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THANK YOU FOR JOINING ISMPP U TODAY!

April 30, 2014

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ISMPP ANNOUNCEMENTS

• For those who signed up for an ISMPP Committee for the 2014-2015 cycle, please complete your COI form by Friday, May 2nd

• Applications are now being accepted and are due August 1st for the September 2014 ISMPP Certified Medical Publication Professional™ (CMPP) exam.

• BMJ Open has published the results from the Global Publication Survey. The article is available at: http://bmjopen.bmj.com/content/4/4/e004780.full.pdf+html

• This program qualifies for 1 credit towards recertification

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NEW OPPORTUNITIES FOR PUBLISHINGNEGATIVE STUDY RESULTSIN THE SCIENTIFIC LITERATURE

INTRODUCTIONS

• Faculty: Louise Wyhopen has held various roles in scientific/medical communications since entering the pharmaceutical industry 16 years ago. She currently focuses on oncology global scientific communication/publication activities working closely with internal cross-functional teams to drive, develop, and implement Global Scientific Communication Strategies, including publication analysis, planning and execution as well as support for global medical education programs. Louise is a registered nurse and a member of several professional societies including the Oncology Nursing Society and ISMPP. She is also a Certified Medical Publication Professional (CMPP).

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INTRODUCTIONS

• Faculty: John Overbeke (1947) was graduated as physician in 1973 at the Free University in Amsterdam. He specialised as a general surgeon and was registered in 1980. In 1982 he defended his thesis “Perioperative autotransfusion.” He was 4 years chef de clinique in the department of Surgery of the Saint Luke’s Hospital in Amsterdam.

• In 1984 he was appointed as executive editor of the Nederlands Tijdschrift voor Geneeskunde (Dutch Journal of Medicine). Besides assessing and solliciting scientific articles, he was lecturing and researching the processes around medical scientific publishing. He was secretary of the Association Nederlands Tijdschrift voor Geneeskunde, is past president of the Netherlands Association of Scientific Editors, was member of the International Committee of Medical Journal Editors (the so called Vancouver Group), was 11 years treasurer of the World Association of Medical Editors (WAME) and was last year the past-president of this organazation, he was representative for the Council of Scientific Editors (CSE) to the European Association of Scientific Editors (EASE), he was member of the council of The British Journal of Surgery Society Ltd. and is still chair of the Advisory Board of the Dutch Cochrane Centre. In July 1999 he was appointed as a associate professor in medical scientific publishing in the department of Medical Informatics in the Radboud University Nijmegen Medical Center and retired in 2012. He left the journal in May 2006 and received the medal of honour in January 2007 at the celebration of the 150th anniversary of the journal.

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INTRODUCTIONS

• Faculty: Rebecca Lawrence is Managing Director of F1000 Research Ltd. She was responsible for the launch in January 2013 of the novel open science and open data journal F1000Research that uses rapid publication, followed by formal but completely transparent peer review, post-publication. She was also responsible for the launch in June 2010 of F1000Posters, an open access repository of posters and slides across biology and medicine. She is a member of ISMPP, a co-founding member of the International Association of STM Publishers Data Group, and an active member of the Research Data Alliance/World Data System Working Group on Publishing Data.

• She has worked in STM publishing for 15 years, at Elsevier Life Sciences where she built and ran the Drug Discovery Group, and then as Editorial Director for Current BioData Ltd, a drug target intelligence service for the pharmaceutical industry. She originally trained and qualified as a pharmacist, and holds a PhD in cardiovascular pharmacology.

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INTRODUCTIONS

• Moderator: Neil Adams has worked in medical publishing for the past 15 years at companies such as John Wiley & Sons, Springer Science & Business Media and Informa Healthcare. He is currently publishing manager for the Pharma Solutions division at Nature Publishing Group, where he works with pharmaceutical and medical communications companies, lead investigators and medical journal editors to publish clinical studies in NPG journals. Neil is an active member of ISMPP, currently serving on its ISMPP U committee and is a Certified Medical Publication Professional (CMPP).

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DISCLAIMER

• Information presented reflects the personal knowledge and opinion of the presenters and does not represent the position of their current or past employers or the position of ISMPP

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TODAY’S OBJECTIVES

• At the conclusion of this educational session, attendees should be able to:– Understand the importance of and obligation to publishing negative

study results in the scientific literature– Define the publication of negative results vs. the publication of null

results– Recognize the barriers that may exist in publishing negative studies

and develop strategies to overcome them– Identify the new opportunities to publish negative study results and

consider them for future submissions

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Louise Wyhopen, RN, CMPPTM

Associate Director Global Scientific Communications Novartis Oncology

AGENDA

• Obligation to publish• Industry perspectives• Overcoming internal obstacles• Where to publish (or who will publish a negative study?)

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ETHICAL OBLIGATION TO PUBLISH

• “...trial participants are performing a service to humanity, entering a potentially risky situation for the sake of determining the toxicity and effectiveness of a new drug. Withholding the results of such trials...seems ethically dubious.”1

• The selective reporting of only clinical trials with positive results may degrade the base of publicly available information on approved drugs2

– Flawed estimates of drug effectiveness

– May provide an erroneous impression of the risk-benefit ratio of treatments

– May lead physicians to make inappropriate prescribing decisions

1 Jefferson et al. BMJ 2011; 342:c7258 2 Rogawski et al. Sci Trans Med 2011

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MANDATORY OBLIGATION TO PUBLISH

• FDAAA Section 8011

– Required for controlled clinical trials (other than phase 1) of drugs or biologics subject to FDA regulation

– Generally within 12 months

1 FDA Amendments Act 2007

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COMPLYING WITH THE PHARMA 2010 JOINT POSITION1

1Joint Position on the Disclosure of Clinical Trial Information via Clinical Trial Registries and Databases available online at www.ifpma.org/clinicaltrials

• All industry-sponsored clinical trials – positive or negative • All phase 3 clinical trials and clinical trial results of significant medical importance • Includes investigational products• Includes trials from programs that are discontinued

• Results to be submitted within 12 months of: • Trial completion• Regulatory approval• Discontinuation of drug development• Submit to an indexed peer-reviewed journal

• Authorship guidelines follow ICMJE Uniform Requirements• Authors must meet all ICMJE criteria• Include appropriate acknowledgements

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COMPLYING WITH THE PHARMA 2010 JOINT POSITION1 (CON’T)

• Publication of results– Primary efficacy analyses, safety results– If relevant to patient care, secondary and exploratory analyses – Methods should include sufficient details in order to judge the validity

and generalizability of the results. – Include a discussion of the strengths and limitations of the study– Provide study protocols and amendments to journals if requested

• Use confidentiality agreement with journal to ensure protection of information

1Joint Position on the Disclosure of Clinical Trial Information via Clinical Trial Registries and Databases available online at www.ifpma.org/clinicaltrials

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INDUSTRY PERSPECTIVES –CHALLENGES COMPANIES FACE

• Perceptions– Proprietary information

• Publication may constrain future development– No commercial benefit– Limits competitors’ access– Negative feelings and perceptions

• We are not obligated to publish• Medical community is not interested

• Limited resources– Study is deprioritized and clinical team reassigned

• No time to write or review• No additional analyses to answer questions raised by reviewers

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PUBLICATION PLANNING AND REPORTING BIAS RELATED TO NEGATIVE STUDY RESULTS

• Types of publication bias related to negative study results– Time lag bias – Location bias – Citation bias – Language bias – Outcome reporting bias

McGauran et al. Trials 2010

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WHAT CAN WE DO AS PUBLICATION PROFESSIONALS

• Educate internal teams on importance of publishing negative results• Focus on the positive

• Sharing data to advance research • Eliminate duplicate studies• Physicians need complete knowledge to treat their patients• There are journals that publish negative results

• Work with clinical teams to identify all trials for publication• Include in publication plans• Provide writing support if resources allow• Gain early alignment on appropriate journals• Submit letter of interest to journal editors describing relevance of research

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WHERE TO PUBLISH (FINDING A JOURNAL)

• Several studies have shown no significant difference in publication rates between studies with positive and studies with negative results1

– Large phase 3 trials can be submitted to any high tiered journal

– JAMA found no difference in acceptance of positive and negative trial results2

• Journal of Negative Results in Biomedicine (JNRBM) launched in 2002

– Open access, peer-reviewed, online journal – Unexpected, controversial, provocative and/or negative results

• Nature Publishing Group introduced “Negative Results Section” in 20103

– Published as a one-page summary (maximum 500 words, two figures) in print

– Accompanying full paper published online1McGauran et al. Trials 2010, 11:37.Lee KP, et al. Med J Aust 2006, 184:621-626. 2Olson CM, et al. JAMA 2002, 287:2825-2828. Okike K, et al. J Bone Joint Surg Am 2008, 0:595-601.3Dirnagl U, Lauritzen M. Journal of Cerebral Blood Flow & Metabolism (2010) 30, 1263–1264.

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A. John Overbeke, MD, PhDProfessor Emeritus Medical Scientific Publishing Dept. of Primary and Community Care Radboud University Nijmegen Medical Centre Nijmegen, The Netherlands

ROLE OF EDITORIAL AND PEER REVIEW PROCESSES IN PUBLICATION BIAS: ANALYSIS OF DRUG TRIALS SUBMITTED TO 8 MEDICAL JOURNALS

Marlies van Lent MScJohn Overbeke MD PhDHenk Jan Out MD PhD

Radboud University Nijmegen Medical Centre, The Netherlands

Conflict of interest disclosure: This research was supported by an unrestricted educational grant from MSD (Dutchsubsidiary of Merck & Co., Inc.). The funder had no role in the study design, data collection, analysis, or preparation ofthis presentation. HJO is employed by Teva Pharmaceuticals; JO is the immediate past-president of the WorldAssociation of Medical Editors.

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PUBLICATION BIAS

• Definition: Studies with positive results more likely to be published than studies with negative results

• Industry sponsorship particularly associated with publication of favorable results (Lundh et al, Cochrane Database Syst Rev 2012)

• Potential causes:

– Prior to submission: authors & sponsors failing to submit studies with negative results to journals

– Once submitted: favoritism towards publication of positive studies among peer reviewers, editors & publishers

• Objective: To determine whether submitted manuscripts reporting results of drug RCTs are more likely to be published if they report positive results

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METHODS

• Retrospective analysis of manuscripts submitted to 8 journals:

– One general medical journal: BMJ

– Seven specialty journals: Ann Rheum Dis - Brit J Ophthalmol - Gut -Heart - Thorax - Diabetologia - J Hepatol

• Access to:

– Submitted manuscripts

– Peer review comments

– Final decisions on publicationManuscripts on drug RCTs Non-industry Industry-supported Industry-sponsored Total

(n)Positive Negative Positive Negative Positive NegativeSubmitted (n)Sent to peer reviewers (n)Accepted for publication (n)

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METHODS

• Manuscript selection: – Original research manuscripts submitted January 2010 - April 2012 screened for eligibility

– RCTs included, if at least 1 study arm assessed efficacy/safety of a drug, and statistical test was used to evaluate treatment effects

• Data extraction:– Publication status

– Trial results

– Sponsorship

– Sample size

– Number of centers

– Corresponding author’s country of residence

– Trial registration

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METHODS – CLASSIFICATION OF RESULTS

Positive results Negative results

Results for primary endpoint statistically significant and supporting efficacy of test drug X

Results for primary endpoint do not reach statistical significance X

Results for primary endpoint statistically significant in favor of control treatment X

Treatments equivalent regarding primary endpoint in non-inferiority or equivalence trials X

Test drug as safe or safer than control treatment in trials with safety parameter as primary endpoint X

Treatments equally harmful in trials with safety parameter as primary endpoint, when test drug is expected to be safer than comparator

X

Results for >50% of (primary) endpoints statistically significant in favor of test drug, when no/multiple primary endpoints are reported

X

Van Lent et al. ‘Recommendations for a Uniform Assessment of Publication Bias Related to Funding Source’ - BMC Med Res Methodol

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METHODS – CLASSIFICATION ACCORDING TO SPONSORSHIP

Non-industry

Industry-supported

Industry-sponsored

Pharmaceutical company explicitly reported as study sponsor in manuscript X

Company funding the trial participated in design, conduct, analysis, writing of article and/or decision to publish X

Trial funded by industry and author(s) affiliated to industry, but role of funding source not reported X

Financial support received from pharmaceutical company X

Donation of study medication or placebos by manufacturer X

One or more authors employed by pharmaceutical company manufacturing the test drug X

Pharmaceutical industry not in any way involved in trial X

Van Lent et al. ‘Recommendations for a Uniform Assessment of Publication Bias Related to Funding Source’ - BMC Med Res Methodol

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RESULTS

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RESULTS

N=287

N=135

N=91N=60

N=185N=86

N=61

N=38

0

10

20

30

40

50

60

70

Submitted Outright rejected Rejected after peerreview

Accepted forpublication

% o

f sub

mitt

ed m

anus

crip

ts


Note: One manuscript reporting positive results was withdrawn by authors before editorial decisions were made.

Publication status of submitted manuscripts with positive vs negative results

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RESULTS

N=6

N=25

N=2 N=6N=1

N=3N=10

N=7N=8

N=8

N=2N=5 N=2

N=1N=6

N=6

0

10

20

30

40

50

60

70

BMJ Ann Rheum Dis Brit JOphthalmol

Gut Heart Thorax Diabetologia J Hepatol

% ac

cept

ed fo

r pub

licat

ion


Acceptance rates of manuscripts with positive vs negative results by journal

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RESULTS

Submission rates of manuscripts with positive vs negative results by sponsor type

N=287 N=138

N=71

N=78

N=185 N=75

N=78

N=32

0

10

20

30

40

50

60

70

80

Total Non-industry Industry supported Industry sponsored

% o

f sub

mitt

ed m

anus

crip

ts


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RESULTS

N=98

N=27N=27

N=44

0

10

20

30

40

50

Total Non-industry Industrysupported

Industrysponsored

% ac

cept

ed fo

r pub

licat

ion

Acceptance rates of submitted manuscripts by sponsor type

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RESULTS

Accepted (n=98) vs all rejected (n=373)

Characteristic Odds ratio (95% CI) P-value

Positive results (n=287) vs negative (n=185) 1.00 (0.61-1.66) .994

Industry-sponsored (n=110) vs non-industry (n=213) 1.79 (0.90-3.58) .097

Industry-supported (n=149) vs non-industry (n=213) 1.13 (0.60-2.13) .698

Trial registration (n=374) vs not registered (n=98) 1.55 (0.75-3.20) .237

Number of participants >100 (n=211) vs ≤100 (n=261) 1.91 (1.11-3.31) .020

Multicenter (n=224) vs single center (n=248) 1.87 (1.02-3.40) .042

Corresponding authors’ country of residence EU or US (n=295) vs rest of the world (n=177) 2.02 (1.14-3.57) .015

Characteristics associated with publication: Multivariable analysis

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CONCLUSION

• Submitted manuscripts on drug RCTs not more likely to be published if they reported positive results

• Proportion of submitted manuscripts with positive results outnumbered those with negative results, irrespective of sponsor type

• Publication bias seems to occur mainly before manuscripts are submitted to journals

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ACKNOWLEDGEMENTS

• Participating journals

– BMJ

– Annals of the Rheumatic Diseases

– British Journal of Ophthalmology

– Gut

– Heart

– Thorax

– Diabetologia

– Journal of Hepatology

• BMJ

– Dr Sara Schroter (study design, contact BMJ Group)

• Radboud University Nijmegen Medical Centre

– Dr Joanna in ‘t Hout (statistics)36


Rebecca Lawrence, PhD Managing Director F1000 Research Ltd@RNL_S | @F1000RESEARCH

IS ‘NEGATIVE RESULTS’ THE RIGHT TERM?

• The term ‘negative results’ often has misleading connotations

@rnl_s | @f1000research

Negative result is when there is a negative impact following the change agentNull result is when there is no impact (positive or negative) following the change agent

• Negative result sounds like a ‘bad’ result but often just not the result that was hoped for

• In most instances, ‘null result’ would be a better term

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TYPES OF NULL / NEGATIVE RESULTS?

Different types of null and negative results:• Large study that shows lack of efficacy or adverse events• Small studies that in themselves may not show much:

– Don’t know reason for null result– Little incentive to explore further– Together with other small null results, this might become significant

@rnl_s | @f1000research 39

PUBLISHING NULL / NEGATIVE RESULTS

• As a business, recognise is hard to share ‘bad news’• Start by sharing small null results on cmpds that won’t take

further– Often shared in posters at conferences – already have legal approval– Contributes positively to public image (esp if publish Open Access)– If all share such results, reduce # cmpds that reach late phases. Cost benefits, further improving public profile

– Academic groups / small biotechs may be able to repurpose findings


AUDIENCE QUESTION

AUDIENCE QUESTION

What do you think is the biggest hindrance currently to your organisation publishing such small null studies?

A. Journals won’t publish themB. Takes too much time to write them up and resubmit from journal to journalC. Costs too much money (in time, writing agency fees)D. No benefit to writing them upE. Potential negative impact on company profile

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RESTORING INVISIBLE AND ABANDONED TRIALS

In 2013, Peter Doshi and colleagues published paper on RIAT initiative (BMJ 2013;346:f2865).

call for sponsors and investigators of abandoned studies to publish (or republish) and propose a system for independent publishing if sponsors fail to respond

Overall support from PLOS Medicine Editors, BMJ Editors, BMC Editors etc.

~2 M pages of Clinical Study Reports and other docs released by EMA (more likely now AbbVie discontinued case)

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WHAT IS BEING DONE BY PUBLISHERS?

• Long list of publishers signed in support of AllTrials campaigne.g. BMJ, PLOS, BMC, Royal Society of Medicine, SAGE, Wiley, F1000Research, eLife, PeerJ

Easy to sign, has helped raise awareness, but much harder to really change things

• However, publishers are largely keen to:• Support the idea of publishing all results, irrespective of outcome• Advocate and influence government policy and legislation in Europe to

move towards the ideas behind the AllTrials campaign

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PUBLISHER INITIATIVES

• Aug 13 - PLOS Medicine publicly acknowledged that they allow retrospective registration of clinical trials (even though this contravenes the 2005 ICMJE policy that many journals follow); Oct 13 - PLOS ONE followed

• Oct 13 - BMC wrote an open letter to UK government encouraging the registration of clinical trials in Europe and the public disclosure of the results

• F1000Research did a 4-month campaign in 2013 to offer free publication for any negative/null results

Generated a huge amount of supportBut hard to get people to actuallysubmit these

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MANY PLACES TO PUBLISH NULL/NEGATIVE FINDINGS

• For significant null / negative findings, the ‘big’ journals will typically accept these

• For small null / negative findings, there are several journals that expressly state they publish them:– Journal of Negative Results in Biomedicine (BMC)– Trials (BMC)– PLOS ONE– F1000Research


JOURNAL OF NEGATIVE RESULTS IN BIOMEDICINE

• From BioMed Central• “Publication and discussion of unexpected, controversial,

provocative and/or negative results”• Open Access ($1960)• Moved to open peer-review in Feb 2014 – to remove concerns

that these papers would be filtered by the peer-review firewall

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PLOS ONE

• “We will consider the following article types:... Studies reporting negative results.”

• Peer review model focusing on whether good science helps remove much of the publication bias

• Open Access ($1350)• Between Jan 2011 and Jul 2013, published 406 clinical trials

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F1000RESEARCHOPEN SCIENCE JOURNAL IN THE LIFE SCIENCES


Remove the publication delay.Invited peer review (post-publication).Transparent refereeing.

Inclusion of all data (with access control where necessary).Open Access ($250-$1000).

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F1000RESEARCH: ALL ARTICLE TYPES PUBLISHED

• We publish all article types– Research Articles, Reviews, Opinion, Trial Protocols, Case

Reports, Systematic Reviews etc– Negative/null results, single-result papers, papers from

posters, small updates

• Immediate publication process – minimises time and money, esp for findings that won’t be taken further

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SUMMARY

• Publishing negative & null results demonstrates a willingness to improve transparency and share information

• It may be easier to start with small null studies for compounds that are not taken further

• There are several journals that make a point of accepting negative and null results

• Publication of these studies can be done with minimal time and effort required.

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Thank [email protected]


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UPCOMING ISMPP U WEBINARS

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thank you for joining ismpp u today! · • in 1984 he was appointed as executive editor of the...

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