|2004N-0355 - Scientific Considerations Related to Developing Biotechnology Products|
|FDA Comment Number :||EC5|
|Submitter :||Ms. J Leclair||Date & Time:||09/23/2004 04:09:11|
|Organization :||Ms. J Leclair|
| Request to Fast Track High Priority Cancer Prevention Vaccines
continuation from previous comments 7995.
5. HPV 16 Human papilloma virus (all cervical cancer, 25% oral cancers, ~60% larangeal cancers, ~60% skin cancers, indications of breast cancer involvement 20 to 60% depending on geographic location and a % of nasopharyngeal carcinoma)
Disease burden. Human Papillomavirus 16 (HPV) causes cervical cancer, and is the second biggest cause of female cancer mortality worldwide with 288 000 deaths yearly. About 510 000 cases of cervical cancer are reported each year with nearly 80% in developing countries: 68 000 in Africa, 77 000 in Latin America, and 245 000 in Asia.
In the absence of screening programmes (routine Pap smear and Digene HPV PCR test), cervical cancer is detected too late and leads to death in almost all cases. The highest yearly incidences are found in some countries of Central and South America (93.8 per 100 000 women in Haiti, IARC 1996), highest national incidence in the world), in Southern Africa (61.4 per 100 000 women in Tanzania), and in Asia (30 per 100 000 in India). The prevalence of HPV infection is 167,000 in Northern America, . Epidemiological studies have reported that in the US, 75% of the 15-50 year old population is infected, 60% with transient infection (antibodies), 10% with persistent infection (detection of DNA), 4% with cytological signs, and 1% with clinical lesions. The prevalence of HPV infection among sexually active women may range from 18 to 25%, especially in some populations of sexually active teenagers. In each case, these women may transmit HPV to their partners or to their infants. In neonates, HPV infection may lead to papillomas in the oral cavity and in the upper respiratory tract. In HIV-infected individuals, HPV infection appears to cause extensive warts and severe and rapidly progressing disease.
Vaccines. HPV belongs to the Papovaviridae family. Of the many types of HPV moleculary identified to date (over 100), more than 30 types have been shown to infect the genital mucosa. It has been established that over 95% of cervical cancer cases contain HPV DNA, and five specific oncogenic HPV types (HPV-16, 18, 33 and 45) cause more than 80% of the cervical cancers diagnosed worldwide. The fact that over 99% of cervical cancer cases are associated with the presence of sexually transmitted HPV virus DNA has substantiated the basis for vaccine development. Viral recombinant proteins are being studied as antigenic components of prophylactic and therapeutic vaccine candidates. Prophylactic vaccine candidates are based on recombinant capsid proteins (L1 and L2), that self assembly into virus like particles (VLPs), which can induce antibodies that neutralize the infectious virus, while therapeutic vaccine candidates are based on the well characterized viral oncogenic proteins E6 and E7, and are designed to induce cell mediated immune responses to eliminate infected cells.
Three prophylactic vaccine candidates are at the level of Phase III clinical evaluation. The US National Cancer Institute is developing a monovalent HPV-16 VLP vaccine produced in insect cells using the recombinant baculovirus technology. GlaxoSmithKline has licensed the product development programme from MedImmune and is now pursuing the Phase II clinical trials focusing on the bivalent HPV-16/18 VLPs vaccine candidate, also based on baculovirus technology. Merck is developing a quadrivalent vaccine using yeast-recombinant technology and based on VLPs from HPV-6, 11, 16, and 18, which is currently well into Phase III in the USA, Europe, Southeast Asia and South America. The results of a controlled efficacy trial of HPV-16 VLP became available recently and showed that the incidence of persistent HPV-16 infection and HPV-16- related cervial intraepithelial neoplasia was reduced in vaccinated women with a 100% efficacy rate over a 1.7 year follow-up period. These results suggest that immunizing HPV-16-negative