Publication bias in clinical

trials

Kamran AbbasiDeputy editor, BMJ

Merhaba

I want to talk about . . . What is publication bias?

Why does it matter?

What is the evidence for it?

What can be done about it?

How has the BMJ responded?

There are many types of bias Selection bias: biased allocation to

comparison groups Performance bias: unequal provision of care

except treatment being evaluated Detection bias: biased assessment of outcome Attrition bias: biased occurrence and handling

of deviations from protocol and loss to follow up . . . and on and on(From Egger et al BMJ 2001;323:42-46 (7 July)

What is publication bias (1)?

A definition:

“Publication bias refers to the greater likelihood that studies with positive results will be published”

JAMA 2002;287:2825-2828

What is publication bias (2)?

An alternative definition:

Publication bias is the selective or multiple publication or suppression of trial results so that the scientific record is distorted

Why does it matter?Distorts the scientific recordHides the “truth” Influences doctors’ decision makingMisleads policy makersCauses harm to patientsCostly for the health serviceA form of scientific and research

misconduct

Who is to blame?

Wicked researchers?

Very wicked sponsors?

Editors: the wickedest of all?

(and let’s not forget reviewers)

What is the evidence for it (1)?

Stern and Simes BMJ 1997;315:640-645

Question: To what extent is publication influenced by study outcome?

Studies submitted to an Australian ethics committee over 10 years

Examined protocols Questionnaire to authors (70%

response)

Stern and Simes: results

4.7 vs 8.0 yrs

4.8 vs 8.0 yrs

Time to publication

3.13 (1.76 to 5.58)

2.32 (1.47 to 3.66)

Positive> negative

Clinical trials (n=130)

All studies (n=520)

Stern and Simes: conclusions Positive trials are more likely to be

submitted for publication Positive trials are more likely to be

published Positive trials are more likely to be

published quickly

Implications for systematic reviews Important to register all trials

What is the evidence for it (2)?

Lexchin and Bero BMJ 2003;326:1167-70

Question: Does drug industry sponsorship influence research quality and outcome?

Meta-meta-analysis Industry research less likely to be

published (more likely in symposium proceedings)

No difference in methodological quality More likely to have a positive finding

(OR 4.05 95% CI 2.98 to 5.51)

Lexchin and Bero A wide range of diseases

eg osteoarthiritis of the knee, multiple myeloma, psychiatric problems, Alzheimer’s disease, venous thromboembolism

A wide range of drugseg tacrine, clozapine, 3rd generation OCP, erythropoietin, antidepressants, topical glucocorticoids, treatment for HIV

Lexchin and Bero: conclusions Published research from drug companies is

more likely to be favourable to the product

Do companies selectively fund trials? Unlikely Is it of poorer quality?

No Are inappropriate comparators chosen?

Sometimes/often/a lot Is it publication bias?

Yes

What is the evidence for it (3)?

Melander et al BMJ 2003;326:1171-3

Question: Is there selective reporting of sponsored studies by drug companies?

Trials submitted to the Swedish drug regulatory authority (5 SSRIs, 42 trials)

Multiple publication Selective publication Selective reporting

Melander et al: conclusion

“Any attempt to recommend a specific selective serotonin reuptake inhibitor from the publicly available data ONLY is likely to be based on biased evidence.”

What is the evidence for it (4)? Olson et al JAMA 2002;287:2825-2828

Question: Is there publication bias in editorial decision making?

3 years, 745 manuscripts Positive vs negative OR 1.30 (0.87 to

1.86) Small effect of editorial decision making,

much less than researchers not submitting negative studies

Will this be true for journals less grand than JAMA?

What can be done about it (1)? Better conduct and reporting of RCTs

(CONSORT) Better conduct and reporting of systematic

reviews (QUORUM) “Publication” of unpublished trials Enlightened sponsors (a code of good

practice Wager et al 2003 http://www.gpp-guidelines.org)

Better editorial policies Vigilant editors and reviewers Responsible authors

What can be done about it (2)?

Publication of original protocols and deviations from protocol

Declaration of competing (financial) interests by authors, reviewers, and editors

Declaration of sponsorship/funding Registering all clinical trials

How has the BMJ responded? A change in editorial thinking: Is it the question that matters? It is

Amnesty on unreported clinical trials More transparency (CONSORT, QUORUM,

sponsorship, funding, competing interests) Theme issue on doctors and the drug industry ?Protocols ?Registering clinical trials

Conclusions Publication bias is an important

problem that impacts on patient care There is much evidence to support its

existence There are many players There are many ways to reduce its

effect, examples of good practice Ultimately there is a big responsibility

on sponsors of trials, authors, and editors