Trials registers, trials results registers and

other research registers: background and overview

InterTASC ISSG Workshop

Wednesday 9 July 2014, Exeter, UK

Carol Lefebvre

Independent Information Consultant, Lefebvre Associates Ltd, Oxford

and

Co-Convenor, Cochrane Information Retrieval Methods Group

Carol@LefebvreAssociates.org

© Lefebvre Associates LtdLefeb

vre A

ssoc

iates

Ltd

Session overview

• What are trials registers?

• Developments in trials registers and trials results registers

• Influences and encouragements to register trials prospectively

• A chronological perspective

Followed by Julie Glanville – details of searching challenges

2© Lefebvre Associates LtdLefeb

vre A

ssoc

iates

Ltd

What are trials registers?

• Databases of trial records

• Record is trial information –

not published citation

• Typical citation record:

– AU, TI, SO, YR

• Typical trials register record:

– PI, study name, recruitment status etc

3© Lefebvre Associates LtdLefeb

vre A

ssoc

iates

Ltd

Types of trials (results) registers

• National, regional and international trials registerse.g. ClinicalTrials.gov

• http://www.clinicaltrials.gov

• Subject-specific trials registerse.g. NCI's List of Cancer Clinical Trials

• http://www.cancer.gov/clinicaltrials

• Industry trial registerse.g. GlaxoSmithKline (GSK) Clinical Study Register

• http://www.gsk-clinicalstudyregister.com/

https://sites.google.com/a/york.ac.uk/yhectrialsregisters/

4© Lefebvre Associates LtdLefeb

vre A

ssoc

iates

Ltd

Searching trials registers for HTA can:

• reduce biases (e.g. publication bias)• inform decisions as to when / whether to undertake /

update a systematic review or HTA • ensure that studies, when completed, can be included • facilitate obtaining data from sponsor / investigator if trial

is not published (not completed?)• facilitate obtaining data ahead of publication • increase robustness of existing evidence syntheses with

additional data (e.g. from a large recently completed but as yet unpublished study)

Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org

(Adapted from the Unpublished and Ongoing Studies section)

5© Lefebvre Associates LtdLefeb

vre A

ssoc

iates

Ltd

Developments in trials registration (1)

1992 - subject specific trials registers (e.g. cancer)

1997 - ‘Schering is sharing too!’

Cochrane News 1997;10:9.

– outline details of 30+ trials submitted to CENTRAL by Schering Health Care Ltd

6© Lefebvre Associates LtdLefeb

vre A

ssoc

iates

Ltd

Developments in trials registration (2)

1998 - GSK announced access to trial information

‘Being a modern pharmaceutical company’. BMJ, 1998 ‘GlaxoWellcome will register information on its future clinical trials protocols on its R&D website’

- now available in GSK Clinical Study Register

http://www.gsk-clinicalstudyregister.com/

1998 - Current Controlled Trials web site launched

Current Controlled Trials metaRegister of Controlled Trials

The International Standard Randomised Controlled Trial Number (ISRCTN) Register scheme launched as the first online service that provided unique numbers for randomized controlled trials in all areas of health care and from all countries around the world http://www.controlled-trials.com/mrct/

7© Lefebvre Associates LtdLefeb

vre A

ssoc

iates

Ltd

Developments in trials registration (3)

2000 - ClinicalTrials.gov - launched as a result of the Food and Drug Administration Modernization Act (FDAMA) (of Nov 1997)

2004 - The support of trial registration at inception by the leading medical journal publishers (ICMJE) and their refusal to publish subsequently any reports of trials not prospectively registered (De Angelis 2004 JAMA)

2007 - World Health Organization (WHO) launched the International Clinical Trials Registry Platform (ICTRP) Search Portal to search across a range of trials registers

(currently 15 ‘primary registries’ and 3 ‘partner registries’)

http://apps.who.int/trialsearch/Default.aspx

8© Lefebvre Associates LtdLefeb

vre A

ssoc

iates

Ltd

Developments in trials registration (4)

2008 - U.S. Public Law 110-85 or the Food and Drug Administration Amendments Act of 2007 (FDAAA)

(enacted 2007 w.e.f. 2008)

- The law includes a section on clinical trial databases (Title VIII) that expands the types of clinical trials that must be registered in ClinicalTrials.gov, increases the number of data elements that must be submitted, and also requires submission of certain results data (including adverse events)http://grants.nih.gov/clinicaltrials_fdaaa/faq.htm

9© Lefebvre Associates LtdLefeb

vre A

ssoc

iates

Ltd

Developments in trials registration (5)

2008 - US National Institutes for Health (NIH) voluntary Public Access Policy changed

- Now requires that ‘all investigators funded by the NIH submit or have submitted for them to the National Library of Medicine's PubMed Central an electronic version of their final, peer-reviewed manuscripts upon acceptance for publication to be made publicly available no later than 12 months after the official date of publication’http://publicaccess.nih.gov/FAQ.htm#753

10© Lefebvre Associates LtdLefeb

vre A

ssoc

iates

Ltd

Developments in trials registration (6)

2011 - MECIR - mandatory standards for Cochrane Reviews –searching for studies http://methods.cochrane.org/standards

• Searching Trials Registers – mandatory standard

• ‘Search trials registers and repositories of results, where relevant to the topic through ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) portal and other sources as appropriate.’

11© Lefebvre Associates LtdLefeb

vre A

ssoc

iates

Ltd

Developments in trials registration (7)

2011 – MECIR cont.

• Rationale for the Searching Trials Registers standard:

• ‘Searches for studies should be as extensive as possible in order to reduce the risk of publication bias and to identify as much relevant evidence as possible.’

• ‘Although ClinicalTrials.gov is included as one of the registers within the WHO ICTRP portal, it is recommended that both ClinicalTrials.gov and the ICTRP portal are searched separately due to additional features in ClinicalTrials.gov.’

12© Lefebvre Associates LtdLefeb

vre A

ssoc

iates

Ltd

Developments in trials registration (8)

Jan 2013 - +AllTrials campaign

“All trials registered. All results reported.”

http://www.alltrials.net/

2013 - Cochrane Collaboration Access to Data Statement

– consultation

2013 - GSK established clinicalstudydatarequest.com to provide access for researchers to patient-level data

13© Lefebvre Associates LtdLefeb

vre A

ssoc

iates

Ltd

Developments in trials registration (9)

Apr 2013 - the European Court issued interim injunctions against the European Medicines Agency (EMA) after AbbVie and InterMune challenged the EMA’s decisions to grant access to clinical study reports (CSRs) regarding clinical trials of their drugs

Sept 2013 - UK Science and Technology Commons Select Committee inquiry into clinical trials and disclosure of data:

report publishedhttp://www.publications.parliament.uk/pa/cm201314/cmselect/cmsctech/104/10402.htm

© Lefebvre Associates Ltd 14Lefeb

vre A

ssoc

iates

Ltd

Developments in trials registration (10)

Dec 2013 – agreement in principle reached in the European Parliament for a publicly accessible EU database, set up and run by European Medicines Agency (EMA), to contain:

- a register of all trials carried out in the EU

- a summary of results for all trials, uploaded 1 year after the end of the trial at the latest

- also a summary understandable for a layperson

- Clinical Study Reports for all trials used in a marketing authorisation request, whether approved, rejected or withdrawn

© Lefebvre Associates Ltd 15Lefeb

vre A

ssoc

iates

Ltd

Developments in trials registration (11)

Dec 2013 European Parliament cont. –

• A statement that Clinical Study Reports should, in general, not be considered commercially confidential

• Fines to be imposed by Member States for non-compliance with the transparency requirements

• A requirement for all trials to be registered or published in order to be used to back up a new clinical trial authorisation (will encourage the retrospective registering/publishing of old trials)

• The Clinical Trial Master File retained for at least 25 years

© Lefebvre Associates Ltd 16Lefeb

vre A

ssoc

iates

Ltd

Developments in trials registration (12)

Dec 2013 - Pfizer announced they would launch a portal through which researchers could request access to anonymised patient data from completed trials of approved (or discontinued) medicines and indications and they would publish synopses of clinical study reports (CSRs) on their website for trials dating back to September 2007

Jan 2014 - Johnson & Johnson (J&J) / Janssen announced they would give all the data from pharmaceutical clinical trials they hold to researchers at Yale for further dissemination to researchers

© Lefebvre Associates Ltd 17Lefeb

vre A

ssoc

iates

Ltd

Developments in trials registration (13)

Apr 2014 - AbbVie dropped its legal case against the EMA

Apr 2014 - Boehringer announced release of data (1998+)

Apr 2014 - Cochrane Review of Tamiflu & Relenza published (based on CSRs (not published data) from GSK and Roche)http://www.cochrane.org/features/tamiflu-and-relenza-getting-full-evidence-picture

By May 2014 - Bayer, Boehringer Ingelheim, GSK, Novartis, Roche, Sanofi and ViiV Healthcare joined clinicalstudydatarequest.com

May 2014 - InterMune dropped its legal case against the EMAhttp://curia.europa.eu/juris/document/document.jsf?text=&docid=152979&pageIndex=0&doclang=en&mode=lst&dir=&occ=first&part=1&cid=82640

© Lefebvre Associates Ltd18Le

febvre

Ass

ociat

es Lt

d

Developments in trials registration (14)

Jun 2014 - EMA produced a further draft of their policy:

researchers can access the data on screen only with printing, sharing or saving of the data forbidden

the company who supplied the data to the EMA could decide which information to redact

researchers would be asked to agree that the companies who produced the trial data could take legal action directly against them if the trial sponsor considers the researchers broke any of the conditions of use

© Lefebvre Associates Ltd 19Lefeb

vre A

ssoc

iates

Ltd

Developments in trials registration (15)

Jun 2014 – Eli Lilly announce increased access to datahttps://investor.lilly.com/releasedetail.cfm?ReleaseID=851703

https://www.clinicalstudydatarequest.com/

Jun 2014 – “EMA agreed the policy on publication of clinical trial data … that will not only allow the Agency to proactively publish clinical trial data that are submitted as part of marketing authorisation applications, but also give the possibility to download, save and print the trial data for academic and non-commercial research purposes”.

(but concerns over redaction and legal action remain)http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/06/news_detail_002124.jsp&mid=WC0b01ac058004d5c1

© Lefebvre Associates Ltd 20Lefeb

vre A

ssoc

iates

Ltd

Recommendations on searching for regulatory data (1)

Agency for Healthcare Research and Quality (AHRQ) guidance

“Sources of grey literature including regulatory data, clinical trial registries and conference abstracts should be searched in addition to bibliographic databases.” Relevo R, Balshem H. Finding Evidence for Comparing Medical Interventions. Agency for Healthcare Research and Quality; January 2011. Methods Guide for Comparative Effectiveness Reviews. AHRQ Publication No. 11-EHC021-EF. Available at http://effectivehealthcare.ahrq.gov/

US Institute of Medicine (IOM) guidance

“Thus, the search for trial data should include trial registries (ClinicalTrials.gov, Clinical Study Results, Current Controlled Trials, and WHO International Clinical Trials Registry), FDA medical and statistical reviews records …”IOM (Institute of Medicine). 2011. Finding What Works in Health Care: Standards for Systematic Reviews. Washington, DC: The National Academies Press. http://books.nap.edu/openbook.php?record_id=13059

© Lefebvre Associates Ltd 21Lefeb

vre A

ssoc

iates

Ltd

Recommendations on searching for regulatory data (2)

Cochrane guidance:

Next ‘minor update’ of the Cochrane Handbook Chapter (in press – almost!):

“Trials registers, trials results registers and other sources such as regulatory agencies are an increasingly important source of information.”Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Cochrane Handbook for Systematic Reviews of Interventions Version 6.0.0 (in press). The Cochrane Collaboration, 2014.

Next release of the Cochrane MECIR standards:

likely to mandate the searching of regulatory agency data

(note: searching trials registers is already mandatory)

Next ‘major revision’ of the Cochrane Handbook Chapter (due 2015 / 2016):

will contain much of the background information discussed here

also likely to mandate the searching of regulatory agency data

© Lefebvre Associates Ltd 22Lefeb

vre A

ssoc

iates

Ltd

Guidance in searching trials registers (1)

“Finding clinical trials, research registers and research results”

• a web resource providing listings of trials registers, trials results registers and other research registers

• a quick reference guide to the search basics for most resources

• developed following three training events in 2009 presented by Julie Glanville and myself

• course participants assisted with the preparation and checking of the data tables (gratefully acknowledged)

• regularly updated

• contact Julie Glanville to suggest registers to add and for any comments / corrections / updates

https://sites.google.com/a/york.ac.uk/yhectrialsregisters/

julie.glanville@york.ac.uk

© Lefebvre Associates Ltd 23Lefeb

vre A

ssoc

iates

Ltd

Guidance in searching trials registers (2)

© Lefebvre Associates Ltd 24Lefeb

vre A

ssoc

iates

Ltd

Guidance in searching trials registers (3)

© Lefebvre Associates Ltd 25Lefeb

vre A

ssoc

iates

Ltd

Guidance in searching trials registers (4)

© Lefebvre Associates Ltd 26Lefeb

vre A

ssoc

iates

Ltd

Guidance in searching trials registers (5)

© Lefebvre Associates Ltd 27Lefeb

vre A

ssoc

iates

Ltd

Summary

• Considerable development in trials registers, trials results registers and trials registration over the last 20 years –

but especially over the last few years

• Various influences / mechanisms to: provide access to trial informationprovide access to trial resultsregister trials prospectivelypublish trial results

• Organizations increasingly mandating searching of trials registers and regulatory sources:e.g. AHRQ, IOM, Cochrane

• Guidance is available:for example: “Finding clinical trials, research registers and research results”

https://sites.google.com/a/york.ac.uk/yhectrialsregisters/

28© Lefebvre Associates LtdLefeb

vre A

ssoc

iates

Ltd