The Cochrane HPV vaccine review was incomplete and ignored important evidence of bias

• Published in: BMJ evidence-based medicine Vol. 23; no. 5; pp. 165 - 168
• Main Authors: Jørgensen, Lars, Gøtzsche, Peter C, Jefferson, Tom
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.10.2018
• Subjects: Bias; Cancer; Cervical cancer; Clinical trials; Conflict of Interest; Evidence-based medicine; Female; Gynecology; Human papillomavirus; Humans; Immunization; Papillomavirus Infections; Papillomavirus Vaccines - adverse effects; Papillomavirus Vaccines - therapeutic use; Pediatrics; Public health; Systematic review; Systematic Reviews as Topic; Treatment Outcome; Uterine Cervical Neoplasms - prevention & control; Vaccines; paediatrics; paediatric infectious disease & immunisation; health services administration & management; infectious diseases; preventive medicine; gynaecology; gynaecological oncology; public health; quality in health care
• ISSN: 2515-446X; 2515-4478
• DOI: 10.1136/bmjebm-2018-111012

The only saline placebo trial of approved HPV vaccines is a Gardasil 9 trial (V503-006; NCT01047345) that was published in 2015.4 Its participants had previously been vaccinated with four-valent Gardasil, but according to the Cochrane review protocol,5 this was not an exclusion criterion. Since many countries are shifting to Gardasil 9,6 it is unfortunate that the Gardasil 9 trial was not included in the Cochrane review. According to the Food and Drug Administration (FDA), adjuvants are unreliable comparators.7 One HPV vaccine manufacturer (GlaxoSmithKline that produces Cervarix) states that its aluminium-based comparator induces harms: ‘higher incidences of myalgia might namely be attributable to the higher content of aluminium in the HPV vaccine (450 μg Al[OH]3) than the content of aluminium in the HAV [hepatitis A] vaccine (225 μg Al[OH]3)’.8 The comparator hepatitis vaccines also used the HPV vaccines’ aluminium-based adjuvant. The included HPV vaccine trials used composite surrogate outcomes for cervical cancer In line with World Health Organization (WHO) recommendations,14 the Cochrane review was based on composite surrogate outcomes: ‘cervical intraepithelial neoplasia grade 2 and above [CIN2+], CIN grade 3 and above [CIN3+] and adenocarcinoma in situ [AIS]’.1 The use of such outcomes seemed reasonable for a preliminary assessment of HPV vaccine benefits, but the outcomes can be difficult to interpret. According to ClinicalTrials.gov, this particular trial (‘CVT’ or ‘Costa Rica trial’1) was sponsored by GlaxoSmithKline.27 Therefore, all included trials were funded by the HPV vaccine manufacturers and the meta-regression was meaningless.