Benefits and harms of the human papillomavirus (HPV) vaccines: systematic review with meta-analyses of trial data from clinical study reports

Jørgensen, Lars Nannestad; Gøtzsche, Peter C; Jefferson, Tom

doi:10.1186/s13643-019-0983-y

Cited by 23 publications

(23 citation statements)

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“…This was likely a main reason why the clinical study reports were superior at reporting trial design aspects. If our systematic review of clinical study reports [9] had relied on trial register entries or journal publications, it would have had no data for a quarter of our prespecified outcomes (11/40). Although the inclusion of clinical study reports led to significantly more eligible and available data, no changes in the direction of available results occurred when comparing the risk ratios of corresponding meta-analyses as ratios of relative risks.…”

Section: Discussionmentioning

confidence: 99%

“…We compared corresponding HPV vaccine study documents of clinical study reports, trial register entries and journal publications to investigate the degree of reporting bias for prespecified outcomes and the reporting of trial design aspects; see our protocol on PROSPERO [11] (registered as 'Protocol amendment no. 3' for our systematic review of the HPV vaccines [9]).…”

Section: Methodsmentioning

confidence: 99%

“…Clinical study reports were obtained from EMA and GlaxoSmithKline [9]. We identified the clinical study reports' corresponding trial register entries on ClinicalTrials.gov and corresponding primary journal publications from our published index of the HPV vaccine studies.…”

Section: Methodsmentioning

confidence: 99%

“…For each study document, we extracted and compared data on the outcomes we assessed in our systematic review [9]. As our review contained 166 meta-analyses, we only compared the 20 most clinically relevant outcomes (or statistically significant outcomes with a p value ≤ 0.05; noted in parentheses).…”

Section: Methodsmentioning

confidence: 99%

“…We carried out a systematic review of the human papillomavirus (HPV) vaccines' clinical study reports [9] based on an index we constructed of 206 HPV vaccine studies [10]. As of July 2017, 62% (92/149) of the completed studies were not published in journal publications and 48% (71/147) of the completed studies on ClinicalTrials.gov had no study results posted [10].…”

Section: Introductionmentioning

confidence: 99%

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Benefits and harms of the human papillomavirus (HPV) vaccines: comparison of trial data from clinical study reports with corresponding trial register entries and journal publications

2020

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Background No study has looked at differences of pooled estimates—such as meta-analyses—of corresponding study documents of the same intervention. In this study, we compared meta-analyses of human papillomavirus (HPV) vaccine trial data from clinical study reports with trial data from corresponding trial register entries and journal publications. Methods We obtained clinical study reports from the European Medicines Agency and GlaxoSmithKline, corresponding trial register entries from ClinicalTrials.gov and corresponding journal publications via the Cochrane Collaboration’s Central Register of Controlled Trials, Google Scholar and PubMed. Two researchers extracted data. We compared reporting of trial design aspects and 20 prespecified benefit and harm outcomes extracted from each study document type. Risk ratios were calculated with the random effects inverse variance method. Results We included study documents from 22 randomized clinical trials and 2 follow-up studies with 95,670 healthy participants and non-HPV vaccine comparators (placebo, HPV vaccine adjuvants and hepatitis vaccines). We obtained 24 clinical study reports, 24 corresponding trial register entries and 23 corresponding journal publications; the median number of pages was 1351 (range 357 to 11,456), 32 (range 11 to 167) and 11 (range 7 to 83), respectively. All 24 (100%) clinical study reports, no (0%) trial register entries and 9 (39%) journal publications reported on all six major design-related biases defined by the Cochrane Handbook version 2011. The clinical study reports reported more inclusion criteria (mean 7.0 vs. 5.8 [trial register entries] and 4.0 [journal publications]) and exclusion criteria (mean 17.8 vs. 11.7 and 5.0) but fewer primary outcomes (mean 1.6 vs. 3.5 and 1.2) and secondary outcomes (mean 8.8 vs. 13.0 and 3.2) than the trial register entries. Results were posted for 19 trial register entries (79%). Compared to the clinical study reports, the trial register entries and journal publications contained 3% and 44% of the seven assessed benefit data points (6879 vs. 230 and 3015) and 38% and 31% of the 13 assessed harm data points (167,550 vs. 64,143 and 51,899). No meta-analysis estimate differed significantly when we compared pooled risk ratio estimates of corresponding study document data as ratios of relative risk. Conclusion There were no significant differences in the meta-analysis estimates of the assessed outcomes from corresponding study documents. The clinical study reports were the superior study documents in terms of the quantity and the quality of the data they contained and should be used as primary data sources in systematic reviews. Systematic review registration The protocol for our comparison is registered on PROSPERO as an addendum to our systematic review of the benefits and harms of the HPV vaccines: https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20180320.pdf: CRD42017056093. Our systematic review protocol was registered on PROSPERO on January 2017: https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20170030.pdf. Two protocol amendments were registered on PROSPERO on November 2017: https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20171116.pdf. Our index of the HPV vaccine studies was published in Systematic Reviews on January 2018: 10.1186/s13643-018-0675-z. A description of the challenges obtaining the data was published on September 2018: 10.1136/bmj.k3694.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%