Ramazzini Days 2016 CONFLICT OF INTEREST AND THE

Ramazzini Days 2016 CONFLICT OF INTEREST AND THE OUTCOMES OF REVIEWS ON ARTIFICIALLY SWEETENED BEVERAGES: A SYSTEMATIC REVIEW Daniele Mandrioli Cesare Maltoni Cancer Research Center Ramazzini Institute Carpi, October 28° 2016

DECLARATION OF INTERESTS I declare I have no actual or potential competing financial interests, including travel funding, consultancies, board positions, patent and royalty arrangements, stock shares, or bonds. 2

THE (ADDED) VALUE OF INDEPENDENCE 3

CONFLICT OF INTEREST AND OF RISK OF BIAS The Cochrane Collaboration authors showed that industry sponsorship is able to affect research outcome in the medical field. COI has been proposed as a risk of bias item by the Cochrane Collaboration and AHRQ and is already include as an item in the assessment of the Navigation Guide. NTP-OHAT handbook includes screening for conflict of interest, while funding source is recommended as a factor to consider when evaluating risk of bias of individual studies for selective reporting and then again for evaluating the body of evidence for publication bias. Viswanathan M, Ansari M, Berkman ND, Chang S, Hartling L, Mc. Pheeters LM, Santaguida PL, Shamliyan T, Singh K, Tsertsvadze A, Treadwell JR. 2012. Assessing the risk of bias of individual studies when comparing medical interventions (March 8, 2012). Agency for Healthcare Research and Quality Methods Guide for Comparative Effectiveness Reviews. March 2012. Woodruff TJ, Sutton P. 2014. The Navigation Guide systematic review methodology: a rigorous and transparent method for translating environmental health science into better health outcomes. Environ Health Perspect 122: 1007– 1014; doi: 10. 1289/ehp. 1307175 NTP-OHAT 2015. Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration. Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. 2012. Industry sponsorship and research outcome. Cochrane Database Syst Rev 12: MR 000033; doi: 10. 1002/14651858. MR 000033. pub 2. 4

CONFLICT OF INTEREST AND OF RISK OF BIAS Questions: èIs conflict of interest a systematic source of bias also in the field of toxicology and environmental health? èCan the bias induced by conflict of interest be captured by other items in the risk of bias assessment? èCan the peer review process prevent the potential risk of bias derived from conflict of interest? Viswanathan M, Ansari M, Berkman ND, Chang S, Hartling L, Mc. Pheeters LM, Santaguida PL, Shamliyan T, Singh K, Tsertsvadze A, Treadwell JR. 2012. Assessing the risk of bias of individual studies when comparing medical interventions (March 8, 2012). Agency for Healthcare Research and Quality Methods Guide for Comparative Effectiveness Reviews. March 2012. Woodruff TJ, Sutton P. 2014. The Navigation Guide systematic review methodology: a rigorous and transparent method for translating environmental health science into better health outcomes. Environ Health Perspect 122: 1007– 1014; doi: 10. 1289/ehp. 1307175 NTP-OHAT 2015. Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration. Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. 2012. Industry sponsorship and research outcome. Cochrane Database Syst Rev 12: MR 000033; doi: 10. 1002/14651858. MR 000033. pub 2. 5

SYSTEMATIC REVIEWS IN TOXICOLOGY è A Systematic Review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. è Cochrane is recognized as the most authoritative source for systematic reviews in medicine and is official partner of WHO for evidence-based evaluation. è Current Guidelines for Systematic Reviews and Risk of Bias Assessment in Environmental Health and Toxicology: NTP -OHAT Handbook, Navigation Guide, GRADE. Mandrioli D, Silbergeld EK. Evidence from Toxicology: The Most Essential Science for Prevention. Environ Health Perspect. 2016 Jan; 124(1): 6 -11. 6

SYSTEMATIC REVIEW PRINCIPLES AND METHODS è Clarity in defining the question under analysis defining populations, exposures, comparators, outcomes, timings, and settings of interest (PECOTS) è Transparent and replicable research strategy è Transparent data extraction and presentation è Comprehensive assessment of risk of bias è Transparent criteria for determining if quantitative data integration is appropriate and conducting data integration, such as meta-analysis è Appropriate statistical models for integrating data è Discussion of limitations and cautions in interpretation è Disclosure of Conflicts of Interest 7

RISK OF BIAS A bias is a systematic error, or deviation from the truth, in results or inferences Why is risk of bias important? è More rigorous studies are more likely to yield results that are closer to the truth è Results may be consistent among studies but all the studies may be flawed 8

RISK OF BIAS ITEMS Items accepted and proposed for risk of bias assesment and other methodological criteria of interest for nonhuman models in toxicology*: èTreatment allocation/randomization. èConcealment of allocation. èBlinding. èInclusion/exclusion èSelective Reporting èIncomplete èFinancial Outcome Data conflict of interest. èDose–response èOptimal criteria. model. time window investigated. *David Krauth, 1 Tracey J. Woodruff, 2, 3 and Lisa Bero 1, 4 Instruments for Assessing Risk of Bias and Other Methodological Criteria of Published Animal Studies: A Systematic Review. Environ Health Perspect; DOI: 10. 1289/ehp. 1206389 9

SYSTEMATIC REVIEW ON COI AND RISK OF BIAS Background Several reviews examining the effects of artificially sweetened beverages on obesity have discrepancies in their results and conclusions. Objectives To determine whether risk of bias, results, and conclusions of reviews of effects of artificially sweetened beverage consumption on weight outcomes differ depending on review sponsorship, authors’ financial conflicts of interest and journal funding. Characteristics Risk of bias performed according to Cochrane methods. Conflict of interest assessed according to ICMJE criteria. Over 900 records screened (31 reviews met our inclusion criteria) 10

TRANSPARENCY è Authors of 42% (13/31) of reviews had conflicts of interest that were not disclosed in the article; è Most of these (n = 8) were in reviews that also had no disclosed funding sources 11

REVIEW FUNDING AND REVIEW OUTCOMES è Artificial sweetener industry sponsored reviews were more likely to have favorable results (3/4) than non-industry sponsored reviews (1/23), RR: 17. 25 (95% CI: 2. 34 to 127. 29), as well as favorable conclusions (4/4 vs. 15/23), RR: 1. 52 (95% CI: 1. 14 to 2. 06). è All reviews funded by competitor industries reported nonfavorable results and conclusions (4/4). 12

COI OF THE AUTHORS AND REVIEW OUTCOMES è Reviews performed by authors that had a financial conflict of interest with the food industry were more likely to have favorable conclusions (18/22) than reviews performed by authors without conflicts of interest (4/9), RR: 7. 36 (95% CI: 1. 15 to 47. 22). 13

JOURNAL FUNDING AND REVIEW OUTCOMES è Almost all the reviews published in industry or mixed funded journals reported favorable conclusions (11/12), while the majority of the reviews published in non-industry funded journals did not reported favorable conclusions (8/19) RR: 2. 18 (95% CI: 1. 25 to 3. 79). 14

RISK OF BIAS è Risk of bias of the reviews was generally high è No difference in risk of bias among study funded by different sources or performed by conflicted authors 15

PEER-REVIEW è Almost all the reviews were published in peer-reviewed journals (27/31). No difference in peer-review process among review funded by different sources or performed by conflicted authors. 16

CONCLUSIONS è Financial conflicts of interest introduced a bias at all levels of the research and publication process (author financial ties, review sponsorship and journal funding), affecting the outcomes of reviews è The bias introduced by financial interests could not be ascribed to the overall risk of bias of the reviews and was not prevented by the peer review process. è Our results confirm the need for including conflict of interest as an item in risk of bias assessment 17

CONCLUSIONS è The opposite direction of bias in the outcomes of reviews funded by producers and competitors. Fair evaluations of safety and effectiveness of products might be potentially undermined by reviews performed by competitors. è Need for increased transparency and accountability in policies for declaration of interest 18

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Acknowledgments Fiorella Belpoggi and the Ramazzini Institute Staff Ellen Silbergeld, Johns Hopkins Lisa Bero, University of Sydney Cristin Kearns, University of California Elizabeth Waters, Cochane Collaboration 20

REMEMBERING CESARE MALTONI Maltoni-1974 -La cancerogenesi ambientale e professionale. Nuove prospettive alla luce della cancerogenesi da cloruro di vinile. 21

REMEMBERING CESARE MALTONI “The reward of great men is that, long after they have died, one is not quite sure that they are dead” Jules Renard , 1864 -1910