trial registry at the time, contained
13 153 trials; this number climbed to 22 714 a month
after the policy went into eff ect.3 In April 2007, the
registry contained over 40 000 trials, with more
than 200 new trial registrations occurring weekly
(Zarin D, personal communication). The four other
registries that meet the ICMJE criteria have also grown
as scores of journals have adopted the ICMJE clinical
trials registration policy. In response to burgeoning
registration, many investigators, sponsors, and govern-
ment agencies have asked the ICMJE to recognise
their local registries as databases that meet the policy.
Fortunately, WHO’s International Clinical Trial Registry
Platform (ICTRP), which was nascent when the ICMJE
began to require trial registration, has matured rapidly
and provides options for those that desire a wider
array of registries. The ICTRP has taken the fi rst steps
toward developing a network of primary and partner
registers that meet WHO-specifi ed criteria.4 Primary
registers are WHO-selected registers managed by not-
for-profi t entities that will accept registrations for any
interventional trials, delete duplicate entries from their
own register, and provide data directly to WHO. Part ner
registers, which will be more numerous, will include
registers that submit data to primary registers but limit
their own register to trials in a restricted area (such as
a specifi c disease, company, academic institution, or
The ICMJE strongly supports WHO’s eff orts, through the
ICTRP, to develop a coordinated process for identifying,
gathering, deduplicating, and searching trials from
registries around the world, thus eventually providing
a one-stop search portal for those seeking information
about clinical trials. In addition to the fi ve existing
registries, the ICMJE will now also accept registration in
any of the primary registers that participate in WHO’s
ICTRP (panel). Because it is critical that trial registries
are independent of for-profi t interests, the ICMJE policy
requires registration in a WHO primary register rather
than solely in a partner register, since for-profi t entities
manage some partner registers. As previously, trial
registration with missing or uninformative fi elds for the
minimum data elements is inadequate.1
Initially, the ICMJE required registration of all clinically
directive trials, which it defi ned as “any research
project that prospectively assigns human subjects
to intervention or comparison groups to study the
cause-and-eff ect relationship between a medical
intervention and a health outcome”.1 In May, 2005, the
ICMJE clarifi ed this defi nition to exclude preliminary
trials designed to study pharmacokinetics or major
unknown toxicity (phase I trials).5 However, the ICMJE
recognises the potential benefi t of having information
about preliminary trials in the public domain, because
these studies can guide future research or signal safety
concerns. Consequently, the ICMJE is expanding the
defi nition of the types of trials that must be registered
to include these preliminary trials and adopts WHO’s
defi nition of clinical trial: “any research study that
prospectively assigns human participants or groups of
humans to one or more health-related interventions
to evaluate the eff ects on health outcomes.”4 Health-
related interventions include any intervention used
to modify a biomedical or health-related outcome
(eg, drugs, surgical procedures, devices, behavioural
treatments, dietary interventions, and process-of-care
changes). Health outcomes include any biomedical
or health-related measures obtained in patients or
participants, including pharmacokinetic measures and
adverse events. As previously, purely observational
studies (those in which the assignment of the medical
Panel: Key summary points
In addition to accepting registration in any of the fi ve existing
registries, the ICMJE will accept registration of clinical trials in
any of the primary registers that participate in WHO’s ICTRP.
Registration in a partner register only is insuffi cient.
The ICMJE will begin to implement the WHO defi nition of
clinical trials for all trials that begin enrolment on or after
July 1, 2008. This defi nition states that a clinical trial is “any
research study that prospectively assigns human participants
or groups of humans to one or more health-related
interventions to evaluate the eff ects on health outcomes”.
The ICMJE will not consider results posted in the same clinical
trials registry in which the primary registration resides to be
previous publication if the results are presented in the form
of a brief structured (<500 words) abstract or table.
Comment Download full-text
www.thelancet.com Vol 369 June 9, 2007 1911
intervention is not at the discretion of the investigator)
will not require registration. The ICMJE member journals
will start to implement the expanded defi nition of
clinically directive trials for all trials that begin enrolment
on or after July 1, 2008. Those who are uncertain
whether their trial meets the expanded ICMJE defi nition
should err on the side of registration if they wish to seek
publication in an ICMJE journal.
Over the time during which registration of trial
methods has become common practice, several forces
have begun advocating for registration of trial results.
We recognise that the climate for results registration
will probably change dramatically and unpredictably
over coming years. For the present, the ICMJE will not
consider results posted in the same primary clinical
trials register in which the initial registration resides as
previous publications if the results are presented in the
form of a brief structured (<500 words) abstract or table.
The ICMJE favours a standard abstract format for results
reporting, and the CONSORT (Consolidated Standards
for the Reporting of Trials) group’s forthcoming
guidelines for abstracts related to trials may be one
such option. The ICMJE believes that parties interested
in results registration should consider requiring the
deposition of such an abstract in the registry 24 months
after closure of data collection if results are not published
in a peer-reviewed venue by that time. The registered
abstract should either cite any related full peer-reviewed
publications or include a statement that indicates that
the report has not yet been published in a peer-reviewed
journal. Researchers should be aware that editors may
consider more detailed deposition of trial results in
publicly available registries to be prior publication. When
submitting a paper, authors should fully disclose to
editors all posting in registries of results of the same or
closely related work.
3 years ago, trials registration was the exception; now
it is the rule. Registration facilitates the dissemination
of information among clinicians, researchers, and
patients, and it helps to assure trial participants that
the information that accrues as a result of their altruism
will become part of the public record. WHO’s global
eff orts towards comprehensive trials registration and
the ICMJE’s requirements for registration aim to increase
public trust in medical science.
Christine Laine, Senior Deputy Editor, Annals of Internal
Medicine; Richard Horton, Editor, The Lancet;
Catherine D DeAngelis, Editor-in-Chief, Journal of the
American Medical Association; Jeff rey M Drazen,
Editor-in-Chief, New England Journal of Medicine;
Frank A Frizelle, Editor-in-Chief, The New Zealand Medical
Journal; Fiona Godlee, Editor-in-Chief, BMJ; Charlotte Haug,
Editor-in-Chief, Norwegian Medical Journal; Paul C Hébert,
Editor-in-Chief, Canadian Medical Association Journal;
Sheldon Kotzin, Executive Editor, MEDLINE, National Library
of Medicine; Ana Marusic, Editor, Croatian Medical Journal;
Peush Sahni, Representative and Past President, World
Association of Medical Editors; Torben V Schroeder, Editor,
Journal of the Danish Medical Association; Harold C Sox,
Editor, Annals of Internal Medicine;
Martin B Van Der Weyden, Editor, The Medical Journal of
Australia; Freek W A Verheugt, Executive Editor, Nederlands
Tijdschrift voor Geneeskunde (Dutch Journal of Medicine)
PS’s affi liation as a representative and past president of the World Association of
Medical Editors (WAME) does not imply endorsement by WAME member
journals that are not part of the ICMJE; he was a WHO Temporary Advisor for the
meeting Mental Health Research in Developing Countries: Role of Scientifi c
Journals, Nov 20–21, 2003, Geneva, Switzerland, for which he received travel and
accommodation support, and for the workshop Improving Scientifi c
Communication in South-East Asia, Nov 17–19, 1996, New Delhi, India, for
which he received a subsistence allowance. FG is was previously editorial director
of Current Controlled Trials, which owns the ISRCTN (International Standard
Randomised Controlled Trial Number) trials register. SK is employed by the
National Library of Medicine, which produces ClinicalTrials.gov; he is not
responsible for activities or policies regarding ClinicalTrials.gov. FG has given
expert testimony. RH is Co-Chair of the WHO ICTRP Scientifi c Advisory Group,
and JMD and HCS are members of that group. MB Van Der W is a member of the
government advisory committee for the Australian and New Zealand Clinical
1 Clinical trial registration: a statement from the International Committee of
Medical Journal Editors. http://www.icmje.org/clin_trial.pdf (accessed
May 22, 2007).
Simes RJ. Publication bias: the case for an international registry of clinical
trials. J Clin Oncol 1986; 4: 1529–41.
Zarin DA, Tse T, Ide NC. Trial registration at ClinicalTrials.gov between May
and October 2005. N Engl J Med 2005; 353: 2779–87.
World Health Organization. Internation clinical trials registry platform
(ICTRP). May 2, 2007. http://www.who.int/ictrp/about/details/en/index.html
(accessed May 22, 2007).
International Committee of Medical Journal Editors. Is this clinical trial fully
registered? A statement from the International Committee of Medical Journal
Editors. http://www.icmje.org/clin_trialup.htm (accessed May 22, 2007).