Gardasil®, Human Papillomavirus Vaccine [types 6,11,16,18] (Recombinant, adsorbed), is the only licensed vaccine for the prevention of cervical cancer and other Human Papillomavirus diseases that occur before cervical cancer and beyond the cervix.
In clinical trials, including FUTURE I and II, Gardasil® prevented up to 100% of cervical cancer, precancerous and potentially precancerous cervical lesions, precancerous vulval and vaginal lesions, and genital warts due to Human Papillomavirus virus types 6, 11, 16 and 18.1,, a), b) It is estimated that Human Papillomavirus types 6, 11, 16 and 18 together cause 75% of cervical cancer,4 70% of precancerous5,6 and 50% of potentially precancerous cervical lesions7, a significant proportion vulval and vaginal cancers and their associated precancerous lesions8,,,91011, and 90% of genital warts in Europe.12,13
"I can more than understand that the board felt the responsibility not to leave these women unprotected. To be able to prevent Human Papillomavirus-related cervical cancer and their pre-cancerous stages as well as other Human Papillomavirus-related lower genital tract pre-cancerous lesions and infections so effectively, hardly allows any other conclusion. Young women are at the age of maximal exposure to the virus. Even though some years exist between infection and cancer development, prevention should start at this time so as to prevent later complications inherent in diagnostic and treatment procedures.", comments Albert Singer, Professor of Gynaecological Research, University of London, United Kingdom.
In Europe, vaccination of women in the placebo groups of the FUTURE I and II studies has already begun in study centres in Germany, Sweden, Denmark and Austria. In other countries, vaccination will start within the next days or weeks. In the United Kingdom, vaccination starts today. In total, approximately 4,300 women are anticipated to be vaccinated in European study centres, with the objective of completing before the end of the year 2007. In a similar way, vaccination of almost 4,500 women in many other countries around the world, including the United States, Australia and Canada, has begun or is anticipated to begin soon.
Gardasil® licence applications have been filed in 120 countries and approved in 55 countries (all under accelerated review timelines), including the European Union, the United States, Canada and Australia.
In addition to the women in the placebo group of the FUTURE I and II studies, women in the vaccine group of these studies who have either received less than three doses of Gardasil® or the monovalent precursor of Gardasil® instead of Gardasil® should also complete vaccination with Gardasil®. The monovalent precursor of Gardasil® targets only the Human Papillomavirus type 16 whereas Gardasil® targets the Human Papillomavirus types 6, 11, 16 and 18.
Current recommendation and funding of Human Papillomavirus vaccination
Just four months after gaining a licence in the European Union, Gardasil® is now available in 15 European countries. Accelerated discussions are under way in most European countries to integrate Human Papillomavirus vaccination in each country's recommendation and reimbursement programme.
As of 1 January 2007 vaccination is recommended in Austria for girls and boys aged 9 to 15 years as well as for women, preferably before the start of sexual activity.
In Germany, decisions are anticipated soon. Since early December 2006, several statutory health insurance funds in Germany, which together cover half of the population, have announced immediate and full reimbursement of Human Papillomavirus vaccination for females even before any recommendations by the authorities have been published. Other funds are anticipated to follow soon.
The French health minister has announced recommendations for March 2007 and reimbursement by the national social security system by July 2007 the latest. Since October 2006, three large private health insurance funds in France have announced immediate partial reimbursement of Human Papillomavirus vaccination also even before any recommendations by the authorities have been published.
The Italian Health Minister has recently announced that Italy will have a vaccination programme with Gardasil® next spring actively proposed of the young girls 12 years old.
In Spain, the region Navarra has recently announced the vaccination of young girls (aged 12 or 13 years) as soon as Gardasil® becomes available. The opportunity to add a catch-up vaccination programme for females >12 or 13 years and/or vaccination of boys will be investigated.
In Sweden, the first county has recently announced to offer Gardasil® girls and women even before the decision of the national health authorities.
Some Belgian health insurance funds have announced partial reimbursement of Human Papillomavirus vaccination before any recommendations by the authorities have been published.
Four Dutch health insurance funds have announced in December 2006 to completely reimburse Human Papillomavirus vaccination for females aged 9 to 26 years and males aged 9 to 15 years as of January 2007.
In the UK, the Joint Committee on Vaccinations and Immunisations (JCVI) have said they will meet to make a decision about a recommendation in early 2007.
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 9 and 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 or previously had an abnormal Pap test, a positive Human Papillomavirus test or genital warts. In the meantime, health insurers covering approximately 94% of privately insured lives in the US have decided to reimburse Gardasil®. In November, the authorities added Gardasil® to their Vaccines for Children (VFC) contract for girls and women aged 9 to 18 years.
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 13 year 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 aged 9 to 26 years. 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 aged 16 to 26 years 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.
Cervical Cancer and other HPV diseases before Cervical Cancer and beyond the Cervix
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.,14 In Europe, approximately 33,500 women are diagnosed with, and 15,000 women die from cervical cancer each year (40/day or nearly 2/hour).15 Hundreds of thousands of women are diagnosed with cervical, vulval or vaginal precancerous lesions. Genital warts are a growing problem. It is estimated that Human Papillomavirus types 16 and 18 cause 25,000 new cases of cervical cancer each year in Europe4, 15and 1,900 new cases of vulval and vaginal cancer.8,9,16
It is estimated that types 16 and 18 cause 112,000 new cases of precancerous cervical lesions (CIN2/3)5,, 617and 24,000 new cases of precancerous vulval and vaginal lesions (VIN2/3 and VaIN2/3) each year in Europe.8,9,,,,, 1011161819It is estimated that types 6,11,16 and 18 cause 280,000 cases of potentially precancerous cervical lesions (CIN1) each year in Europe.7,,1718 Types 6, 11, 16 and 18 also cause 225,000 new cases of genital warts each year in Europe in women.12
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 our new vaccines, including Gardasil®, available at dramatically lower prices to developing world countries. http://www.gardasil.com
About Sanofi Pasteur MSD
Sanofi Pasteur MSD 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.
Clinical study details
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.
Gardasil® prevented 100% of precancerous cervical lesions (high grade, CIN2/3) related to Human Papillomavirus types 16 and 18.
Gardasil® prevented 100% of precancerous vulval lesions (VIN2/3) and 100% of precancerous vaginal lesions (VaIN2/3) related to Human Papillomavirus types 16 and 18.
Gardasil® prevented 100% of potentially pre-cancerous cervical lesions (low grade, CIN1) related to Human Papillomavirus types 6,11,16,18 in Future I study in which cervical lesions of all grades (CIN1 to CIN3) were a co-primary endpoint and 93.1% efficacy in the combined analysis of grouped clinical studies .
Gardasil® prevented 100% of genital warts related to Human Papillomavirus types 6,11,16,18 in Future I study where external genital lesions were a co- primary endpoint and 98.9% efficacy in the combined analysis of grouped clinical studies.
1 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.
2 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.
3 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.
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