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In favor: Allos, Beck, Campbell, Finger, Gilsdorf, Hull, Lieu, Morita, Treanor, Womeodu, Abramson
The vote passed.
HUMAN PAPILLOMAVIRUS VACCINE
Gardasil™ H.P.V. Vaccine
Presenter: Dr. Eliav Barr, Director, Vaccine Clinical Program
Merck Research Laboratories
Overview: Data of the Phase III clinical trials for Gardasil™ H.P.V. Vaccine
Human papillomaviruses (H.P.V.) cause anogenital cancers and benign lesions such as genital warts. Gardasil™ is a quadrivalent vaccine (H.P.V. types 16,18, 6,11) and is administered in a three-dose schedule. . The vaccine was developed to reduce the incidence of these viral subtypes, which cause:
Target populations. The inclusion of H.P.V. 6 and 11 was designed to reduce the incidence of the common but low-risk C.I.N. 1 lesions that cause significant healthcare expenditures and anxiety among women. Other than cancer, inclusion of both types was designed to prevent the transmission of the virus to women. The populations targeted are adolescents aged 9 to less than 18 years, as a prophylactic vaccine before sexual debut, and sexually active adults aged 18 to 45 years, all of whom are at lifelong risk for sexually-transmitted H.P.V. infection.
The Papanicolaou (Pap) test for cervical cancer screening routinely identifies the disease before invasive cancer develops. With the disease’s approximately 20-year incubation period, H.P.V. prevention can be demonstrated by use of the Pap smear in clinical trials through surrogate markers. H.P.V. infection, as cervical cancer’s etiology, is the primary marker; it and C.I.N. 1 lesions, are important relative to the health and economic standpoint of disease burden. But since they both clear quickly, vaccine efficacy in clinical trials is demonstrated by prevention of C.I.N. 2 per 3 lesions, which typically develop from 0 to 5 years after infection. Screening and the uniform removal of C.I.N. 2 per 3 lesions has dramatically reduced cervical cancer rates in the U.S.
The prevention of C.I.N. 2 per 3 lesions was selected as the primary efficacy endpoint. Since 1997, four clinical efficacy studies have been conducted. Phase III data were presented during this A.C.I.P. meeting session.
Methodology. Lesions are removed, fixed and sectioned. Histological studies are conducted on the first and last sections and H.P.V.-DNA testing is conducted on the central section. A case is defined as a lesion positive for a vaccine genotype and with positive histological diagnosis. The trial included approximately 20,000 women world-wide; mean age was 20 years, with sexual debut at approximately 17 years; most were sexually active and had two lifetime partners at enrollment. History of past pregnancy was variable, as was history of chlamydia and baseline H.P.V. disease. Importantly, 75 percent of the women were naïve to the vaccine’s four H.P.V. genotypes, a factor relevant to vaccine implementation considerations.
The per protocol analysis included those who remained uninfected during the vaccination period and received all three doses - 71 percent to 81 percent of the entire Phase II/III efficacy population.
Overall prophylactic efficacy was measured in a modified intention to treat (M.I.T.T.) cohort. These were also naïve to the vaccine H.P.V. genotypes at Day 1 and constituted 80 percent to 91 percent of the entire Phase II/III efficacy population.
Findings were as follow:
Long term surveillance. Duration of immunity has been observed through 3.5 years after dose 3 and long term surveillance is planned. A (unneeded) booster dose will be administered to participants of protocol 007 to evaluate response to revaccination and to evaluate immune memory.
Scandinavian studies will extend the Phase III studies:
Summary. Gardasil’s™ prophylactic efficacy in 16 to 26 year-olds was high against development of cervical cancers caused by H.P.V.-16 and -18; and, for all four H.P.V. types, it was effective against the overall C.I.N. disease burden and that of condyloma, V.I.N., and V.a.I.N. Duration of efficacy has been shown for greater than 2.5 years post-vaccination and the Scandinavian registry cohort will provide still more data four years ahead of those vaccinated post- licensure.
Population efficacy was presented to the H.P.V. Working Group the previous day, which showed reductions in overall incidence of C.I.N. 2 per 3, C.I.N., and many of the procedures related to screening (for example, abnormal Pap tests, excision of genital warts). More data on the vaccine’s impact on H.P.V. 16 and 18 will be available soon.
C.D.C. Survey of Sentinel Pediatricians on H.P.V. Vaccine Acceptability
Presenter: Dr. Nicole Liddon, Division of S.T.D. Prevention
Overview: Preliminary data from a national study of pediatricians and H.P.V. vaccine acceptability.
A national survey of pediatricians, to determine their receptivity to an H.P.V. vaccination recommendation, was conducted by the University of Colorado, Denver, Health Sciences Center, the N.I.P. and the Division of S.T.D. Prevention.
A sentinel network of pediatricians selected from the A.A.P. was surveyed on 1) their knowledge of H.P.V., 2) their attitudes regarding introduction of an H.P.V. vaccine, and 3) their intentions to recommend an H.P.V. vaccine to adolescent patients. These pediatricians are surveyed 2 to 4 times a year on various topics relevant to clinical practice and immunization; they were drawn from a stratified sample of A.A.P. members to resemble the general membership in terms of geographic location, practice setting and type. They are also comparable to A.M.A. members in terms of sex, mean years since graduation and practice location. The survey was conducted in September-October, 2005, prior to the IDSA conference and publication of Merck’s vaccine trial results.
Of 431 surveyed pediatricians, 298 (69 percent) responded. They were about equally distributed by sex. The mean period since medical school graduation was 21 years; 44 percent had an urban practice, approximately 50 percent were suburban, and approximately 15 percent were rural. For approximately 33 percent, greater than 25 percent of their patients were aged 13 to 18, and 41 percent of practices had ≥25 percent of patients on Medicaid or CHIP.
H.P.V. Knowledge. When asked: 1) if genital warts and cervical cancer are caused by the same H.P.V. types (false) , 20 percent were correct, 54 percent incorrect and 26 percent did not know; 2) whether incidence of H.P.V. in women is highest among women in their 30s (false), 29 percent answered correctly, 23 percent were incorrect and 48 percent did not know; 3) if H.P.V. vaccines under development appear to be highly effective at preventing cervical cancer precursors (true), 56 percent were correct, 1 percent incorrect, and 43 percent did not know; and 4) that almost all cervical cancers are caused by H.P.V. infection (true), 68 percent were correct, 12 percent were incorrect and 20 percent did not know. Almost all knew that H.P.V. can be asymptomatic and represents a common cause of S.T.D. (83 percent for both) and can cause genital warts in both males and females (97 percent).
Beliefs about H.P.V. Vaccine: Few (11 percent) thought that the vaccination may encourage more risky sexual behavior; 54 percent cited the difficulty in maintaining continuity of care with adolescent patients (a potential implementation problem): 64 percent thought that the introduction of other adolescent vaccine recommendations would ease introduction of an H.P.V. vaccine; 84 percent expected to have to talk about sex when discussing the vaccine; and 88 percent were comfortable doing so with their female patients.
Expected barriers to H.P.V. vaccine administration were: lack of adequate reimbursement (77 percent); parental refusal (57 percent) or concern about vaccine safety (53 percent); up-front vaccine purchase (51 percent) and vaccine supply problems (42 percent).
Results: Intent to vaccinate. Responses were as follow on aspects of intent to vaccinate:
Barriers: Perception of parent refusal significantly affected intent to vaccinate (36 percent would vaccinate versus 61 percent among those who did not see parent refusal as a barrier).
Conclusions of the analysis were as follow:
Some of these results may pertain more to adolescent vaccination in general than H.P.V. in particular. A study of meningococcal conjugate vaccine administration also found problems with reimbursement as a barrier.
Among ongoing and developing research projects to look at these and other issues related to H.P.V. vaccine acceptability is a C.D.C./N.I.P. study of the acceptability of H.P.V. and other adolescent vaccines to family physicians, internists, pediatricians and samples of parents and adolescents. Other studies about vaccinating children, by industry and academia, are underway.
|Jane D. Siegel, md; Emily Rhinehart, rn mph cic; Marguerite Jackson, PhD; Linda Chiarello, rn ms; the Healthcare Infection Control Practices Advisory Committee||Ranch hand advisory committee|
|Veterinary medicine advisory committee||Medical Devices Advisory Committee|
|External Advisory Committee on Cities and Communities||Wildlife Diversity Policy Advisory Committee|
|National Vaccine Advisory Committee (nvac)||Peer reviewed by the Arizona Department of Commerce Economic Research Advisory Committee|
|Food and drug administration national institutes of health advisory Committee on: transmissible spongiform||Advisory Committee, Cuyahoga Valley School-to-Career Consortium, Broadview Heights, Ohio 1996-2002|