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The Latin AmericanOngoing Clinical TrialRegister (LATINREC)

Ludovic Reveiz,1 Martha B. Delgado,2

Gerard Urrutia,3 Zulma Ortiz,4

Marcelo Garcia Dieguez,5

Arturo Martí-Carvajal,6 Erwin Calgua,7

Armando Vieyra,8 Agustín Ciapponi,9

Ricardo Hidalgo,10 Tomás Pantoja,11

Luis María Sanchez,12

Flora Martínez Pecino,13

and Mario Tristan14

1 Coordinator, Colombian Collaborating Branch of the IberoamericanCochrane Network, Instituto de Investigaciones Fundación Univer-sitaria Sánitas (II-FUS), Santa Fe de Bogotá, Colombia. Director,LATINREC. Send correspondence and reprint requests to: LudovicReveiz, Edificio de Consultorios Clínica Reina Sofía Diag 127 A # 3–48cons 221, Santa Fe de Bogotá, Colombia; fax: (57) 1 6159435; e-mail:lureveiz@colsanitas.com

2 Coordinator, Colombian Collaborating Branch of the IberoamericanCochrane Network, Unidad de Epidemiología Clínica, Pontificia Uni-versidad Javeriana. Editorial Project Manager, LATINREC. Santa Fede Bogotá, Colombia.

3 Iberoamerican Cochrane Center. Servei d’Epidemiologia Clinica i SalutPublica de l’Hospital de la Sant Creu i Sant Pau, Barcelona, Spain.

4 Coordinator, Argentine Collaborating Branch of the IberoamericanCochrane Network (CIE, Academia Nacional de Medicina), BuenosAires, Argentina.

5 Coordinator, Argentine branch of LATINREC. Argentine Collabo-rating Branch of the Iberoamerican Cochrane Network (CIE, Acade-mia Nacional de Medicina), Buenos Aires, Argentina.

6 Coordinator, Venezuelan Collaborating Branch of the IberoamericanCochrane Network, Universidad de Carabobo, Valencia, Venezuela.

7 Coordinator-Director, International Health Central American Insti-tute Foundation (Guatemala), Central American CollaboratingBranch of the Iberoamerican Cochrane Network; Universidad de SanCarlos de Guatemala, Guatemala City, Guatemala.

8 Coordinator, Mexican Collaborating Branch of the IberoamericanCochrane Network. Instituto Nacional de Salud de México, México,D.F., México.

9 Coordinator, Argentine Colombian Collaborating Branch of theIberoamerican Cochrane Network (IECS), Buenos Aires, Argentina.

10 Coordinator, Ecuatorian Collaborating Branch of the IberoamericanCochrane Network, Quito, Ecuador.

11 Coordinator, Chilean Collaborating Branch of the IberoamericanCochrane Network, Unidad Medicina Basada en Evidencia, Pontifi-cia Universidad Católica de Chile, Santiago, Chile.

Although the need to request researchers and re-search institutions to register clinical trials at theirinception in a publicly and universally accessibleregister has been considered for years (1), it hasonly recently become a major issue (2–4). The com-munity and scientific world have been confrontinga complex and chaotic mass of information withconflicting messages about scientific evidence of ef-ficacy and harms. A recent editorial by the Inter-national Committee of Medical Journal Editors(ICMJE) supported the need for a comprehensivetrial register that meets several criteria (2). Addi-tionally, the World Health Organization (WHO) ispromoting an international initiative to develop ametaregister of controlled trials that would offer a one–stop search portal fed from existing regis-ters and provide a unique identification number for clinical trials from certified registries that meetstandard criteria for the exchange of essential trialdata (4).

Some important challenges are to develop ascheme to reduce duplication of work, inequitablefunding of research, and neglected diseases; toavoid research on irrelevant issues or the measure-ment of irrelevant outcomes; and to enhance ethicsand transparency. Research should be freely avail-able to the public to avoid publication bias and se-lective reporting and to improve access to informa-tion on benefits and harms.

Despite the intense interest in this topic thereis a wide gap between theoretical postulates on trialregistration and their implementation. This gapmay be due to the absence of universal criteria forregistration and differing interests of researchers,the pharmaceutical industry, funders, government,and society. In addition, registers are at differentstages of development, particularly those in devel-oping countries.

The purpose of this article is to discuss theconcepts of publication bias and prospective reg-istration of clinical trials. Subsequently, we willconsider Latin America as a source of ongoing trialsand propose The Latin American Ongoing ClinicalTrial Register (LATINREC) as a solution to mitigate

Key words: clinical trial, conflict of interest, ethicscommittees, publication bias, randomized controlledtrials.

12 Coordinator, Madrid Collaborating branch of the IberoamericanCochrane Network, Madrid, Spain.

13 Coordinator, Andalucian Collaborating Branch of the IberoamericanCochrane Network. Agencia de Evaluación de Tecnologías Sani-tarias de Andalucía (CC-AETSA), Seville, Spain.

14 Coordinator, Costa Rica Collaborating Branch of the IberoamericanCochrane Network, San José, Costa Rica.

the problem of publication bias in Latin Americaand the Caribbean.

PUBLICATION BIAS, SELECTIVEREPORTING, AND MULTIPLEPUBLICATIONS

Publication bias refers to the bias introducedby the selective publication of research results (5).For example, publication bias is known to occur“because studies with results that are statisticallysignificant, interesting, from large well-fundedstudies, or of higher quality are more likely to besubmitted, published, or published more rapidlythan work without such characteristics” (5). Thistendency is particularly relevant when results ap-pear significant, because negative or near-neutralresults are almost never published.

For a range of reasons, including keepingreadership high and costs low, journals limit theirtrial reporting to a fraction of the available trialsand findings. People searching for biomedical in-formation may remain oblivious to or unable toaccess trial results published in journals not in-dexed in broadly available databases. To addressthis issue, the Cochrane Collaboration publishedCENTRAL, a database fed by hand-searching fortrials from a broad range of publications from 1948to the present. Approximately one third of the trialsfound in CENTRAL were not indexed in MEDLINE,the most widely used open access biomedical bibli-ographic database (1). Hand searching has helpedto reduce publication bias and duplicate research,but is a costly and time-consuming option that re-mains susceptible to the omission of relevant or es-sential trials.

Trials may not be published for a variety ofreasons, such as methodological errors in design,failure to enroll an adequate number of patients,lack of statistical power, publication of similar re-sults that make the trial irrelevant, the materialbeing the subject of an undergraduate thesis, fund-ing cuts, lack of time for statistical analysis andmanuscript preparation, editorial rejection, or be-cause the trial results were unfavorable to the spon-sor’s product (6, 7). There is good empirical evi-dence of a significant difference between the resultsfrom unpublished and published trials. However,the direction, impact, and extent of publication biasmay vary. Publication bias can arise from differentcomponents involved in research and its dissemi-nation, and investigators, peer reviewers, editors,funding bodies and research sponsors are fre-quently found to be involved (7–9).

Egger and colleagues evaluated the character-istics of “difficult-to-locate trials” and estimated the

impact of excluding these trials on the pooled esti-mates of metaanalyses. They found that unpub-lished trials contributed, on average, about 18% ofthe weight in individual metaanalyses. The changesin pooled estimates of metaanalyses when unpub-lished trials were removed ranged from a reductionof 28% to an increase of 24% in the benefits of the in-tervention. These authors also found that unpub-lished trials were less frequently about evaluatingdrugs, had smaller sample sizes, and were lesslikely to present statistically significant results (7).

Major ethical issues have been raised by sev-eral authors regarding not publishing and not re-porting trials results (1, 10–12). Dickersin and Renniehave rightly argued that “the distortion of medicalevidence, aside from being unethical, actually harmsthe patients” (1).

Outcome reporting bias refers to the bias in-troduced in trials where a range of outcome mea-sures may be collected but not all are always re-ported. This type of bias has been found in severalstudies of published trials, including trials ap-proved by ethical review boards (13, 14). The spec-ification of primary outcomes and analysis plans inprotocols before trial initiation has been suggestedto prevent outcome reporting bias (2).

Duplicate publication is publication of an ar-ticle that overlaps substantially with an article pub-lished in print or electronic media (15). Von Elmand colleagues identified six distinct duplicationpatterns and found that the prevalence of covertduplicate articles (without a cross-reference to themain article) was 5.3%. Systematic reviewers fre-quently have to deal with this practice, whichwastes resources and time and is misleading, as theconclusion of a systematic review may changewhen the results of a trial are included twice (16).

An additional problem in metaanalyses thatspeaks in favor of more visible access to scienceproduced in Latin America is the inclusion of re-search published in languages other than English.This could lead to a particular form of publicationbias called language bias, in which randomizedcontrolled trials (RCTs) with positive effects orgreater estimates of effect size tend to be publishedin English-language journals rather than in the orig-inal authors’ native languages (17, 18). A compari-son of the estimated effect of non-English languagetrials to those published in English found little in-fluence on summary treatment effect, but the im-portance is difficult to predict for individual sys-tematic reviews (19). Comprehensive searches arestrongly suggested as Anglophone databases andjournals considerably under-represent the totalityof RCTs (20–22).

Pharmaceutical industry funding of biomed-ical research has increased dramatically in the last

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two decades, leading to frequent conflicts of interestand complex financial relationships between corpo-rate sponsors of research and the investigators whoperform clinical trials (23, 24). The CONSORT state-ment increased the awareness of the need to ade-quately report the findings of RCTs (25). In addi-tion, a number of industry members have proposeda series of guidelines to promote good publicationpractices in order to achieve greater transparency(26, 27). However, a substantial number of com-pleted trials are believed to remain unpublished (6);therefore, many safeguards are needed to ensure atransparent trial reporting system.

PROSPECTIVE TRIAL REGISTERS

The prospective, universal registration of allstudies at their inception has been proposed as a so-lution to mitigate publication bias, selective report-ing and multiple publication. Proponents includethe International Committee of Medical JournalEditors, the World Association of Medical Editors(WAME), and the Cochrane Collaboration (2, 28,29). During the Twelfth Cochrane Colloquium heldin Ottawa in 2004, this issue was debated and theOttawa group created. The Ottawa Group is an in-dependent grassroots organization of interestedstakeholders that has been conducting a worldwidedialogue on trial registration. It developed the Ot-tawa Statement Part 1 on the principles of trial reg-istration, which was recently published and en-dorsed by about 150 individuals and groups (3).The Ottawa Statement Part 2, on the principles ofimplementation of trial registration, is currentlyopen for comments and endorsement at http://ottawagroup.ohri.ca.

Numerous database registers have been de-veloped and used, most of them based in wealthycountries. Some database registers have imple-mented rules that allow users to search, registerand share information about RCTs with a minimumdata set that provides basic information for eachclinical trial and a unique identification scheme.The Current Controlled Trials register (www.controlled-trials.com) developed in the UK, andClinicalTrials.gov (www.clinicaltrials.gov), spon-sored by the United States National Library ofMedicine, have accumulated practical experience inrecent years and are recognized participants in dis-cussions and decision-making processes relating totrial registration (22, 30).

The Ottawa group and WHO are promotingthe agreement and international norms and stan-dards for clinical trial registration and reporting (3,4). WHO proposed the development of an Interna-tional Clinical Trials Registry Platform (ICTRP),

whose primary objectives are “to ensure that allclinical trials are registered and thus publicly de-clared and identifiable, so as to ensure that for alltrials, a minimum set of results will be reported andmade publicly available.” By registering ongoingand forthcoming clinical trials, researchers are en-couraged to provide general information and par-ticular details about the methods of the study pro-tocol and interventions for human participantsrelated to prevention, screening, diagnosis, treat-ment, health promotion, rehabilitation, or organiza-tion and financing of care.

The ICTRP suggested that trial sponsors or re-searchers should record in a certified and publiclyaccessible registry a minimum data set prior toparticipant recruitment, and should then conveythis information to ICTRP (Table 1). This platformwould produce a unique identification numberonce it has checked that the trial is unique and cri-teria are fulfilled, and feed back to the registers. Tri-alists can apply for a unique identification numberat the time of application to their institutional re-view board, but they would always need to providea final copy of the protocol as approved by the in-stitutional review board. As defined by the WHOtechnical consultation on Clinical Trials Registra-tion Standards, “[a]ny research project that pro-spectively assigns human participants or groups toone or more health-related interventions to evalu-

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TABLE 1. Minimum data set that should be recorded forclinical trial registration, according to the World Health Or-ganization, 2005

• Primary register trial number

• Trial registration date

• Secondary IDs

• Source(s) of monetary or material support

• Primary sponsor

• Secondary sponsor(s)

• Contact for public queries

• Contact for scientific queries

• Public title (of the study)

• Scientific title

• Countries of recruitment

• Health condition or problems studied

• Intervention(s)

• Key inclusion and exclusion criteria

• Study type

• Date of the first enrollment (anticipated or actual date of theenrollment of the first study participant)

• Target sample size

• Recruitment status

• Primary outcome(s)

• Key secondary outcomes

ate the effects on health outcomes should be regis-tered” (4).

In addition, the Ottawa Group recommendsprospective registration of all trials, public disclo-sure of standard key trial details, registration of anysubsequent amendments, and registration and pub-lic disclosure of all results once the analyses arecompleted and verified. However, some stakehold-ers have asked for delayed public disclosure ofsome data items (official scientific title of the study,interventions, primary outcome, key secondary out-comes, and target sample size) in instances wherethey may be considered sensitive for competitivecommercial reasons (31, 32). In addition, they con-sider that early phase trials do not result in infor-mation that can inform clinical practice and shouldnot be registered (32). But as Michael Goodyear re-cently noted, “[t]he recent tragic events in a phase Itrial at Northwick Park Hospital in London, and the subsequent lack of available information, high-light the necessity of registration of the details of alltrials” (33).

Several majors barriers have been recognizedto development of a comprehensive register of clin-ical trials: the lack of funding appropriation forsustained effort, resistance from different parties in-cluding the pharmaceutical industry, lack of mech-anisms for enforcement, and lack of awareness ofthe importance of the problem (1). Also, differentregisters address the needs of different constituen-cies (e.g., countries and regions; disease-specific orsponsor-specific aspects) and have different pur-poses (e.g., administrative, enrollment, scientificdatabase), making it unrealistic to consider a single,unique register. In addition, registers frequently failto identify and register trials conducted in develop-ing countries or with local funding, partly becauseof a lack of awareness, language barriers, costs, orsimply because trialists remain unaware of the rea-sons for registering and how to do it, can’t afford it,or fail to identify clear benefits of registration (1).

CLINICAL TRIALS IN LATIN AMERICA

In 2003, Latin America and the Caribbean pub-lished 35 299 (3.3%) references in Science CitationIndex and 12 359 (2.2%) references in MEDLINE,representing an increase in the number of citationsof 14% and 30%, respectively, compared to 1999.About 80% of all Latin American citations in thesetwo databases during 2003 came from Brazil, Ar-gentina, or Mexico (34).

Based on a MEDLINE search, 2 149 articlespublished between January 2004 and December2004 were identified as dealing with or having au-

thors from the Latin American countries Argentina,Barbados, Belize, Bolivia, Brazil, Chile, Colombia,Costa Rica, Cuba, Dominican Republic, Ecuador, El Salvador, Guatemala, Guyana, Haiti, Honduras,Jamaica, Mexico, Nicaragua, Panama, Paraguay,Peru, Puerto Rico, Trinidad and Tobago, Uruguayor Venezuela. The search was limited to referencesof RCTs using the PubMed filter recommended byRobinson (35).

The Latin American and Caribbean Center onHealth Sciences Information (LILACS) database isavailable in Latin America and Caribbean countries.This database is a regional collection of the healthscience-related literature published since 1982.LILACS gathers data from about 670 medical jour-nals and has over 150 000 records. Roughly 104 000records were found using the clinical trial filter rec-ommended on its website (www.bireme.br/bvs/I/ibd.htm) (36). However, this filter may have lowspecificity for detecting RCTs (37, 38)

LATIN AMERICAN ONGOING TRIALSREGISTER (LATINREC)

The Colombian Branch of The Iberoameri-can Cochrane Network has been developing theLatin American Ongoing Clinical Trials Register(LATINREC) to collect information on clinical trialsundertaken in Latin American countries, make thisinformation available to the public, and providemethodological information and other tools asrequired by trialists. This project was funded by the International Clinical Epidemiology Network(INCLEN) in 2003, and its website is www.latinrec.org.

LATINREC will be a freely available andsearchable register. To register a study, trialists will submit information including the basic datarequired by the ICTRP and will receive a WHO-assigned unique identification number. In addition,LATINREC will allow trialists to include subsequentprotocol amendments and preliminary results.

To populate the register, LATINREC will workwith government entities, research centers, univers-ities, companies producing and developing medi-cines, diagnostic tests and other healthcare inter-ventions, foundations, and funding agencies. Asearch will be performed periodically on MEDLINE,the Cochrane Library and LILACS to identify re-searchers possibly involved in clinical trials in LatinAmerica, and these researchers will be contacted.LATINREC is also considering e-mail contact withknown researchers to learn about other ongoing tri-als (7). Protocols can be completed in the trialist’snative language (Spanish, French, English, or Por-

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tuguese) but information will be translated to En-glish to apply for a unique identifier.

The Cochrane Collaboration (www.cochrane.org) is committed to providing the most reliable ev-idence of the effectiveness of health care throughsystematic reviews of RCTs. The Collaboration rec-ognizes the importance of prospectively registeringtrials to ensure that the evidence assessed is validand comprehensive, and to minimize the risk ofpublication and reporting bias. The IberoamericanCochrane Center is based at the Hospital de la SantaCreu i Sant Pau in Barcelona, Spain. This Center hasevolved into a network and has assisted twelveCollaborative Centers in ten Latin American coun-tries (Argentina, Chile, Colombia, Costa Rica, Cuba,Ecuador, Guatemala, Mexico, Peru and Venezuela),all of which participate in LATINREC.

CONCLUSION

The Iberoamerican Cochrane Network of theCochrane Collaboration has set up the Latin Amer-ican Ongoing Clinical Trials Register (LATINREC)to facilitate sharing basic information for ongoingclinical trials. This register will comply with theOttawa Statement criteria and WHO’s ICTRP. Theregister will be launched in June 2006 (visit www.latinrec.org), registration will be free of charge, andthe contents will be freely available to the public. Itshould be noted that pharmaceutical industry regu-lations sometimes restrict public access to some in-formation to ensure intellectual property protectionand avoid the financial implications of making pro-prietary knowledge available to competitors. How-ever, registration of clinical trials is expected to helpenhance the general public’s trust in medical sci-ence and the pharmaceutical industry.

Acknowledgment. The authors wish to ac-knowledge the valuable contributions made byLuis Gabriel Cuervo towards enriching and im-proving this manuscript.

SINOPSIS

El Registro Latinoamericano de EnsayosClínicos en Curso (LATINREC)

Debido a los sesgos que afectan a la publicación de ensayosclínicos y sus resultados, los estudios cuyos resultados son po-sitivos son más fáciles de encontrar que los que tienen resul-tados sin significación estadística y a ello se debe que los pri-meros estén sobrerrepresentados. Para contrarrestar este tipode sesgo se ha propuesto ingresar en un registro toda investi-gación, desde sus comienzos. No obstante, estos registros seencuentran en distintas fases de evolución, especialmente enpaíses en desarrollo, de tal manera que la Red Cochrane Ibe-roamericana, parte de la Colaboración Cochrane, ha esta-blecido el Registro Latinoamericano de Ensayos Clínicos enCurso (LATINREC, por Latin American Clinical Trial Re-gistry) con la idea de facilitar el registro de los datos conteni-dos en el protocolo de todo ensayo clínico que se esté llevandoa cabo en un momento dado y poner esa información a la dis-posición del público. El LATINREC, que viene a respaldar losobjetivos de la Organización Mundial de la Salud (OMS), re-presenta un intento por reducir la duplicación de trabajo y elfinanciamiento poco equitativo de la investigación sobre en-fermedades rezagadas al olvido; por evitar que se efectúen in-vestigaciones sobre asuntos de poca cuantía o que se midan re-sultados poco útiles; y por fomentar las prácticas éticas y latransparencia. Se han detectado algunos obstáculos mayoresque hasta ahora han impedido crear un registro único y comúnde ensayos clínicos. Con el fin de franquearlos, LATINRECserá un registro gratuito que permitirá hacer búsquedas y quese ceñirá a la Plataforma Internacional de Registro de Ensa-yos Clínicos (ICTRP) de la OMS. Además, LATINREC per-mitirá que los investigadores ingresen en el registro cualquiermodificación del protocolo, así como los resultados prelimina-res. LATINREC ofrecerá grandes ventajas para los consumi-dores, el gobierno, los profesionales de la salud pública y la in-dustria farmacéutica al incrementar la accesibilidad de lainformación y la participación en los ensayos clínicos. La dis-ponibilidad de información objetiva acerca de todo ensayo clí-nico que se inicie ayudará a garantizar que todos tengan libreacceso a los conocimientos generados.

Key words: Ensayos clínicos, conflicto de intereses,comités de ética, sesgo de publicación, ensayos clí-nicos aleatorios.

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1. Dickersin K, Rennie D. Registering clin-ical trials. JAMA. 2003;290:516–23.

2. DeAngelis C, Drazen JM, Frizelle FA,Haug C, Hoey J, Horton R, et al. Clinicaltrial registration: a statement from theInternational Committee of MedicalJournal Editors. N Engl J Med. 2004;351:1250–1.

3. Krleza-Jeric K, Chan AW, Dickersin K,Sim I, Grimshaw J, Gluud C (for the Ot-tawa group). Principles for international

registration of protocol information andresults from human trials of health re-lated interventions: Ottawa statement(part 1). BMJ. 2005;330(7497):956–8.

4. World Health Organization. The Inter-national Clinical Trials Registry Plat-form (ICTRP). Available from: http://www.who.int/ictrp/en/. Accessed 23March 2006.

5. Sutton AJ, Duval SJ, Tweedie RL,Abrams KR, Jones DR. Empirical assess-

ment of effect of publication bias onmeta-analyses. BMJ. 2000;320:1574–7.

6. Reveiz L, Cardona AF, Ospina EG.Using e-mail for identifying Random-ized Controlled Trials that are difficultto locate for systematic reviews. J ClinEpidemiol. (in press).

7. Egger M, Juni P, Bartlett C, Holenstein F,Sterne J. How important are comprehen-sive literature searches and the assess-ment of trial quality in systematic re-

REFERENCES

422 Rev Panam Salud Publica/Pan Am J Public Health 19(6), 2006

views? Empirical study. Health TechnolAssess. 2003;7:1–76.

8. Song F, Eastwood AJ, Gilbody S, DuleyL, Sutton AJ. Publication and relatedbiases. Health Technol Assess. 2000;4:1–115.

9. McAuley L, Pham B, Tugwell P, MoherD. Does the inclusion of grey literatureinfluence estimates of intervention effec-tiveness reported in meta-analyses?Lancet. 2000;356:1228–31.

10. Antes G. Registering clinical trial is nec-essary for ethical, scientific and economicreasons. Bull World Health Organ. 2004;82:321.

11. Antes G, Chalmers I. Under-reporting ofclinical trials is unethical. Lancet. 2003,361:978–9.

12. Reveiz L, Cardona AF, Ospina EG. Clin-ical trial registration. N Engl J Med. 200513;352:198–9.

13. Chan AW, Krleza-Jeric K, Schmid I, Alt-man DG. Outcome reporting bias in ran-domized trials by the Canadian Insti-tutes of Health Research. CMAJ. 2004;171:735–40.

14. Chan AW, Haahr MT, Hróbjartsson A,Gotzsche PC, Altman DG. Empiricalevidence for selective reporting of out-comes in randomized trials: comparisonof protocols to published articles. JAMA.2004;291:2457–65.

15. International Committee of MedicalJournal Editors. Uniform requirementsfor manuscripts submitted to biomed-ical journals. Available from: http://www.icmje.org. Accessed 5 April 52006.

16. von Elm E, Poglia G, Walder B, TramerMR. Different patterns of duplicate pub-lication: an analysis of articles used insystematic reviews. JAMA. 2004;25;291(8):974–80.

17. Egger M, Zellweger-Zahner T, Antes G.Randomised trials in German-languagejournals. Lancet. 1996;347:1047–8.

18. Egger M, Zellweger-Zahner T, Schnei-der M, Junker C, Lengeler C, Antes G.Language bias in randomised controlledtrials published in English and German.Lancet. 1997;350:326–9.

19. Juni P, Holenstein F, Sterne J, Barlett C,Egger M. Direction and impact of lan-guage bias in meta-analyses of con-trolled trials: empirical study. Int J Epi-demiol. 2002;31:115–23

20. Bereczki D, Gesztelyi G: A. A Hungar-ian example for handsearching special-ized national healthcare journals ofsmall countries for controlled trials. Is it worth the trouble? Health Libr Rev.2000;17:144–7.

21. Rafalski V, Andreeva I, Ryabkova E.Searching for randomized clinical trialsand controlled clinical trials in Russianmedical journals: Handsearching vs.Medline. Available from: http://www.antibiotic.ru/en/cc/tudor.shtml. Ac-cessed 3 April 2006.

22. Marti J, Bonfil X, Urrutia G, Lacalle J,Bravo R. Identicación y descripción delos ensayos clínicos publicados en re-vistas españolas de medicina general einterna durante el periodo 1971–1995.[The identification and description ofclinical trials published in Spanish jour-nals of general and internal medicineduring the period of 1971–1995]. MedClin (Barc) 1999;112(Suppl 1):28–34.

23. Moses H, Martin JB. Academic relation-ships with industry: a new model forbiomedical research. JAMA. 2001;285:933–5.

24. Bekelman JE, Li Y, Gross CP. Scope andimpact of financial conflicts of interest in biomedical research: a systematicreview. JAMA. 2003;289(4):454–65.

25. Begg C, Cho M, Esatwood S, Horton R,Moher D, Olkin I, et al. Improving thequality of reporting of randomized con-trolled trials. The CONSORT statement.JAMA. 1996;276:637–9.

26. Publication standards for clinical re-search sponsored by the pharmaceuticalindustry. Rev Panam Salud Publica.2003;14:62–6.

27. Wager E. Special article. Good publi-cation practice for pharmaceutical com-panies: where are we now? MedscapeGen Med, Posted 04/18/2005. Availablefrom: http://www.medscape.com/ viewarticle/501752. Accessed 3 April 2006.

28. World Association of Medical Editors.WAME policy statement: the registra-tion of clinical trials 2005. Availablefrom: www.wame.org/wamestmt.htm#trialreg. Accessed 3 April 2006.

29. Cochrane Collaboration statement onregistering clinical trials prospectively.2004. Available from: http://www.cochrane.org/news/articles/2004.07.26.htm. Accessed 3 April 2006.

30. Tonks A. A clinical trials register for Eu-rope. BMJ. 2002;326: 1314–5.

31. Grimes L (Campbell Alliance). The eraof clinical trial registries, a white paper.Available from: http://www. campbellalliance.com/articles/Final_Clinical_Trial_Registries_3-23-05.pdf. Accessed23 March 2006.

32. Abbott response to World Health Orga-nization International Clinical TrialsRegistry Platform (ICTRP) request foropen comments on disclosure timing.Posted 31 March 2006. Available from:ht tp ://www.who. int/ic t rp/005-Abbott_31March06.pdf. Accessed 2April 2006.

33. Goodyear M. Closing the gaps: movingcloser to a collaborative culture. Com-ments on disclosure timing: balancingincreased transparency and competitiveadvantage. Submission to WHO Inter-national Clinical Trials Registry Plat-form March 2006. Available from: http://www.who.int/ictrp/007-Michael_Goodyear_31March06.pdf. Accessed 2April 2006.

34. Red de indicadores de ciencia y tecnolo-gía (RICYT). Datos de producción cientí-fica en bases de datos internacionales.Available from: http://www.ricyt.org/interior/interior.asp?Nivel1=3&Nivel2=1&Idioma=#21. Accessed 25 Septem-ber 2005.

35. Robinson KA, Dickersin K. Devel-opment of a highly sensitive searchstrategy for the retrieval of reports ofcontrolled trials using PubMed. Int JEpidemiol. 2002;31(1):150–3.

36. Virtual Health Library. LILACS—LatinAmerican and Caribbean Health Sci-ences. Available from: http://bases.bireme.br/cgi-bin/wxisl ind.exe/iah/online/?IsisScript=iah/iah.xis&base=LILACS&lang=i. Accessed 25 Sep-tember 2005.

37. Garcia Dieguez M, Esandi ME, KhouryM, Nishishinia MB, Arribas A Compari-son of handsearching with electronicdatabases of clinical trials published inArgentinean indexed journals (abstract).2003. Cochrane Library issue 1 2006.

38. Clark OA, Castro AA. Searching the Li-teratura Latino Americana e do Caribeem Ciencias da Saude (LILACS) data-base improves systematic reviews. Int JEpidemiol. 2002 Feb;31(1):112–4.

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