Table 1.
Benefits and harms of the HPV vaccines: reporting of harms in included HPV vaccine studies
| Reporting of harmsa | Total | GlaxoSmithKline | Merck Sharp and Dohme | |||
|---|---|---|---|---|---|---|
| Studies (N = 24) |
Participants (N = 96,855)a |
Studies (N = 17) |
Participants (N = 66,235)a |
Studies (N = 7) |
Participants (N = 30,620) |
|
| Fatal harms | ||||||
| Reported for the whole study period | 23 | 64,679 (67%) | 16 | 34,059 (51%) | 7 | 30,620 (100%) |
| Reported for the whole study period for someb participants | 1 | 32,176 (33%) | 1 | 32,176 (49%) | 0 | 0 (0%) |
| Serious harmsc | ||||||
| Reported for the whole study period | 14 | 28,245 (30%) | 14 | 28,245 (42%) | 0 | 0 (0%) |
| No breakdown into MedDRA-preferred terms | 3 (21%) | 2586 (9%) | 3 (21%) | 2586 (9%) | 0 (0%) | 0 (0%) |
| Reported 0 to 14 days post-vaccination | 7 | 30,620 (31%) | 0 | 0 (0%) | 7 | 30,620 (100%) |
| Reported for the 7-month vaccination period | 2 | 5814 (6%) | 2 | 5814 (9%) | 0 | 0 (0%) |
| Reported for a subset or the serious harms judged vaccine-related by the trial investigatorsb | 1 | 32,176 (33%) | 1 | 32,176 (49%) | 0 | 0 (0%) |
| New onset diseasesd | ||||||
| Reported as ‘medically significant conditions’ for the whole study period | 15 | 65,741 (68%) | 15 | 65,741 (99%) | 0 | 0 (0%) |
| No breakdown into MedDRA-preferred terms | 2 (13%) | 33,216 (51%) | 2 (13%) | 33,216 (51%) | 0 (0%) | 0 (0%) |
| Reported as ‘new medical history’ for the whole study period | 7 | 30,620 (31%) | 0 | 0 (0%) | 7 | 30,620 (100%) |
| Not reported/included in clinical study report | 2 | 494 (1%) | 2 | 494 (1%) | 0 | 0 (0%) |
| General harmse | ||||||
| Reported as ‘solicited’ and ‘unsolicited’ general harms 7 and 30 days post-vaccination | 14 | 64,010 (66%) | 14 | 64,010 (96%) | 0 | 0 (0%) |
| Reported for a subset of participantsf | 2 (14%) | 7791/50,820 | 2 (14%) | 7791/50,820 | 0 (0%) | 0 (0%) |
| Reported as ‘systemic adverse events’ 14 days post-vaccination | 7 | 30,620 (31%) | 0 | 0 (0%) | 7 | 30,620 (100%) |
| No breakdown into MedDRA-preferred terms | 3 (43%) | 21,441 (70%) | 0 (0%) | 0 (0%) | 3 (43%) | 21,441 (70%) |
| Not reported/included in clinical study report | 3 | 2225 (3%) | 3 | 2225 (4%) | 0 | 0 (0%) |
aSee Additional file 2 for details on the reporting of harms. Table 1 includes all 24 clinical study reports including the two follow-up studies HPV-023 (follow-up for trial HPV-001) of 433 participants and HPV-063 (follow-up for trial HPV-032) of 752 participants, i.e. 1185 participants (433 + 752) are included twice for the trials HPV-001 and HPV-032. The total denominator is 95,670 for the 22 included trials and 96,855 (95,670 + 1185) for the 24 included clinical study reports
bIn one trial (HPV-040), 12% (3703/32,176) of participants were included in a subset population for fatal and serious harms reporting
c(1) GlaxoSmithKline defined serious harms as “any untoward medical occurrence that a resulted in death and b was life-threatening, NOTE: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the subject was at risk of death at the time of the event. It did not refer to an event, which hypothetically might have caused death, if it were more severe. c. required hospitalisation or prolongation of existing hospitalisation, NOTE: In general, hospitalisation signified that the subject had been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occurred during hospitalisation were AEs [adverse events]. If a complication prolonged hospitalisation or fulfilled any other serious criteria, the event was serious. When in doubt as to whether “hospitalisation” occurred or was necessary, the AE was to be considered serious. Hospitalisation for elective treatment of a pre-existing condition that did not worsen from baseline was not considered an AE. d. resulted in disability/incapacity, NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition was not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but did not constitute a substantial disruption. e. was a congenital anomaly/birth defect in the offspring of a study subject”. (2) Merck Sharp and Dohme defined serious harms as “any adverse experience occurring at any dose that: Results in death; or that is life threatening (places the subject/patient, in the view of the investigator, at immediate risk of death from the experience as it occurred. [Note: This does not include an adverse experience that, had it occurred in a more severe form, might have caused death.]); or that results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or that results in or prolongs an existing inpatient hospitalisation (hospitalised is defined as an inpatient admission, regardless of length of stay, even if the hospitalisation is a precautionary measure for continued observation.); or ALSO: Other important medical events that may not result in death, not be life threatening, or not require hospitalisation may be considered a serious adverse experience when, based upon appropriate medical judgement, the event may jeopardise the subject/patient and may require medical or surgical intervention to prevent one of the outcomes listed above”
d(1) 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”. (2) Merck Sharp and Dohme did not provide a formal definition for ‘new medical history’ but described ‘new medical history’ as “all new reported diagnoses” in the clinical study report of trial V501-019
e(1) GlaxoSmithKline defined ‘solicited’ general adverse events as “Adverse events to be recorded as endpoints in the clinical study [i.e. arthralgia, fatigue, headache, myalgia, pyrexia, rash and urticaria]. The presence/occurrence/intensity of these events is actively solicited from the subject or an observer during a specified post-vaccination follow-up period”. (2) 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”. (3) Merck Sharp and 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”
fThe two trials HPV-008 and HPV-040 only reported general harms for 15% (7791/50,820) of included participants