Contemporary Clinical Trials
Volume 52, Pages 1-100 (January 2017)
Study Design, Statistical Design, Study Protocols
Design of a long-term follow-up effectiveness, immunogenicity and safety study of women who received the 9-valent human papillomavirus vaccine
Original Research Article
Alain Luxembourg, Susanne K. Kjaer, Mari Nygard, Misoo C. Ellison, Thomas Group, J. Brooke Marshall, David Radley, Alfred Saah
The 9-valent human papillomavirus (HPV) (9vHPV) vaccine targets four HPV types (6/11/16/18) also covered by the quadrivalent HPV (qHPV) vaccine and five additional types (31/33/45/52/58). Vaccine efficacy to prevent HPV infection and disease was established in a Phase III clinical study in women 16–26 years of age. A long-term follow-up (LTFU) study has been initiated as an extension of the Phase III clinical study to assess effectiveness of the 9vHPV vaccine up to at least 14 years after the start of vaccination. It includes participants from Denmark, Norway and Sweden and uses national health registries from these countries to assess incidence of cervical pre-cancers and cancers due to the 7 oncogenic types in the vaccine (HPV 16/18/31/33/45/52/58). Incidences will be compared to the estimated incidence rate in an unvaccinated cohort of similar age and risk level. This LTFU study uses a unique design: it is an extension of a Phase III clinical study and also has elements of an epidemiological study (i.e., endpoints based on standard clinical practice; surveillance using searches from health registries); it uses a control chart method to determine whether vaccine effectiveness may be waning. Control chart methods which were developed in industrial and manufacturing settings for process and production monitoring, can be used to monitor disease incidence in real-time and promptly detect a decrease in vaccine effectiveness. Experience from this innovative study design may be applicable to other medicinal products when long-term outcomes need to be assessed, there is no control group, or outcomes are rare.