New Clinical Cross Protection Data Submitted To The EMEA For Licence Update For The Human Papillomavirus Vaccine Gardasil®

Main Category: Cervical Cancer / HPV Vaccine
Also Included In: Women's Health / Gynecology;  Pediatrics / Children's Health
Article Date: 26 Apr 2007 - 15:00 PDT

email to a friend   printer friendly   opinions  

United Kingdom - Sanofi Pasteur MSD has submitted cross protection data to the European Medicines Agency (EMEA) to update the licence for the human papillomavirus vaccine Gardasil®. The new data come from large phase III clinical studies, including more than 17,000 womena), b), and show that Gardasil® provides benefits against pre-cancerous and potentially pre-cancerous cervical lesions caused by additional virus types not directly targeted by the vaccine. Details of these new data will be presented at scientific congresses later this year.

Pre-cancerous lesions (CIN*2/3) are the obligate precursor of cervical cancer; their prevention is the best proof for the prevention of cervical cancer. The additional virus types cause more than 10% of cervical cancer and substantial proportions of pre-cancerous and potentially precancerous cervical lesions.

"Throughout the clinical development for Gardasil® we have focussed on proving efficacy against WHO† recommended and clinically relevant endpoints, including pre-cancerous cervical lesions (CIN‡2/3) for demonstrating the prevention of cervical cancer", says Patrick Poirot, Vice President Medical and Scientific Affairs at Sanofi Pasteur MSD. "We proved this for the virus types directly targeted by the vaccine, which led to the marketing authorisation for Gardasil® in Europe in September 2006. We have maintained this very high standard for additional virus types and are now very pleased to have submitted clinically meaningful cross protection data."

According to the current marketing authorisation in the European Union, Gardasil® is indicated for the prevention of cervical carcinoma (cervical cancer), high grade cervical dysplasia CIN*2/3 (precancerous cervical lesions), high grade vulvar dysplastic lesions VIN+2/3 (pre-cancerous vulvar lesions) and external genital warts (condyloma acuminata) caused by human papillomavirus types 6, 11, 16 and 18. In addition, Gardasil® is efficacious in the prevention of potentially precancerous lesions (CIN‡1) caused by the virus types 6, 11, 16 and 18.

The virus types 6, 11, 16 and 18 directly targeted by Gardasil® cause many genital human papillomavirus diseases. It is estimated that human papillomavirus types 6,11,16 and 18 together cause 75% of cervical cancer,1 70% of pre-cancerous (CIN‡2/3)4,5 and 50% of potentially precancerous cervical lesions (CIN‡1)6, a significant proportion of vulvar and vaginal cancers and their associated pre-cancerous lesions2,3,7,8, and 90% of genital warts in Europe.9,10

In clinical trials, Gardasil® prevented up to 100% of cervical cancer, pre-cancerous and potentially pre-cancerous cervical lesions, pre-cancerous vulval and vaginal lesions, and genital warts due to human papillomavirus types 6, 11, 16 and 18.11,12,13 a), b)

The additional types, against which Gardasil® has shown to provide clinical benefits, cause more than 10% of cervical cancer (in the overall female population)14 and have been found to cause around 25% to 40% of pre-cancerous and potentially pre-cancerous cervical lesions (CIN‡1-3 or AIS**) in the placebo groups of the Gardasil® clinical trials.15

On 17th April 2007, Merck & Co., Inc. announced the submission of the new clinical cross protection data to the US Food and Drug Administration (FDA).

About cervical cancer and other human papillomavirus diseases

Despite screening for early detection, cervical cancer remains the second most common cause of death from cancer (after breast cancer) among young women (15-44 years) in Europe‡‡.16 Around 33,500 women are diagnosed with, and 15,000 women die from cervical cancer each year (the equivalent of 40 women per day or nearly 2 per hour).17 In addition, hundreds of thousands of women are diagnosed with other human papillomavirus diseases that start before cervical cancer and go beyond the cervix. These diseases include pre-cancerous and potentially pre-cancerous cervical lesions4,6,18, vulvar and vaginal cancer2,3,19, pre-cancerous vulvar and vaginal lesions7,8,20,21 and genital warts.22 Pre-cancerous and potentially pre-cancerous cervical lesions may result in abnormal screening results and need further medical care, and can lead to considerable worry for the women affected.

Cervical cancer is caused exclusively by human papillomavirus.++23,24 The link between human papillomavirus infection and cervical cancer is far stronger than that between smoking and lung cancer.25,26 human papillomavirus is very common, with 70% of sexually active people estimated to become exposed at some point in life.27,28,29 Genital infections with human papillomavirus are very common with the majority of infections occurring in adolescence or early adulthood.30,31

Gardasil® has been approved in more than 60 countries (many under accelerated review timelines), including the EU, the US, Canada and Australia and has met with very broad acceptance. Additional applications are currently under review with regulatory agencies in more than 50 countries around the world. The EU licensed Gardasil® within just 9 months compared to a usual review time of 13-15 months. After gaining the license in September 2006, Sanofi Pasteur MSD has made Gardasil® available in 18 European countries.##

Current recommendation and funding status of human papillomavirus vaccination In Europe, Germany, France, Italy and Austria have recommended human papillomavirus vaccination of girls and young women. Decisions were taken after accelerated review times compared to decisions upon recommendations and funding for vaccination programmes against other diseases in the past.

The German health authorities recommend the universal vaccination of girls aged 12 to 17 years and add that girls and women who have not received vaccination during the recommended age period can still benefit from vaccination. Vaccination should be completed before sexual debut and measures for the early detection of cervical cancer should continue. Since December 2006, several German health insurance funds, which together cover around 65% of the population, fully reimburse human papillomavirus vaccination. The remaining health insurance funds are anticipated to follow soon.

In Italy, the health authorities have recommended universal and free vaccination of 12 years old girls. Vaccination in the first vaccination centres at regional level is anticipated to start as of April 2007.

The French health authorities recommend the universal vaccination of 14 year old girls and also recommend offering vaccination to girls and young women aged 15 to 23, who have not yet had sexual relations, or in the year following the start of their sexual activity at the latest. The authorities have reiterated that vaccination does not replace screening and that women must be screened, whether they are vaccinated or not. In February 2007, the French Health Minister announced that the reimbursement of human papillomavirus vaccination by the National Social Security system would be decided before July 2007. In March, the French President expressed the wish that human papillomavirus vaccination should be reimbursed under the best conditions and as fast as possible.

In Luxemburg, the health authorities recommend the universal vaccination of 12 years old girls and a catch-up vaccination programme for girls up to the age of 18 years.

In Norway, the health authorities recommend the universal vaccination of 12 years old girls and a catch-up vaccination programme for girls up to the age of 16 years.

In Austria vaccination is recommended for girls and boys aged 9 to 15 years as well as for women, preferably before the start of sexual activity.

In June 2006, the US health authorities recommended the routine vaccination of 11- and 12- year-old females and the vaccination of females aged 13 to 26 who have not previously been vaccinated and that 9and 10- year-old females can be vaccinated at the discretion of their physicians. Pap*** and human papillomavirus screening prior to vaccination are not necessary according to the recommendation. The US authorities also recommended that females can receive Gardasil® regardless of whether they have now or have previously had an abnormal Pap test, a positive human papillomavirus test or genital warts. In the meantime, health insurers covering approximately 97% of privately insured lives in the US have implemented vaccination with Gardasil®. In November 2006, the authorities added Gardasil® to their Vaccines for Children (VFC) contract for eligible girls and women aged 9 to 18 providing coverage for many who do not have private health insurance. To date, 53 out of 55 immunisation projects (which cover 94 % of the public sector birth cohort in the U.S.) have adopted Gardasil®.

In November 2006, the Australian government announced the funding of Gardasil® for girls and women aged 12 to 26 years from 2007. Gardasil® will be put on the national immunisation programme for 12- to 13year-old girls to be delivered through schools. The government will also fund a two year catch-up programme for 13- to 18-year-old girls in schools and 18- to 26-year-old women to be delivered through general practitioners.

As of 15th February 2007, Gardasil® is recommended in Canada for females between 9 and 26 years of age. Females who had previous Pap abnormalities including cervical cancer or have had genital warts or known Human Papillomavirus infection would still benefit from Gardasil according to the recommendations of the Canadian authorities.

EU indication of Gardasil®

According to the licence in the EU, Gardasil®, Human Papillomavirus Vaccine [types 6,11,16,18] (Recombinant, adsorbed), can be given to children and adolescents 9 to15 years and adult females 16 to 26 years of age and is indicated for the prevention of cervical carcinoma (cervical cancer), high grade cervical dysplasia CIN2/3 (precancerous cervical lesions), high grade vulvar dysplastic lesions VIN 2/3 (precancerous vulvar lesions) and external genital warts (condyloma acuminata) caused by human papillomavirus types 6, 11, 16 and 18.

Cytological screening, named after its inventor George Papanicolaou.

More about Gardasil®

Gardasil® has been developed by Merck & Co., Inc. and Sanofi Pasteur MSD. In Europe, the vaccine is marketed by Sanofi Pasteur MSD. Merck is actively working to accelerate the availability of Gardasil® in the developing world. Clinical trials for the development of Gardasil® have already included participants from 33 countries on 5 continents in a variety of settings. In December 2005, Merck and the Indian Council of Medical Research announced a collaboration to study Gardasil® in populations in India. Clinical trials in developing world countries are being initiated this year to assess the efficacy of Gardasil® in other environments; first studies are underway in Africa. In June 2006, PATH announced the launch of a 5-year effort to help bring HPV vaccines to those nations where cervical cancer rates are highest. PATH selected Uganda, Peru, India & Vietnam to participate in this project. Merck is committed to provide Gardasil® to support PATH in this effort. Upon completion of the study in India, the two partners will work together to assess the public health role of Gardasil® in the population of India and to identify ways of providing access to Gardasil®. Merck will make its new vaccines, including Gardasil®, available to developing world countries at prices at which the company will not profit.

About Sanofi Pasteur MSD

Sanofi Pasteur MSD (www.apmsd.co.uk) is a joint venture between sanofi pasteur, the vaccine division of sanofi-aventis, and Merck & Co., Inc. Combining innovation and expertise, Sanofi Pasteur MSD is the only company in Europe dedicated exclusively to vaccines. Sanofi Pasteur MSD is able to draw on the research expertise of sanofi pasteur and Merck & Co., Inc., together with their teams throughout the world, to focus on the development of new vaccines for Europe, which aim to extend protection to other diseases and perfect existing vaccines in order to improve the acceptability, efficacy and tolerability of vaccination.

a) Gardasil® efficacy was assessed in 4 placebo-controlled, double-blind, randomized Phase II and III clinical studies. The first phase II study evaluated the human papillomavirus 16 component of Gardasil® (Protocol 005, N=2391) and the second evaluated all components of Gardasil® (Protocol 007, N=551). The Phase III studies evaluated Gardasil® in 5,442 (FUTURE I or Protocol 013) and 12,157 (FUTURE II or Protocol 015) subjects. Together, these 4 studies evaluated 20,541 women 16 to 26 years of age at enrolment who received in three studies 3 injections of the quadrivalent human papillomavirus (types 6, 11, 16, 18) vaccine at day 1, month 2 and month 6 of the study and in one study women received 3 injections of the monovalent human papillomavirus (type 16) at day 1, month 2 and month 6 of the study. At specific pre-determined times during the study the women were examined and tests carried out for the presence of human papillomavirus and cervical lesions. The median duration of follow-up was 4.0, 3.0, 2.4, and 2.0 years for Protocol 005, Protocol 007, FUTURE I, and FUTURE II, respectively.

b) 18,150 women (16-26 yrs) from the Americas, Europe and Asia were enrolled in 1 of 3 trials (protocol 007, FUTURE I, FUTURE II). Subjects were randomised to either quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine or placebo. For all trials, vaccination occurred at day 1, and months 2 and 6. Genital tract specimens were obtained at day 1 and at 6 - 12 month intervals thereafter for a maximum of 48 months. Colposcopy referral was algorithm-based. Biopsies were HPV-typed. Cytology, histology, and HPV detection were conducted centrally. Analyses were done per protocol (PP) (subjects received 3 doses, had no major protocol violations, were HPV 16 or 18 seronegative at day 1 and HPV 16 or 18 DNA negative day 1 through month 7, n=15,513) and modified intention to treat (MITT) (received =1 dose and were HPV 16 or 18 negative at Day 1 by serology and DNA). Endpoint counts began after Month 7 and day 30 in the PP and MITT analyses, respectively.

References 1 - Clifford GM, Smith JS, Plummer M et al. Human Papillomavirus types in invasive cervical cancer worldwide: A meta-analysis. Br J Cancer 2003:88:63 - 73.

2 - Daling JR, Madeleine MM, Schwartz SM et al. A population-based study of squamous cell vaginal cancer: HPV and cofactors. Gynecol Oncol 2002;84:263 - 270.

3 - Madeleine MM, Daling JR, Carter JJ et al. Cofactors with Human Papillomavirus in a population-based study of vulvar cancer. J Natl Cancer Inst 1997;89:1516 - 1523.

4 - Clifford GM, Smith JS, Aguado T et al. Comparison of HPV type distribution in high-grade cervical lesions and cervical cancer: A meta-analysis. Br J Cancer 2003;89101 - 105.

5 - Sotlar K, Diemer D, Dethleffs A et al. Detection and typing of Human Papillomavirus by E6 nested multiplex PCR. J Clin Microbiol 2004;42:3176 - 3184.

6 - Clifford GM, Rana RK, Franceschi S et al. Human Papillomavirus genotype distribution in low-grade cervical lesions: Comparison by geographic region and with cervical cancer. Cancer Epidemiol Biomarkers Prev 2005;14:1157 - 1164.

7 - van Beurden M, ten Kate FJW, Smits HL et al. Multifocal intraepithelial neoplasia grade III and multicentric lower genital tract neoplasia is associated with transcriptionally active Human Papillomavirus. Cancer 1995;75:2879 - 2884.

8 - Hording U, Junge J, Poulson H et al. Vulvar intraepithelial neoplasia III: A viral disease of undetermined progressive potential. Gynecol Oncol 1995;56:276 - 279.

9 - Wieland U, Pfister H. papillomaviruses in human pathology: Epidemiology, pathogenesis and oncologic role.In:Gross,Barasso EDS.Human Papillomavirus Infection:A clinical atlas.Ullstein Mosby1997;p1-18.

10 - Von Krogh G. Management of anogenital warts (condylomata acuminata). Eur J Dermatol 2001;11:598 - 603.

11 - Skjeldestad FE and Koutsky L for the Merck Phase III HPV Vaccine Steering Committee (FUTURE II). Phase III trial of prophylactic quadrivalent HPV 6, 11, 16, 18 L1 virus-like particle vaccine: Prevention of cervical intraepithelial neoplasia (CIN) 2/3 including adeno- and squamous-cell carcinoma in situ (CIS). Abstract presented at the Infectious Diseases Society of America. 7 October 2005. San Francisco, USA.

12 - Ferris D for FUTURE I investigators. Efficacy of a prophylactic quadrivalent Human Papillomavirus (HPV) (types 6, 11, 16, 18) L1 virus-like particle (VLP) vaccine for prevention of precancerous cervical dysplasia and external genital lesions (EGL). Abtract presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). 16 - 19 September 2005. Washington DC, USA.

13 - Joura EA et al. High sustained efficacy of a quadrivalent HPV (types 6/11/16/18) L1 virus-like particle (VLP) vaccine against vaginal and vulvar pre-cancerous lesions: a combined analysis, Oral presentation and abstract, 18th International Congress on Anti Cancer Treatment, Paris, France, 7th February 2007.

14 - Sanofi Pasteur MSD, data on file

15 - Sanofi Pasteur MSD, data on file

16 - Ferlay J, Bray F, Pisani P et al, editors. Globocan 2000: Cancer incidence, mortality and prevalence worldwide. IARC Cancer Base No.5. version 1.0. IARC Press, Lyon 2001.

17 - Ferlay J, Bray F, Pisani P et al, editors. Globocan 2002: Cancer incidence, mortality and prevalence worldwide. IARC Cancer Base No.5. version 2.0. IARC Press, Lyon 2004.

18 - Insinga RP, Glass AG and Rush BB. Diagnoses and outcomes in cervical cancer screening: A population-based study. Am J Obstet Gynecol 2004;191:105 - 113.

19 - Parkin DM, Whelan SL, Ferlay J et al. Cancer incidence in five continents (GIS). Volume VIII. p606 - 611.

20 - Dodge JA, Eltabbakh GH, Mount SL et al. Clinical features and risk of recurrence among patients with vaginal intraepithelial neoplasia. Gynecol Oncol 2001;83:363 - 369.

21 - Jones RW. Vulval intraepithelial neoplasia: Current perspectives. Eur J Gynaecol Oncol 2001;22:393 - 402.

22 - UK Health Protection Agency. CDR Weekly 2003;3(44)

23 - Munoz N. Human papillomavirus and cancer: The epidemiological evidence. J Clin Virol 2000;19:1 - 5.

24 - Walboomers JM, Jacobs MV, Manos MM et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12 - 19.

25 - Munoz N, Bosch FX, de Sanjosé S et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518 - 527.

26 - Khuder SA. Effect of cigarette smoking on major histological types of lung cancer: A meta-analysis. Lung Cancer 2001;31:139 - 148.

27 - Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med 1997;102:3 - 6.

28 - Koutsky LA, Galloway DA and Holmes KK. Epidemiology of genital human papillomavirus infection. Epidemiol Rev 1988;10:122 - 163.

29 - Syrjänen K, Hakama M, Saarikoski S et al. Prevalence, incidence, and estimated life-time risk of cervical human papillomavirus infections in a non selected Finnish female population. Sex Transm Dis 1990;17:15 - 19.

30 - PHLS. CDR Weekly 2001;11(35).

31 - Jacobs MV, Walboomers JMM, Snijders PJF et al. Distribution of 37 mucosotrophic HPV types in women with cytologically normal cervical smears: The age-related patterns for high-risk and low-risk types. Int J Cancer 2000;87:221 - 227.

* Cervical Intraepithelial Neoplasia
**Adenocarcinoma In Situ
† World Health Organisation
+ Vulvar Intraepithelial Neoplasia
++ 99.7% of cervical cancers contain the genetic material (DNA) of the virus
‡‡ European Union 25 member states plus Iceland, Norway & Switzerland
##Austria, Belgium, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Italy, Liechtenstein, Luxemburg, Netherlands, Norway, Portugal, Sweden, Switzerland, United Kingdom.

www.apmsd.co.uk

• Additional
• References
• Citations