Outcome Evaluation of Immunization

(1)

Outcome

evaluation of

immunization

Wei-Chu Chie

(2)

Immunization

• Primary prevention

– specific protection

• baseline (basic) immunization • booster immunization

– active vs. passive – special groups

• infants and children, elderly • adults, high risk groups

(3)

實驗性方法的三要素

• 實驗單位 (experimental unit)

• 處置 (treatment)

(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

(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

(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

(7)

Three elements for

immunization

• Experiment unit

– Individual, usually healthy

• Treatments

– can be viewed as drugs

• Evaluation

– efficacy – safety

(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

(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

(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 Harmoni sation

– GCP: Good Clinical Practice

– IRB: Institutional Review Board – 人體試驗委員會

(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

(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,

(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

(14)

Salmonella

typhi

Vi

• Lin FYC at el. The efficacy of a Salm

onella

typh

i Vi conjugate vaccine in

two-to-five-year-old children

– NEJM 2001;344:1263-9.

– Vi-rEPA: Vi 22.5 ug+rEPA (Psudomonas aer oginosa exotoxin A) 22 ug in 0.5 ml of p hosphate-buffered saline + 0.01% thimero sal

(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

(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

(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

(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

(19)

Vi-rEPA: subjects

• Cao Lanh District of Dong Thap Provin

ce in the Mekong Delta of Vietnam

• 13776 children (96.4% of 14285) enrol

led

– exclusion: with illness requiring ongoin g medical care

• informed consents

(20)

Vi-rEPA: subjects

• At least one injection: 12008

(5991:6017)

• Two injections from correctly labeled

vials: 11091 (5525:5566)

(21)

Vi-rEPA:

exposure/interventio

n

• 0.5 ml Vi-rEPA X 2 six weeks apart

– only one experiment group – control: saline placebo

(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

(23)

Vi-rEPA: endpoints

• Definition of a typhoid fever attack

– typhoid fever: S. typhi isolated from bl ood culture

– detection: weekly visit---fever 37.5C at least 3 days---referred---6 ml blood (5 ml for culture, 1 ml for antibody)

(24)

Vi-rEPA: d

ata analysis

• Basic characteristics

– for confounding and possible selection bias (Table 1)

• Correct label comparison

• Intention-to-treat analysis

(25)

Vi-rEPA: d

ata analysis

• Efficacy (Tables 3-5)

– (1-attack rate (V))/attack rate (P))X10 0%

– paired and unpaired t test for geomatri c means of antibody titer, small sample

• Safety (Table 2)

– chi-square or Fisher’s exact test for adverse effects between two groups (fev er, swelling, erythema)

(26)

Vi-rEPA: m

ajor results/discus

sion

– 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

(27)

Vi-rEPA: m

ajor results/discus

sion

• Discussion

– Confounding, selection bias: randomization

– Information bias: blindness – Definition

– Sample size and power of test

• Conclusion:

(28)

HPV

• Koutsky LA, et al. A controlled trial

of a human papillomavirus type 16 vac

cine

– NEJM 2002;347:1645-51.

– HPV-16 L1 virus-like particle vaccine – purified L1 polypeptide (yeast)

(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)

(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

(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

(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

(33)

HPV: exposure/intervention

• Vaccine

– 40 ug HPV-16 L1 virus-like particles + 2 25 ug of aluminum adjuvant = 0.5 ml

– only one experiment group

– control: placebo 225 ug of aluminum adju vant in 0.5 ml

– im injection at day 0, month 2, and mont h 6

(34)

HPV: endpoints

• Primary

– efficacy: persistent HPV infection (surroga te!)

– safety: adverse effects

• Secondary

– HPV antibody titer 5.9 mMU/ml

• Follow-up

– one month, 6 months after 3rd vaccination, every six months

(35)

HPV: definition and detection of

HPV infection

– method:

• cervical samples: Pap smear, swabs, lavage for HP V-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 (+)

(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)

HPV: data analysis

• Exclusion and reasons (Table 1)

• Basic characteristics

• Fixed-number-of events design

• including and excluding violation

cases

(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

(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

(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)

(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

(42)

HPV: major

results/discussion

– Follow up time

– relation to CIN and CC

• Conclusion:

– for infection high short-term efficacy – for related neoplasia

(43)

Outreach

• Wilcox SA, et al. Registry-driven, co

mmunity-ased immunization outreach: a

randomized controlled trial. AJPH 200

1;91:1507-11.

(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

(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.

(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

(47)

Outreach: subjects

– 1856 children (1696+160)

• 104 did not meet participation criteria… 175 2

• 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

(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

(49)

Outreach:

exposure/intervention

• Outreach

– outreach workers

– locate the family, obtain the

immunization history, assess whether up to date

– update the registry, 4 attempts

(50)

Outreach: endpoints

• Primary

– Receive immunization during observation period

– For not-up-date children only

– missing more than the third DTP (degree of delay)

(51)

Outreach: data analysis

• Exclusion and reasons (Table 1)

• Basic characteristics

(52)

Outreach: data analysis

• Efficacy

– Only for not-on-time

– Adjusting for confounders and assess the effects of predictors (Table 2)

– Improve immunization rate (Table 3)

(53)

Outreach:

major

results/discussion

– Comparability: not comparable?! – Efficacy

• must adjust confounders

• only for not-updated … why not exclude first?

• information bias: no blindness

– Conclusion

• Identify high risk children and bring them to care