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Table 3 Comparison of HPV vaccine clinical study reports with trial register entries and journal publications: results of benefit and harm meta-analyses of intention to treat analyses irrespective of HPV type

From: 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

Results of benefits and harms meta-analyses of intention to treat analyses irrespective of HPV typeaClinical study reportsTrial register entriesJournal publications
HPV vaccine (n = 47,075)Comparator (n = 48,595)Risk ratioe [95% CI]HPV vaccine (n = 47,075)Comparator (n = 48,595)Risk ratioe [95% CI]HPV vaccine (n = 47,044f)Comparator (n = 48,565f)Risk ratioe [95% CI]
 All-cause mortality45381.19 [0.65, 2.19]39311.30 [0.73, 2.30]35281.20 [0.51, 2.80]
 HPV-related cancer mortality211.44 [0.23, 9.12]00Not applicable00Not applicable
 HPV-related cancer incidence731.68 [0.51, 5.49]00Not applicable103.01 [0.12, 73.85]
 HPV-related carcinoma in situ3674900.73 [0.53, 1.00]00Not applicable2122470.85 [0.61, 1.19]
 HPV-related moderate intraepithelial neoplasia5387630.81 [0.59, 1.11]00Not applicable2513080.82 [0.69, 0.96]
 HPV-related moderate intraepithelial neoplasia or worse95212390.78 [0.66, 0.91]00Not applicable6658480.77 [0.65, 0.92]
 HPV-related treatment procedures101814160.71 [0.63, 0.80]76840.90 [0.66, 1.22]1802400.75 [0.62, 0.91]
 Total reported benefit data points29293950Not applicable115115Not applicable13441671Not applicable
 Participants with fatal harms45381.19 [0.65, 2.19]39311.30 [0.73, 2.30]35281.20 [0.51, 2.80]
  Total number of fatal harms or MedDRA classified fatal harms7951Not applicable3931Not applicable3528Not applicable
 Participants with serious harms140413571.01 [0.94, 1.08]139813491.01 [0.94, 1.09]124112341.01 [0.93, 1.09]
  Total number of serious harms or MedDRA classified serious harms17411628Not applicable17631636Not applicable12551249Not applicable
   - Judged ‘definitely associated’ with CRPSb95571.54 [1.11, 2.14]88551.52 [1.08, 2.12]921.94 [0.57, 6.57]
   - Judged ‘definitely associated’ with POTSb56261.92 [1.21, 3.07]52232.00 [1.23, 3.25]621.79 [0.45, 7.22]
   - Nervous system disorders72461.49 [1.02, 2.16]69451.47 [1.01, 2.15]1271.45 [0.53, 3.94]
 Participants with new-onset diseasesc14,25814,0140.99 [0.97, 1.02]487447791.02 [0.95, 1.10]474048011.00 [0.92, 1.09]
  Total number of new-onset diseases or MedDRA classified new-onset diseases47,47446,662Not applicable99728673Not applicable47404801Not applicable
   - Back pain3973361.15 [1.00, 1.33]68631.08 [0.77, 1.52]00Not applicable
   - Vaginal infection3694200.87 [0.76, 1.00]00Not applicable00Not applicable
   - Vascular disorders2342940.80 [0.67, 0.94]00Not applicable00Not applicable
 Participants with general harmsd13,24812,3941.07 [1.03, 1.11]352234681.07 [1.00, 1.15]845776971.05 [1.01, 1.10]
  Total number of general harms or MedDRA classified general harms37,99931,916Not applicable22,23619,793Not applicable21,00118,790Not applicable
   - Fatigue493344891.13 [1.08, 1.18]425539011.13 [1.07, 1.19]234322101.15 [1.04, 1.26]
   - Headache556152461.06 [1.02, 1.11]493445871.07 [1.03, 1.12]244323721.08 [1.01, 1.16]
   - Myalgia398930471.41 [1.24, 1.60]350826881.44 [1.21, 1.71]186811931.57 [1.23, 2.01]
 Total reported MedDRA classified data points87,29380,257Not applicable34,01030,133Not applicable27,03124,868Not applicable
  1. aSee Additional file 2 for the meta-analyses. It was not feasible to present this summary table for the 16 subgroups that the 24 included studies comprised (based on age-group, gender, type of HPV vaccine and comparator)
  2. bWe asked a physician with clinical expertise in complex regional pain syndrome (CRPS) and postural orthostatic tachycardia syndrome (POTS) to assess the reported MedDRA preferred terms as ‘definitely,’ ‘probably,’ ‘probably not’ or ‘definitely not’ associated with the syndromes. We sent an Excel sheet to the physician with all the reported MedDRA terms. The physician was blinded, as the Excel sheet contained no outcome data. When the physician had assessed all the MedDRA terms, we synthesized the data for those MedDRA terms that the physician judged ‘definitely’ associated with POTS or CRPS
  3. cNew-onset diseases were compiled of the harm categories ‘medically significant conditions’ (for Cervarix) and ‘new medical history’ (for Gardasil, Gardasil 9 and the HPV 16 vaccine). GlaxoSmithKline defined ‘medically significant conditions’ as ‘Adverse events prompting emergency room or physician visits that are not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or SAEs [serious adverse events] that are not related to common diseases. Serious adverse events related to common diseases were reported but are not classified as medically significant conditions for analysis purposes. Common diseases include: upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervicovaginal yeast infections, menstrual cycle abnormalities and injury’. Merck Sharp & Dohme did not provide a formal definition for ‘new medical history’ but described the category as ‘all new reported diagnoses’ in the clinical study report of study V501-019
  4. dGeneral harms was compiled of the harm categories ‘solicited general symptoms’, ‘unsolicited general symptoms’ (for Cervarix) and ‘systemic adverse experiences’ (for Gardasil, Gardasil 9 and the HPV 16 vaccine). GlaxoSmithKline defined ‘solicited’ general adverse events as ‘Adverse events to be recorded as endpoints in the clinical study. The presence/occurrence/intensity of these events is actively solicited from the subject or an observer during a specified post-vaccination follow-up period’. GlaxoSmithKline defined ‘unsolicited’ general adverse event as ‘Any AE [adverse event] reported in addition to those solicited during the clinical study. Also, any “solicited” symptom with onset outside the specified period of follow-up for solicited symptoms was reported as an unsolicited AE’. Merck Sharp & Dohme defined ‘systemic adverse event’ as ‘…any systemic clinical adverse event that developed on the day of vaccination or during the 14 days after vaccination was recorded on the VRC [vaccination report card] along with the date it started and the last date it was present’
  5. eRisk ratios were calculated with the random effects inverse variance method
  6. fThe numbers of participants for ‘HPV vaccine’ and ‘comparator’ in the journal publication column were subtracted by 31 and 30 participants, respectively, as no journal publication existed for trial HPV-003 that included 31 and 30 participants