• 2/9/2008
  • Lyon, France
  • staff
  • PharmaLive (www.medadnews.com)

A combined analysis of four phase II/III studies which enrolled more than 20,000 women confirmed that the quadrivalent (6,11,16,18) cervical cancer vaccine Gardasil® has sustained 98% to 100% efficacy in the prevention of vaccine virus type-related precancerous cervical lesions in young women. These new data were presented this week at the 19th International Congress on Anti-Cancer Treatment (ICACT) in Paris, France.[1]

“The results complete Gardasil®’s impressive track record of sustained high efficacy. They include by far the longest follow-up for any cervical cancer vaccine in large phase III studies and strongly substantiate the evidence that the protection provided by Gardasil® will be long-lasting”, comments lead study investigator Prof. Elmar Joura, from the University of Vienna, Austria.

In light of the high and sustained efficacy of Gardasil®, the independent Data and Safety Monitoring Board of the large phase III studies in young women (FUTURE I & II) had recommended that these studies be terminated as soon as feasible in order to provide the benefits of Gardasil® to the women in the placebo group. Thus, the studies were ended earlier than originally planned and the women in the placebo group have been vaccinated.

In the primary study population of young women (16-26 years)[*], Gardasil® prevented 98%[†] of HPV 16/18-related precancerous cervical lesions (CIN2/3[‡] or AIS[§]) according to the combined analysis. Supplementary analyses in a sub-population of young women (16-26 years)[**] revealed 100%[††] efficacy against HPV 16/18-related CIN2/3 or AIS.

The sub-population approximates even better than the primary study population the target group of vaccination programmes (adolescent girls), where maximal benefit of vaccination is expected before exposure to the virus.

The new results are consistent with previous results from the five years follow up of the pivotal phase II study in a smaller population. “This extends the robustness of the data from a few hundred to many thousand women”, adds Patrick Poirot, vice president medical and scientific affairs at Sanofi Pasteur MSD. “Phase III results are of greatest importance for regulatory and health authorities when they evaluate a vaccine.”

The follow up of the pivotal phase II study has ended, too after five years; the women in the placebo group have been vaccinated not to let them any longer unprotected.

In addition to the robust follow ups in phase II and phase III studies, Gardasil® has been demonstrated to induce immune memory. Demonstrating immune memory means demonstrating that the immune system has memorised the vaccine virus types and can be expected to provide protection when exposed again to these types, even many years later.[2] Experts consider the demonstration of immune memory a hallmark of long-term protection.

“With five years of follow up in phase II studies followed by the demonstration of immune memory plus the longest ethically acceptable follow up in our large phase III studies we have provided the three key elements to make mothers, young women, physicians and health authorities confident about long-term protection with Gardasil®”, concludes Patrick Poirot.

About the studies

The FUTURE I and II studies are phase III, prospective, double-blind, placebo-controlled randomised studies conducted in 16 countries. Over 17,000 women participated in the trials. They were aged 16 to 26 and received three doses of either Gardasil® or placebo at day 1, month 2, and month 6.

FUTURE I evaluated the incidence of pre-cancerous and early cervical lesions (CIN 1-3), pre-cancerous and early vulvar and vaginal lesions (VIN1-3 and VaIN1-3) and external genital warts caused by the HPV 6, 11, 16 and 18. FUTURE II evaluated the prevention of pre-cancerous cervical lesions (CIN 2/3) and non-invasive cancers (AIS) caused by HPV types 16 and 18.

For the phase II/III combined analysis, 16,957 women (16–26 years) were enrolled and randomised to receive either Gardasil® (n = 8,493) or placebo (n = 8464) at day 1, and month 2 and 6 and were followed for up to 4 years after the start of vaccination. Pap tests were taken at regular 6 or 12-month intervals and evaluated using the Bethesda System-2001. Comprehensive anogenital examinations were scheduled at day 1, and every 6 to 12 months thereafter. Colposcopy referral was algorithm-based. Biopsies were HPV typed. Histology slides were read by a blinded pathology panel. Analyses were per protocol (received 3 doses, had no major protocol violations, were seronegative at day 1 and DNA negative day 1 to month 7 to the HPV vaccine types). There were two cases of CIN3 observed in the vaccine group (n = 8,493) and 112 cases observed in the placebo group (n = 8,464). Supplementary analyses were done in subjects who were negative to the four HPV vaccine types and ten additional types at day 1 (generally HPV naïve). There was no case observed in the vaccine group compared to 52 cases observed in the placebo group