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

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

doi:10.1186/s13643-020-01300-1

Systematic Reviews

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 type^a	Clinical study reports			Trial register entries			Journal publications
	HPV vaccine (n = 47,075)	Comparator (n = 48,595)	Risk ratio^e [95% CI]	HPV vaccine (n = 47,075)	Comparator (n = 48,595)	Risk ratio^e [95% CI]	HPV vaccine (n = 47,044^f)	Comparator (n = 48,565^f)	Risk ratio^e [95% CI]
Benefits
All-cause mortality	45	38	1.19 [0.65, 2.19]	39	31	1.30 [0.73, 2.30]	35	28	1.20 [0.51, 2.80]
HPV-related cancer mortality	2	1	1.44 [0.23, 9.12]	0	0	Not applicable	0	0	Not applicable
HPV-related cancer incidence	7	3	1.68 [0.51, 5.49]	0	0	Not applicable	1	0	3.01 [0.12, 73.85]
HPV-related carcinoma in situ	367	490	0.73 [0.53, 1.00]	0	0	Not applicable	212	247	0.85 [0.61, 1.19]
HPV-related moderate intraepithelial neoplasia	538	763	0.81 [0.59, 1.11]	0	0	Not applicable	251	308	0.82 [0.69, 0.96]
HPV-related moderate intraepithelial neoplasia or worse	952	1239	0.78 [0.66, 0.91]	0	0	Not applicable	665	848	0.77 [0.65, 0.92]
HPV-related treatment procedures	1018	1416	0.71 [0.63, 0.80]	76	84	0.90 [0.66, 1.22]	180	240	0.75 [0.62, 0.91]
Total reported benefit data points	2929	3950	Not applicable	115	115	Not applicable	1344	1671	Not applicable
Harms
Participants with fatal harms	45	38	1.19 [0.65, 2.19]	39	31	1.30 [0.73, 2.30]	35	28	1.20 [0.51, 2.80]
Total number of fatal harms or MedDRA classified fatal harms	79	51	Not applicable	39	31	Not applicable	35	28	Not applicable
Participants with serious harms	1404	1357	1.01 [0.94, 1.08]	1398	1349	1.01 [0.94, 1.09]	1241	1234	1.01 [0.93, 1.09]
Total number of serious harms or MedDRA classified serious harms	1741	1628	Not applicable	1763	1636	Not applicable	1255	1249	Not applicable
- Judged ‘definitely associated’ with CRPS^b	95	57	1.54 [1.11, 2.14]	88	55	1.52 [1.08, 2.12]	9	2	1.94 [0.57, 6.57]
- Judged ‘definitely associated’ with POTS^b	56	26	1.92 [1.21, 3.07]	52	23	2.00 [1.23, 3.25]	6	2	1.79 [0.45, 7.22]
- Nervous system disorders	72	46	1.49 [1.02, 2.16]	69	45	1.47 [1.01, 2.15]	12	7	1.45 [0.53, 3.94]
Participants with new-onset diseases^c	14,258	14,014	0.99 [0.97, 1.02]	4874	4779	1.02 [0.95, 1.10]	4740	4801	1.00 [0.92, 1.09]
Total number of new-onset diseases or MedDRA classified new-onset diseases	47,474	46,662	Not applicable	9972	8673	Not applicable	4740	4801	Not applicable
- Back pain	397	336	1.15 [1.00, 1.33]	68	63	1.08 [0.77, 1.52]	0	0	Not applicable
- Vaginal infection	369	420	0.87 [0.76, 1.00]	0	0	Not applicable	0	0	Not applicable
- Vascular disorders	234	294	0.80 [0.67, 0.94]	0	0	Not applicable	0	0	Not applicable
Participants with general harms^d	13,248	12,394	1.07 [1.03, 1.11]	3522	3468	1.07 [1.00, 1.15]	8457	7697	1.05 [1.01, 1.10]
Total number of general harms or MedDRA classified general harms	37,999	31,916	Not applicable	22,236	19,793	Not applicable	21,001	18,790	Not applicable
- Fatigue	4933	4489	1.13 [1.08, 1.18]	4255	3901	1.13 [1.07, 1.19]	2343	2210	1.15 [1.04, 1.26]
- Headache	5561	5246	1.06 [1.02, 1.11]	4934	4587	1.07 [1.03, 1.12]	2443	2372	1.08 [1.01, 1.16]
- Myalgia	3989	3047	1.41 [1.24, 1.60]	3508	2688	1.44 [1.21, 1.71]	1868	1193	1.57 [1.23, 2.01]
Total reported MedDRA classified data points	87,293	80,257	Not applicable	34,010	30,133	Not applicable	27,031	24,868	Not applicable

^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)
^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
^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
^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’
^eRisk ratios were calculated with the random effects inverse variance method
^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

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