Clinical trial registration

Clinical trial registration is the practice of documenting clinical trials before they are performed in a clinical trials registry so as to combat publication bias and selective reporting.[1] Registration of clinical trials is required in some countries and is increasingly being standardized.[2] Some top medical journals will only publish the results of trials that have been pre-registered.[3]

Clincal Trial Transparency, a 2017 policy guide, argues for registration

A clinical trials registry is a platform which catalogs registered clinical trials. ClinicalTrials.gov, run by the United States National Library of Medicine (NLM) was the first online registry for clinical trials, and remains the largest and most widely used. In addition to combating bias, clinical trial registries serve to increase transparency and access to clinical trials for the public. Clinical trials registries are often searchable (e.g. by disease/indication, drug, location, etc.). Trials are registered by the pharmaceutical, biotech or medical device company (Sponsor) or by the hospital or foundation which is sponsoring the study, or by another organization, such as a contract research organization (CRO) which is running the study.

There has been a push from governments and international organizations, especially since 2005, to make clinical trial information more widely available and to standardize registries and processes of registering. The World Health Organization is working toward "achieving consensus on both the minimal and the optimal operating standards for trial registration".[4]

Creation and development

For many years, scientists and others have worried about reporting biases such that negative or null results from initiated clinical trials may be less likely to be published than positive results, thus skewing the literature and our understanding of how well interventions work.[5] This worry has been international and written about for over 50 years.[6] One of the proposals to address this potential bias was a comprehensive register of initiated clinical trials that would inform the public which trials had been started.[7] Ethical issues were those that seemed to interest the public most, as trialists (including those with potential commercial gain) benefited from those who enrolled in trials, but were not required to “give back,” telling the public what they had learned.

Those who were particularly concerned by the double standard were systematic reviewers, those who summarize what is known from clinical trials. If the literature is skewed, then the results of a systematic review are also likely to be skewed, possibly favoring the test intervention when in fact the accumulated data do not show this, if all data were made public.

ClinicalTrials.gov was originally developed largely as a result of breast cancer consumer lobbying, which led to authorizing language in the FDA Modernization Act of 1997 (Food and Drug Administration Modernization Act of 1997. Pub L No. 105-115, §113 Stat 2296), but the law provided neither funding nor a mechanism of enforcement. In addition, the law required that ClinicalTrials.gov only include trials of serious and life-threatening diseases.

Then, two events occurred in 2004 that increased public awareness of the problems of reporting bias. First, the then-New York State Attorney General Eliot Spitzer sued GlaxoSmithKline (GSK) because they had failed to reveal results from trials showing that certain antidepressants might be harmful.[8]

Shortly thereafter, the International Committee of Medical Journal Editors (ICMJE) announced that their journals would not publish reports of trials unless they had been registered. The ICMJE action was probably the most important motivator for trial registration, as investigators wanted to reserve the possibility that they could publish their results in prestigious journals, should they want to.

In 2007, the Food and Drug Administration Amendments Act of 2007 (FDAAA) clarified the requirements for registration and also set penalties for non-compliance (Public Law 110-85. The Food and Drug Administration Amendments Act of 2007 .

International participation

The International Committee of Medical Journal Editors (ICMJE) decided that from July 1, 2005 no trials will be considered for publication unless they are included on a clinical trials registry.[9][10] The World Health Organization has begun the push for clinical trial registration with the initiation of the International Clinical Trials Registry Platform. There has also been action from the pharmaceutical industry, which released plans to make clinical trial data more transparent and publicly available. Released in October 2008, the revised Declaration of Helsinki, states that "Every clinical trial must be registered in a publicly accessible database before recruitment of the first subject."[11][12]

The World Health Organization maintains an international registry portal at http://apps.who.int/trialsearch/.[13] WHO states that the international registry's mission is "to ensure that a complete view of research is accessible to all those involved in health care decision making. This will improve research transparency and will ultimately strengthen the validity and value of the scientific evidence base."[14]

Since 2007, the International Committee of Medical Journal Editors ICMJE accepts all primary registries in the WHO network in addition to clinicaltrials.gov. Clinical trial registration in other registries excluding ClinicalTrials.gov has increased irrespective of study designs since 2014.[15]

Reporting compliance

Various studies have measured the extent to which various trials are in compliance with the reporting standards of their registry.[16][17][18][19][20][21]

Overview of clinical trial registries
See also: List of clinical trial registries

Worldwide, there is growing number of registries. A 2013 study[22] identified the following top five registries (numbers updated as of August 2013):

1.ClinicalTrials.gov150,551
2.EU register21,060
3.Japan registries network (JPRN)12,728
4.ISRCTN11,794
5.Australia and New Zealand (ANZCTR)8,216
gollark: https://mw.lojban.org/papri/Lojban
gollark: https://en.wikipedia.org/wiki/Lojban
gollark: Solution: require everyone to use Lojban, which is machine-parseable.
gollark: Probably not very, English is hard.
gollark: There's a Python NLP library but I don't know how good it is.

References
  1. "International Clinical Trials Registry Platform (ICTRP)". Who.int. Retrieved 2017-06-23.
  2. "WHO | Working Group on Best Practice for Clinical Trials Registers (BPG)". Who.int. Retrieved 2017-06-23.
  3. Barrett, Stephen. "Major Journals Press for Clinical Trial Registration". www.quackwatch.org. Retrieved 22 May 2019.
  4. "WHO - Working Group on Best Practice for Clinical Trials Registers (BPG)". www.who.int.
  5. Dickersin, K; Rennie, D (2009). "Registering clinical trials". JAMA. 290 (4): 516–523. doi:10.1001/jama.290.4.516. PMID 12876095. S2CID 10184671.
  6. Sterling, TD (1959). "Publication decisions and their possible effects on inferences drawn from tests of significances – or vice versa". J Am Stat Assoc. 54 (285): 30–34. doi:10.1080/01621459.1959.10501497. JSTOR 2282137.
  7. International Collaborative Group on Clinical Trial Registries (1993). "Position paper and consensus recommendations on clinical trial registries. Ad Hoc Working Party of the International Collaborative Group on Clinical Trials Registries". Clin Trials Metaanal. 28 (4–5): 255–266. PMID 10146333.
  8. Dickersin, K; Rennie, D (2012). "The evolution of trial registries and their use to assess the clinical trial enterprise". JAMA. 307 (17): 1861–4. doi:10.1001/jama.2012.4230. PMID 22550202.
  9. SANCTR. "SANCTR > Home". www.sanctr.gov.za.
  10. "Archived copy". Archived from the original on 2010-07-06. Retrieved 2010-07-23.CS1 maint: archived copy as title (link)
  11. "Archived copy". Archived from the original on 2011-08-30. Retrieved 2010-09-02.CS1 maint: archived copy as title (link)
  12. "ANZCTR". www.anzctr.org.au.
  13. Gülmezoglu, AM; Pang, T; Horton, R; Dickersin, K (2005). "WHO facilitates international collaboration in setting standards for clinical trial registration". Lancet. 365 (9474): 1829–1831. doi:10.1016/s0140-6736(05)66589-0. PMID 15924966.
  14. "International Clinical Trials Registry Platform (ICTRP)". World Health Organization.
  15. Banno, M; Tsujimoto, Y; Kataoka, Y (2019). "Studies registered in non-ClinicalTrials.gov accounted for an increasing proportion of protocol registrations in medical research". Journal of Clinical Epidemiology. 116: 106–113. doi:10.1016/j.jclinepi.2019.09.005. PMID 31521723.
  16. Anderson, Monique L.; Chiswell, Karen; Peterson, Eric D.; Tasneem, Asba; Topping, James; Califf, Robert M. (12 March 2015). "Compliance with Results Reporting at ClinicalTrials.gov". New England Journal of Medicine. 372 (11): 1031–1039. doi:10.1056/NEJMsa1409364. PMC 4508873. PMID 25760355.
  17. Anderson, Monique L.; Chiswell, Karen; Peterson, Eric D.; Tasneem, Asba; Topping, James; Califf, Robert M. (12 March 2015). "Compliance with Results Reporting at ClinicalTrials.gov". New England Journal of Medicine. 372 (11): 1031–1039. doi:10.1056/NEJMsa1409364. PMC 4508873. PMID 25760355.
  18. DeVito, Nicholas J; Bacon, Seb; Goldacre, Ben (February 2020). "Compliance with legal requirement to report clinical trial results on ClinicalTrials.gov: a cohort study". The Lancet. 395 (10221): 361–369. doi:10.1016/S0140-6736(19)33220-9. PMID 31958402.
  19. Pullar, T; Kumar, S; Feely, M (October 1989). "Compliance in clinical trials". Annals of the Rheumatic Diseases. 48 (10): 871–5. doi:10.1136/ard.48.10.871. PMC 1003898. PMID 2684057.
  20. Miller, Jennifer E; Korn, David; Ross, Joseph S (12 November 2015). "Clinical trial registration, reporting, publication and FDAAA compliance: a cross-sectional analysis and ranking of new drugs approved by the FDA in 2012". BMJ Open. 5 (11): e009758. doi:10.1136/bmjopen-2015-009758. PMC 4654354. PMID 26563214.
  21. Miseta, Ed (9 January 2018). "As ClinicalTrialsgov Turns 10 Will We See Compliance Improve". www.clinicalleader.com.
  22. Huser, V.; Cimino, J. J. (2013). "Evaluating adherence to the International Committee of Medical Journal Editors' policy of mandatory, timely clinical trial registration". Journal of the American Medical Informatics Association. 20 (e1): e169–74. doi:10.1136/amiajnl-2012-001501. PMC 3715364. PMID 23396544.
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