Advisory committee on immunization practices




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Vote

In favor: Allos, Beck, Campbell, Finger, Gilsdorf, Hull, Lieu, Morita, Treanor, Womeodu, Abramson

Opposed: None

Abstained: Marcuse


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:

  • H.P.V. 16 and 18 in women: 70 percent of cervical cancers, anal and H.P.V.-related genital cancers, and C.I.N. 2 per 3 (high-risk, high-grade precancerous lesions) and approximately 25 percent of C.I.N. 1 (low-grade lesions clinically indistinguishable from those of higher risk H.P.V. types). In men: (primarily M.S.M.): 70 percent of anal cancers and precancerous lesions; genital warts.

  • H.P.V. 6 and 11 in women and men: 90 percent of genital warts. In women: 10 percent to 20 percent of C.I.N. 1 lesions.


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:

  • V.E. A V.E. of 100 percent was found, with a p value of less than 0.001 in the per protocol analysis, and a 99 percent V.E. (93 percent lower bound) among the M.I.T.T. cohort.

  • Burden of disease due to the four vaccine types was measured by overall cervical intraepithelial neoplasia (C.I.N.), external genital lesions caused by these four types, and evaluation of cervical and genital pathology. The vaccine efficacy was 100 percent (lower bound of 87 percent) overall and 97 percent for the M.I.T.T. cohort (one of the cases was a misidentified placebo subject), for all vaccine types. V.E. for external genital lesions, genital warts, and other lesions (vulvar intraepithelial neoplasia [V.I.N.] 2 per 3, immediate vulvar/vaginal cancer precursors),was 100 percent (lower bound, 88 percent) and 95 percent (lower bound 84 percent) in the broader M.I.T.T. population.

  • Other findings. Efficacy begins during the course of the vaccination and is comparable across variations in dosing intervals. No differences were seen by regional origin or ethnicity, sexual behavior, or use (or non-use) of hormonal contraceptives. Therapeutic efficacy modestly reduced the progression to C.I.N. 2 per 3 among those with early H.P.V. infection who were still seronegative. But the vaccine was not effective among those infected who had mounted an immune response. Infection with one H.P.V. type does not impact efficacy for other 3 H.P.V. types.


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:

  • A registry (the Nordic Cancer Registry Program) will draw on the Norwegian cervical cancer screening program data and follow women to provide interval V.E. updates. Norway now mandates registry participation for all vaccines.

  • Disease burden/V.E. study has already begun. This population survey of 14,000 women measures sexual behavior and genital wart disease burden. Subjects will have H.P.V. PCR testing on liquid-based cytology specimen, and results will be linked to the survey and registry data. This will be repeated regularly over time. The data generated will provide an H.P.V.-type distribution in the general population with negative and positive cytology diagnoses, provide a baseline, and evaluate V.E. over the long term.

  • Extended adolescent immunogenicity study. H.P.V. vaccine has demonstrated high efficacy and no minimal protective level is known. Titers are very high; anti-H.P.V. G.M.T.s exceed by 10 to to 40-times those after natural infection. They wane over time, but post-dose 2 H.P.V. levels are higher than those from dose 1. Data were charted to demonstrate:

    • Anti- H.P.V.16 antibody declined but then stabilized out to 48 months post-vaccination. A similar plateau was charted for anti-H.P.V. 18 G.M.T.s, where levels remained higher than those from natural infection. No late breakthroughs for H.P.V. 18 have been seen.

    • The impact of age at vaccination in the G.M.T.s measured in month 7 post-vaccination. The levels achieved for those aged 9 to 11 years were much higher (in some cases, 2 or 3 times higher ) than those of the 16 to 23 year-olds enrolled in the efficacy trial.

      • The integrated safety database showed little difference in adverse events between the vaccine and placebo groups, other than somewhat higher injection site reactions in the vaccine group than the placebo group. Of four serious adverse events among the greater than 6000 Gardasil™ subjects, two (bronchospasm and gastroenteritis) were possibly related, one (injection site pain/impairment) was probably related, and one (headache/hypertension) was definitely related. The placebo group had two adverse events (hypersensitivity and chills/fever).


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.


Discussion:

  • The homogeneity of the Scandinavian population was noted. Dr. Barr reported an unsuccessful attempt to study women of minority populations in the U.S. This was followed by a large and successful trial among Latina women, African-American and white women in Bahia, Brazil. The V.E. calculated for Brazil was comparable to that of the Scandinavian trials. Anti-H.P.V. levels also were found to be comparable between women of African descent and of Caucasian descent.

  • The Norwegian study will include the impact of the vaccine’s introduction on sexual behavior, which is more discussed in Scandinavia than the U.S. The incidence of genital warts and other conditions will be investigated and a baseline of sexual behaviors has been established by a survey. This will be repeated after vaccination among that group and younger groups as well.

  • Efficacy after two doses (and possibly three in view of the lifelong threat posed by H.P.V.) will be determined over time.

  • It was noted that the period of greatest risk among women is from ages 15 to 25 years, when most H.P.V. infections occur.

  • Data on the duration of antibody response among vaccine recipients who had a higher response to begin with, has been broken out through month 18 post-vaccination and the study was extended through month 36. Preliminary data will be available sometime in mid-2006.


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:

  • Overall intent to vaccinate females with an F.D.A.-approved H.P.V. vaccine showed high acceptance for 16 to 18 year-olds (89 percent); 77 percent for 13 to 15 year-olds; and 46 percent for 10 to 12 year-old patients. There were no significant differences in intent to vaccinate by sex of provider, practice location, or percent adolescent patients.

  • Of the 187 pediatricians who thought 10 percent or more of their 13 to 15 year old patients were sexually active, 51 percent would vaccinate at age 10 to 12, versus only 39 percent of those who thought that less than 10 percent of their patients are sexually active (p less than .05).

  • The only significant difference in intent to vaccinate was related to provider’s knowledge of an efficacious vaccine; those who knew (55 percent) that H.P.V. vaccine is highly efficacious would vaccinate versus those who did not know (36 percent), for a p value of less than .001.

  • Intent to vaccinate was higher among those who thought: 1) that other adolescent vaccine recommendations would make H.P.V. vaccine implementation easier (52 percent would vaccinate versus 37 percent of those who did not believe this); and 2) that discussion about sex would not be necessary before recommending an H.P.V. vaccine (67 percent would vaccinate versus 42 percent who thought sexual discussion would be necessary).


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:

  • Pediatricians are willing to administer an H.P.V. vaccine, particularly to older adolescents.

  • Overall knowledge of H.P.V. and H.P.V. vaccine is low in some areas; pediatricians would benefit from education.

  • Increased intent to vaccinate overall is related to:

  • knowledge of the development of an efficacious vaccine, as is

  • the perception that a discussion of sex is not necessary for vaccination of 10 to 12 year-olds;

  • Absence of parental refusal;

  • belief that other adolescent vaccine recommendations would ease H.P.V. vaccine delivery

  • perceived patient sexual activity at age 13 to 15. This may indicate that pediatricians see a need for vaccinating prior to sexual initiation.

  • The major barrier to H.P.V. vaccination is perception of inadequate reimbursement, even though it did relate to intent to vaccinate.


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.


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