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Outcome evaluation of immunization

Outcome evaluation of immunization. Wei-Chu Chie. Immunization. Primary prevention specific protection baseline (basic) immunization booster immunization active vs. passive special groups infants and children, elderly adults, high risk groups. 實驗性方法的三要素. 實驗單位 (experimental unit)

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Outcome evaluation of immunization

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  1. Outcome evaluation of immunization Wei-Chu Chie outcome research

  2. Immunization • Primary prevention • specific protection • baseline (basic) immunization • booster immunization • active vs. passive • special groups • infants and children, elderly • adults, high risk groups outcome research

  3. 實驗性方法的三要素 • 實驗單位 (experimental unit) • 處置 (treatment) • 評估 (evaluation) outcome research

  4. 實驗單位 • 個人為單位 • 病人 • 藥物臨床試驗 • 教育介入 如病人衛生教育 • 健康人 • 疫苗預防性試驗 篩檢工具試驗 • 教育介入 如健康行為的養成 • 群體為單位 • 社區 班級 團體 outcome research

  5. 處置 • 新藥 • 新的飲食 • 診斷或篩檢 • 手術 • 醫療器材 • 教育介入 • 無治療 outcome research

  6. 評估 • 有效性 • 事件/事件史資料 (event/time to event) • well-being指標: 生活品質(quality of life) • 成本: 直接與間接醫療成本 • 暫時性或替代性指標: 生理 生化 病理資料 • 又稱終點 (end-points) • 安全性 • 不良反應及相關指標 • 經濟學: 成本效益 outcome research

  7. Three elements for immunization • Experiment unit • Individual, usually healthy • Treatments • can be viewed as drugs • Evaluation • efficacy • safety outcome research

  8. Basic characteristics • Easy to follow the rule of randomized controlled double-blinded trials • placebo control with blindness: easy to make, usually difficult to guess • individual randomization possible • requires a large sample size • low incidence of the disease to prevent • low incidence of adverse effects outcome research

  9. ethical concerns • administered on healthy people • autonomy emphasized: informed consent • safety emphasized: lower tolerance to adverse effects • active drug or placebo controls • placebo controls: standard design, required by FDA • active drug: ethical reason-the best available outcome research

  10. 人體實驗方法的倫理 • 以藥物臨床試驗發展最完備 • 赫爾辛基宣言 • ICH: International Conference on Harmonisation • GCP: Good Clinical Practice • IRB: Institutional Review Board • 人體試驗委員會 outcome research

  11. 人體實驗方法的倫理 • 赫爾辛基宣言: 醫學倫理四原則 • 仁愛 無害 自主 公正 • 研究重要性與風險相稱 (什麼題目不可做?) • 好處風險及不適感應有最好診治方法加以權衡 • 每個病人都應保證得到最好和被證實的診治技術 • 研究人員或調查小組判斷如果繼續進行會產生不良影響就應停止 • 自主性: 受試者同意書 informed consent • informed 信息的揭示 理解 • consent 自願的同意 同意的能力 outcome research

  12. Cost and effectiveness/utility • Usually proved to be cost-effective • Old schedule and contents of immunization has been established • New vaccines: suffers high cost for R&D • diminishing of marginal return • very difficult to find new, large-sampled, disease outcome research outcome research

  13. Examples • Salmonella typhi Vi conjugate vaccine for children • HPV vaccine for young women • double-blind randomized controlled trials • efficacy: the diseases to prevent • Registry-driven outreach: • randomized controlled trial • administrative study outcome research

  14. Salmonella typhi Vi • Lin FYC at el. The efficacy of a Salmonella typhi Vi conjugate vaccine in two-to-five-year-old children • NEJM 2001;344:1263-9. • Vi-rEPA: Vi 22.5 ug+rEPA (Psudomonas aeroginosa exotoxin A) 22 ug in 0.5 ml of phosphate-buffered saline + 0.01% thimerosal • enhance immunogenicity outcome research

  15. Vi-rEPA: background/goal/hypothesis • Background: • typhoid fever of children under 5 years in developing countries • the need for vaccination/ previous studies • Goal/hypothesis: • to determine whether ... /the vaccine is safe and can prevent typhoid fever in 2-5-year-old children outcome research

  16. Vi-rEPA: study design • Randomized controlled double-blinded trial • vaccine vs. saline placebo control • five-dose vials, indistinguishable 0.5 mlX5 (2.8 ml/vial) • randomized by individual random number 0-9 • randomization code: kept by the Department of Pharmacy of the NIH Clinical Center and by the chairman of the safety monitoring committee • broken on June 23, 2000 outcome research

  17. Vi-rEPA: study design • Randomization • by individual • for subjects: seven-digit ID • for injection vials: 0-9 on a random basis • subject vs. vial • the same last digit outcome research

  18. Vi-rEPA: study design • Injection protocol • two rounds • 2/21-3/8/1998…4/4-4/20/1998, 64 teams • separate 6 weeks • 0.5 ml with identical last digit • examination before and observations after injection outcome research

  19. Vi-rEPA: subjects • Cao Lanh District of Dong Thap Province in the Mekong Delta of Vietnam • 13776 children (96.4% of 14285) enrolled • exclusion: with illness requiring ongoing medical care • informed consents • parents or guardians outcome research

  20. Vi-rEPA: subjects • At least one injection: 12008 (5991:6017) • Two injections from correctly labeled vials: 11091 (5525:5566) outcome research

  21. Vi-rEPA: exposure/intervention • 0.5 ml Vi-rEPA X 2 six weeks apart • only one experiment group • control: saline placebo outcome research

  22. Vi-rEPA: endpoints • Primary • efficacy: typhoid fever attack rate • safety: rates of adverse effects • Secondary • paired serum IgG antibody titer (ELISA) • antibody persistence • Follow-up • visit weekly to 5/31/2000 (2 years) outcome research

  23. Vi-rEPA: endpoints • Definition of a typhoid fever attack • typhoid fever: S. typhi isolated from blood culture • detection: weekly visit---fever 37.5C at least 3 days---referred---6 ml blood (5 ml for culture, 1 ml for antibody) • review of bacteriologic records outcome research

  24. Vi-rEPA: data analysis • Basic characteristics • for confounding and possible selection bias (Table 1) • Correct label comparison • Intention-to-treat analysis outcome research

  25. Vi-rEPA: data analysis • Efficacy (Tables 3-5) • (1-attack rate (V))/attack rate (P))X100% • paired and unpaired t test for geomatric means of antibody titer, small sample • Safety (Table 2) • chi-square or Fisher’s exact test for adverse effects between two groups (fever, swelling, erythema) outcome research

  26. Vi-rEPA: major results/discussion • Efficacy • primary: attack rates (Table 3) V<P • efficacy 91% • secondary: antibody titer (Tables 4 & 5) • paired serum: only elevated in V group • levels 6mo, 1 yr, & 2 yr after injection • Safety • V>P only for fever 37.5C in two classifications • V>P for swelling 5 cm in who had 2 injections outcome research

  27. Vi-rEPA: major results/discussion • Discussion • Confounding, selection bias: randomization • Information bias: blindness • Definition • Sample size and power of test • Conclusion: • safe and 90% efficacy for 2-5 years outcome research

  28. HPV • Koutsky LA, et al. A controlled trial of a human papillomavirus type 16 vaccine • NEJM 2002;347:1645-51. • HPV-16 L1 virus-like particle vaccine • purified L1 polypeptide (yeast) outcome research

  29. HPV: background/goal/hypothesis • Background: • HPV as a STD/ HVP-16 and cervical cancer • HPV-16 L1 virus-like particle • Goal/hypothesis: • to determine whether ... /the vaccine can prevent HPV-16 infection in women (reduce the incidence of persistent HPV infection) outcome research

  30. HPV: study design • Randomized controlled double-blinded trial • vaccine vs. placebo control • double-blind: indistinguishable • intramuscular injection • randomized by individual • permuted-block design 1:1 outcome research

  31. HPV: subjects • 10/1998-11/1999, 2392 women from 16 centers in the US / advertisement: 1194 vs. 1198 • inclusion criteria: • 16-23 years, not pregnant, reported no prior abnormal Pap smears, no more than 5 male sex partners, virgins seeking contraception • exclusion (Table 1) • positive infection before intervention completed and other reasons • informed consents, IRB, compensation per visit outcome research

  32. HPV: subjects • Sample size • fixed-number-of-events design • at least 31 cases required to show a statistically significant reduction in the primary endpoint • 75% efficacy, 90% power, 2% dropout per yr • 2350 enrolled • 31 cases on 8/31/2001… primary analysis outcome research

  33. HPV: exposure/intervention • Vaccine • 40 ug HPV-16 L1 virus-like particles + 225 ug of aluminum adjuvant = 0.5 ml • only one experiment group • control: placebo 225 ug of aluminum adjuvant in 0.5 ml • im injection at day 0, month 2, and month 6 outcome research

  34. HPV: endpoints • Primary • efficacy: persistent HPV infection (surrogate!) • safety: adverse effects • Secondary • HPV antibody titer 5.9 mMU/ml • Follow-up • one month, 6 months after 3rd vaccination, every six months outcome research

  35. HPV: definition and detection of HPV infection • method: • cervical samples: Pap smear, swabs, lavage for HPV-16 DNA testing • abnormal Pap smear: colposcopic exam biopsy • case of ‘persistent’ HPV-16 infection: • (-) at day 0 & month 7… (+) subsequently in 2 or more consecutive visits 4 or more months apart • … biopsy: CIN or cancer and HPV-16 DNA • … HPV-16 DNA detected in the last visit • transient infection: once (+) outcome research

  36. HPV: definition and detection of adverse effects • Any sign or symptom of illness or abnormal lab test … • asked 14 d (dairy, primary), 2, 6, and 7 months • that occurred during the protocol-specified follow-up period, that was not present at enrollment, or if present, had worsened • body temperature recorded five days after • 37.7 C outcome research

  37. HPV: data analysis • Exclusion and reasons (Table 1) • Basic characteristics • for confounding and possible selection bias (Table 2) • Fixed-number-of events design • including and excluding violation cases outcome research

  38. HPV: data analysis • Efficacy • primary endpoint: efficacy by infection rate per person-time • primary analysis: negative before the end of intervention and no violation • second analysis: negative … + general violation • for transient infection/CIN • secondary endpoint: difference of antibody titer at month 7 • geometric means of antibody titer outcome research

  39. HPV: data analysis • Safety • adverse events during the 14 days after any of the 3 vaccinations • all subjects included • number of cases (almost equal size) • pain at the injection site • systemic • discontinued due to AE outcome research

  40. HPV: major results/discussion • Efficacy • primary on persistent infection rate (Table 3) • primary analysis: 100%! • secondary analysis: 100%! • primary but including transient infection: 91.2% • for neoplasia: P. 1649 • secondary on antibody titer (immunogenicity) • Safety (Table 4) outcome research

  41. HPV: major results/discussion • Discussion • Confounding, selection bias: randomization • exclusion after randomization and intervention! • Information bias: blindness • Definition of cases: persistent, transient? • Sample size and power of test • loss of subjects because of (+) infection in the beginning outcome research

  42. HPV: major results/discussion • Follow up time • relation to CIN and CC • Conclusion: • for infection high short-term efficacy • for related neoplasia outcome research

  43. Outreach • Wilcox SA, et al. Registry-driven, community-ased immunization outreach: a randomized controlled trial. AJPH 2001;91:1507-11. outcome research

  44. Outreach: background/goal/hypothesis • Background: • provider-based vs. community-based registry-driven outreach • Goal/hypothesis: • whether community-based registry-driven outreach can improve immunization rate • whether predictors of under immunization can be used to target at-risk children outcome research

  45. Outreach: study design • Randomized controlled trial • three groups • outreach (two samples) • mailed reminder letter • control: no intervention • no double-blindness • both subjects and raters were not blind. • randomized by individual outcome research

  46. Outreach: subjects • KIDS immunization database/tracking system • Philadelphia, 1997 • 1696 6-10 months children/2 random samples • a second random sample: 160 all assigned to the outreach group • no informed consents • IRB review (Albert Einstein Medical Center) outcome research

  47. Outreach: subjects • 1856 children (1696+160) • 104 did not meet participation criteria… 1752 • 23% immunization history incomplete • 4% refused to give history • 16% fail to contact • 991 with immunization history 57% • outreach 379: control 612 • further exclusion: those up-dated by 7 months • 3 DTO, 2 OPV, 2 Hib, 2 HBV outcome research

  48. Outreach: exposure/intervention • two community-based organizations contracted by the DPH • 2/3 bilingual social services agency • outreach 1/3 • reminder letter 1/3 • no intervention 1/3 • 1/3 university nursing center • outreach 1/2 • reminder letter 1/4 • no intervention 1/4 outcome research

  49. Outreach: exposure/intervention • Outreach • outreach workers • locate the family, obtain the immunization history, assess whether up to date • update the registry, 4 attempts • differences between two agencies outcome research

  50. Outreach: endpoints • Primary • Receive immunization during observation period • For not-up-date children only • missing more than the third DTP (degree of delay) • Secondary outcome research

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