How is trial registration affecting gjournals? Dr Trish Groves Deputy editor, BMJ & Editor in chief, BMJ Open My competing interests Roles at BMJ contributing to, publicising, and leading implementation of the BMJ s policies on research influencing and making decisions on which research articles to send for external peer review and to accept; chairing weekly manuscript committee meeting at BMJ Open leading implementation of BMJ Open s policies and strategy overseeing decisions on peer review and manuscript decisions bmj.com and bmjopen.bmj.com carry advertisements for DIA meetings I have not received a fee or support for taking part in this conference 1
What I will cover ICMJE policy on trial registration What editors can do to promote trial registration and transparent reporting Evidence on the impact of trial registration What else editors could do Drug Information Association www.diahome.org 3 Click to edit Master title style ICMJE policy: background Drug Information Association www.diahome.org 4 2
Trial registration: story so far Drug Information Association www.diahome.org 5 25 years ago 3
ICMJE Sept 2004 mandated registration by Sept 2005 Why trial registration matters I Ottawa statement 2005 Ethical Respects investigator-participant covenant to contribute to public knowledge Provides global open access Reduces unnecessary duplication Assures accountability Enables monitoring of adherence to ethical principles and processes Scientific Increases reliability/availability of evidence for healthcare decisions Improves trial participation Increases collaboration Transparent design and methods Open review of protocols Identifies/prevents biased reporting Accelerates knowledge creation 4
Why trial registration matters II Distortion or loss of information about the true intervention can occur at each of four stages and the intervention may not reach practice without good reporting and trial fidelity Glasziou P et al. BMJ 2010;341:bmj.c3852 Drug Information Association www.diahome.org 9 WHO platform & minimum dataset 2005 No mandated access to protocol in WHO dataset or at registries: www.who.int/ictrp/network/trds/en/index.html http://prsinfo.clinicaltrials.gov/ www.clinicaltrialsregister.eu/index.html www.controlled-trials.com/isrctn/ www.trialregister.nl/trialreg/index.asp https://drks-neu.uniklinik-freiburg.de/drks_web/ 5
Declaration of Helsinki 2008 World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects. Clause B19 Every clinical trial must be registered in a publicly accessible database before recruitment of the first subject. http://www.wma.net/en/30publications/10policies/b3/index.html Drug Information Association www.diahome.org 11 Click to edit Master title style Implementation of ICMJE policy Drug Information Association www.diahome.org 12 6
What are the ICMJE rules? Trials that commenced after 1 July 2005 must have been registered prospectively, before participants enrolment, to be eligible for consideration at an ICMJE member journal * For trials of health services and behavioural interventions, relevant commencement date was 1 July 2008 Annals of Internal Medicine, British Medical Journal, Canadian Medical Association Journal, Chinese Medical Journal, Croatian Medical Journal, Journal of the American Medical Association, Nederlands Tijdschrift voor Geneeskunde (The Dutch Medical Journal), New England Journal of Medicine, New Zealand Medical Journal, The Lancet, The Medical Journal of Australia, Revista Médica de Chile, Tidsskrift for Den Norske Lægeforening (Journal of the Norwegian Medical Association), Ugeskrift for Laeger (Journal of the Danish Medical Association) Displaying registration details 7
But journals vary Drug Information Association www.diahome.org 15 W h a t c a n / s h o u l d e d i t o r s d o? ask authors for registration details up front and if not ask authors for registration details up front and, if not supplied, ask again before external peer review ask for the full protocol and show it to reviewers check registry entries at initial internal peer review ask authors to explain deviations from protocol reject trials that are eligible but unregistered include, on publication, the trial registration details in each RCT s abstract publish protocols and/or post them with papers 8
Click to edit Master title style Impact of trial registration mandates Drug Information Association www.diahome.org 17 Impact of ICMJE mandate in 2005 Zarin DA, Tse T, Ide NC. Trial registration at ClinicalTrials.gov between May and October 2005. N Engl J Med. 2005;353:2779 87 Drug Information Association www.diahome.org 18 9
Quality of trial registration in WHO ICTRP database Viergever RF Ghersi D, 2011. PLoS ONE 6(2): e14701. 5% (n=731) of drug trials June 2008-June 09 >half registered after recruitment of first participant drug name/company serial no. usually there; other details missing of 3643 reported outcomes only 34.9% were specific measures with a meaningful time frame Reveiz L et al 2010. PLoS ONE 5(8): e12484 random sample (n=265) of actively recruiting trials in 2008 adequate reporting of risk of bias: sequence generation 5.7%, allocation concealment 1.4%, blinding 41%, primary outcomes 66% adequate reporting of other key elements: eligibility criteria 81%, secondary outcomes 46%, harms 5%, follow-up duration 62%, description of interventions 53%, sample size calculation 1% Drug Information Association www.diahome.org 19 Outcome reporting in Clinical Trials.gov in 2009 546 trials of drugs in 5 classes industry 63%, government 14%, nonprofit or nonfederal 23% industry funded trials more often: were not published within 2 years of completion reported favourable outcomes when published Bourgeois F T et al. Ann Intern Med 2010;153:158-166 Drug Information Association www.diahome.org 20 10
Registry and publications often vary RCTs in cardiology, rheumatology, gastroenterology in PubMed 2008 in the 10 general medical journals and specialty journals with the highest IFs. For each article trial registration was then checked Mathieu, S. et al. JAMA 2009;302:977-984 Drug Information Association www.diahome.org 21 Update from ClinicalTrials.gov in 2010 As of September 27 2010: 79,413 registered trials and 2178 records with results approx 330 new and 2000 revised registrations each week approx 30 new and 80 revised results each week from a sample of results records, 78 of 150 (52%) had associated publications within 2 years after posting of 100 recorded outcome measures, 61% lacked specificity of 700 results records 24% reported results for <90% participants Zarin DA, Tse T, Williams RJ, Califf RM, Ide NC. The ClinicalTrials.gov Results Database Update and Key Issues. N Engl J Med 2011;364:852-60. Drug Information Association www.diahome.org 22 11
Click to edit Master title style Next steps in transparent reporting Drug Information Association www.diahome.org 23 Publish or post protocols 12
Ensure transparent reporting of industry trials: BMJ policies Good Publication Practice 2 guidelines (gpp-guidelines.org) European Medical Writers Association guidelines on role of medical writers (emwa.org/ghostwriting-guidelines.html) MPIP authors toolkit (http://www.mpip-initiative.org/) Describe role and independence of study sponsor Provide with manuscript, on submission: trial protocol trial registration details CONSORT checklist, abstract, flowchart statements: competing interests, contributorship, ethics approval, funding, data sharing Promote good publication practice www.gpp-guidelines.org www.mpip-initiative.org Drug Information Association www.diahome.org 26 13
Is there more editors & publishers can do? Ask authors to: register studies and share results & raw data report new studies in context of what s known and what s added use reporting guidelines Develop and implement: more open access initiatives detailed policies on transparency focus on implementation research, comparative effectiveness policies to help mass media report science accurately ESF Forward Look Report May 2011: Implementation of Medical Research in Clinical Practice http://www.esf.org/activities/forward-looks/medical-sciences-emrc/current-forward-looks-in medical-sciences/implementation-of-medical-research-in-clinical-practice.html European Science Foundation & European Medical Research Councils 2011 www.esf.org/flipreport May 2011 FL report: top 10 recommendations include: Promote rigorous reporting of all clinical studies Strengthen shared national and international open access databases on protocols, data, reports, systematic reviews and health technology assessment Drug Information Association www.diahome.org 28 14
Systematic review registration http://www.crd.york.ac.uk/prospero/ Drug Information Association www.diahome.org 29 Registries for data on medical devices Call for prospective registration of data on: outcomes & harms before regulatory approval postmarketing surveillance James S et al. BMJ 2011;342:doi:10.1136/bmj.d2826 Drug Information Association www.diahome.org 30 15
Sharing research data: 2011 Signatories: Wellcome Trust, Hewlett Foundation, NIH, MRC, CIHR, Gates Foundation, INSERM, DFG, AHRQ among other major funders How can journals encourage data sharing? http://bmjopen.bmj.com/site/about/ resources/datamanagement.xhtml Drug Information Association www.diahome.org 32 16
Where to deposit data? http://datadryad.org Drug Information Association www.diahome.org 33 Thanks tgroves@bmj.com Drug Information Association www.diahome.org 34 17