VACCINE FIELD TRIALS, MY EXPERIENCE IN US AND CHINA疫苗的生产试验：我的美国和中国经验

Keith Erlandson, MS, MBA, DVM, DABVP (SHM)厄兰森，博士

副总裁

猪兽医服务

中国区猪事业线

正大畜牧投资（北京）有限公司

Why Do We Conduct Vaccine Field Trials?为什么我们要执行疫苗生产试验？

• Field Trial 生产试验

– Use vaccines we are interested in 使用我们有意向的疫苗

– Compare them “in the field” 在“生产中”进行比较

• Benefits 优势

– “Real World” data – We see how the vaccine works in our system “真实”数据-可以观察疫苗在本生产系统的效果

– Decisions about vaccines can be made with good data 关于疫苗决策有优质数据支持

• Drawbacks 缺点

– Labor intensive 花费人力较多

– More vaccines = more pigs to weigh 测试越多疫苗=要秤更多的猪

Designing the Field Trial 设计生产试验

Planning the Trial 计划试验

1. Define objectives 确定目标

2. Define the interventions of interest 确定感兴趣的干预措施

3. Define populations 确定猪群

4. Define parameters to be measured 确定测量参数

5. Define the experimental unit and unit of analysis 确定试验组和分析组

6. Identify models that will be used for assessment 确定用于评估的模型

Conducting the Trial执行生产试验

1. Enrolment and Allocating treatments 决定和分配处理

2. Follow up and compliance 随访和遵守规则

3. Measure parameters 测量指标

Define objectives – What do we want to know?确定目标-我们想知道什么？

• Examples: 举例：

–Evaluate efficacy of vaccine or treatment 评估疫苗或治疗的作用

–Economic evaluation of an intervention 干预的经济评估

• Field trials in our organization focus on economic outcomes 我们的生产试验关注经济效果

–We keep score in 元我们用元积分

Trial Objective 试验目标

• Determine if PCV2 vaccine increases growth rate and the economic impact

• 确定PCV2疫苗能否增加生长率和经济影响

• Determine if PCV2 vaccine decreases morbidity, mortality and cull rates and the economic impact

• 确定PCV2能否降低发病率、死亡率、淘汰率和经济影响

Define the Interventions of Interest确定有意向的干预

• What intervention are you interested in testing? 在试验中，你对什么样的干预有兴趣

–A vaccine versus no vaccine 有疫苗与无疫苗

–A new vaccine verses a vaccine you are currently using 新疫苗与正在使用的疫苗

–A new antibiotic treatment 新型的抗生素治疗

–A new method for breeding sows 母猪繁殖的新措施

Our Intervention of Interest确定有意向的干预

• Our intervention of interest was to evaluate two new vaccines against a vaccine that we were using 我们的干预意向是为评估两个新疫苗和正在使用的疫苗

– We also included a non-vaccinated control group 我们也包括了不使用任何疫苗的控制组

• Four Treatments 四个处理组

– Vaccine 疫苗 A– Vaccine 疫苗 B – Vaccine 疫苗 C– Unvaccinated Control 未接种的控制组

• Why 为什么

– Are the new vaccines superior to the vaccine we currently use 新疫苗比我们正在使用的疫苗好？

– Are vaccines superior to no vaccine 有疫苗比无疫苗好？

• Do we need to be using any vaccine at all 我们是否需要使用任何疫苗？

Define Populations 确定群体

• Populations that need to be defined: 需要确定的群体– Sample population 样本群

• The pigs that are in the trial 试验中的猪– Study population 试验群

• The pigs that could have been in the trial 在试验中的猪– Target 目标

• The pigs for which the information from the trial will be used to make decisions 从试验中获取信息的将用来做决定的猪

– External 外面的• The pigs for which it ‘might be possible’ to extrapolate study results 可以用来使用推断出研究结果的猪

Population hierarchies in theory (Doohoo et al., 2003)

Populations 群体

• Sample population 样本群–All pigs in pens 1-38 in barns 1 , 2 and 3 at the study finisher site 在试验的育肥舍，猪舍1，2 和3的圈栏1-38的所有猪

• Study population 试验群–All pigs weaned to the study finisher site 所有送到试验育肥舍的断乳猪

• Target 目标–All pigs weaned from the sow farm 母猪农场所有断乳猪

• External 外面的–All pigs in our system 系统中所有的猪

Dates日期

Pens 栏 Start Weight 起始重 End Weight 实验结束重 Trial Days 实验天数

1-9 1/28/2016 6/27/2016 153

10-18 1/31/2016 6/27/2016 148

23-38 2/2/2016 6/28/2016 147

Define the Parameters to be Measured确定测量参数

• What characteristics will you measure? 你需要测量的特征？

• Examples 例子

–ADG 平均日增重

–F:G –Number of treatments given 处理组数目

–Cost of medications 药物花费

–Mortality 死亡率

–% Full value pigs 猪全部价值%–Carcass premium 胴体的溢价

Parameters Measured测量参数

• ADG 平均日增重

• Morbidity (as measured by number of individual treatments) 发病率（根据个体处理的数量测量）

• Mortality 死亡率

• Culls 淘汰数量

• Full Value Pigs at marketing 上市全价值猪

Define the experimental unit and unit of Analysis确定试验组和分析组

• Experimental Unit 试验组

– Level at which the intervention is applied 实施干预的水平

– The smallest unit that can receive any treatment after appropriate randomization 在适当的随机化后，最小的组可以接受任何处理

• pig vs pen vs. barn; piglet vs. litter; cow vs. quarter

• 猪：圈栏：农舍；小猪：窝产数；

– Independence of experimental units? 独立的试验单位？

• Vaccination studies, deworming trials 疫苗研究，

• Pigs within pens 圈栏里的猪

• Unit of Analysis 分析组– Unit of ‘n’ in the statistical test that

determines statistical significance (α) and power (1-β) n在统计测试中确定统计显著性(α) 和统计力度(1-β)

• May be different from experimental unit, e.g. 可

能和实验组有所不同，比如：

– all pigs in randomly selected pens 随机抽选的圈栏里的所有猪

– sow treatment to increase piglet survival 母猪治疗来增加小猪生存能力

– groups vaccinated to reduce morbidity 小组免疫来降低发病率

– If exp. unit > unit of analysis: apply same treatment to all animals in lower unit, adjust in analysis 如果实验组>分析组：

给较低单位的所有动物相同的处理，给分析组做调整

Experimental Unit试验组

• In this trial, the pig was the experimental unit 在这个试验中，猪是实验组

–All animals individually identified and tracked throughout the study 在整个研究过程中，所有的动物都被单独识别并追踪

Identify models that will be used for assessment确定用于评估的模型

• Knowing how the data will be evaluated allows better study design 知道如何评估数据可以更好的设计试验– Statistical hypothesis test 统计假设检验

• ‘P value’ 概率值

• Probability of the observed data given the null hypothesis 零假设的观测数据概率

• P<0.05 has become the default P<0.05已成为默认值

• Small effect with low P value 低概率值的小效应– Statistically significant but perhaps not biologically or economically significant 统计上有意义但可能不是生物学的或经济的意义

– Statistically not significant at P=0.05 but may be economically significant 统计上没有显著的P=0.05但可能在经济上意义重大

• Effect estimation 效应评估

– How large is the observed effect 观察到的效果有多大

– Confidence intervals 可信区间

– 95% CI: if repeat many times, in 95% of cases the CI will include the true value 95%可信区间：如果重复多次，在95%的情况下可信区间会包括真正的价值

Our Analysis 我们的分析

• ANOVA to be run to determine if there are differences between groups 用ANOVA来决定小组之间的区别

–If the ANOVA is statistically significant, pairwise test will be run如果ANOVA有统计学上的显著，成对测试将运行

• Economic Analysis based on cost of treatment, value of full value pigs sold 经济分析基于治疗花费和已出售的全价值猪

Enrollment 登记

• Inclusion and exclusion criteria 包括和排除的标准

–Eligibility 合格性

–Representativeness 代表性

• Inclusion and exclusion criteria for this trial 这个实验的包括和排除的标准

– Excluded any animal that was lame 排除任何有跛足的动物

– Excluded any animal that had an umbilical or scrotal rupture 排除任何有脐或阴囊破裂的动物

– Excluded any animal that was too small 排除任何体型很小的动物

– Excluded any animal that was visibly ill 排除任何有明显疾病的动物

Allocation 分配

• Essential to make treatment groups ‘identical’ 使处理组完全一致同的基本要素

–Same age 相同年龄

–Same weight 相同体重

–Same male: female ratio 相同公:母比例

• Preferably random and blind 最好是随机和盲选

–simple or systematic random 简单或系统的随机

–blocking 确定

• More complex allocation 更多复杂的分配

Allocation 分配

• In this study, all animals were weighed, ear tagged and had their sex recorded

• 在这个研究中，所有的动物都已称重，耳朵标记和性别记录

• Data sent to a statistician who used a computer to randomly allocated pigs to treatments

• 统计学家把收集到的数据用电脑随机分配处理给猪

5.95 5.95 5.97 5.95 5.95

0.00

1.00

2.00

3.00

4.00

5.00

6.00

7.00

Initial Weight

Initial Weight起始体重

Vaccine A Vaccine B Vaccine C Control （对照） All （总计）

Blinding 盲测

•Very few people know which group received which treatment 几乎没有人知道哪组接受到治疗

•People are only unblinded after the analysis is done 只有在分析完成后，才会去除屏障

Measuring the Outcome 测量结果

• Preferably objective measurements 最好是客观测量

–Mortality 死亡率

–ADG 平均日增重

• When subjective, blinding is essential 主观测量时，盲法是必须的

–‘Clinical scores’ 临床分数

• Measurement error 测量错误

–Random: increased sample size 随机性：增加样本大小

–Systematic (bias): problem for study 系统的（偏见）：研究的问题

107.98

112.9

111.27

106.24

109.63

102

104

106

108

110

112

114

Vaccine A Vaccine B Vaccine C Control （对照） All （总计）

Final Weight最终体重

Final…

0

20

40

60

80

100

120

Vaccine A Vaccine B Vaccine C Control （对照） All （总计）

Dead + Culls (<80 kg)死亡＋淘汰

Dead

Cull

Dead + Cull

疫苗对全价值猪的影响PCV Study-Value of Vaccine 圆环病毒研究-疫苗价值

108

112.9

111.3

106.2

14.10%

10.80%11.90%

15.30%

5.00%

10.00%

15.00%

20.00%

25.00%

30.00%

100

102

104

106

108

110

112

114

Vaccine A Vaccine B Vaccine C Non-VX Control

CV, %

End

Wei

ght,

kg

Final weight Market CV

Summary of Data 数据统计

Vaccine 疫苗 A Vaccine 疫苗 B Vaccine 疫苗 C Control 对照 TOTAL 总计

Pigs Entered实验猪只数量

408 408 408 408 1632

Entry Weight (kg)起始体重

5.95a 5.95a 5.97a 5.95a 5.95

SD 标准差 1.000 0.9266 0.986 0.938 0.962Pigs Died 死亡 22a 7b 17a 19a 65

Mortality %死亡率

5.4 % 1.7 % 4.2 % 4.7 % 4.0 %

Pigs Missing丢失的猪只

1 1 1 1 4

Pigs Ended实验结束猪只数量

385 400 390 388 1563

End Weight (kg)最终体重

107.98a 112.90b 111.27b 106.24a 109.63

SD 标准差 15.21 12.17 13.25 16.29 14.53

疫苗对全价值猪的影响PCV Study-Value of Vaccine 圆环病毒研究-疫苗价值

779201

847837

816744

770474

720000

740000

760000

780000

800000

820000

840000

860000

Vaccine A Vaccine B Vaccine C Non-VX Control胴体

总价

值/T

otal

car

cass

val

ue,

RMB

胴体总价值(扣除疫苗成本) Total Carcass Value (subtract vaccine cost)

胴体总价值/Total carcass value, RMB

疫苗对全价值猪的影响PCV Study-Extra profit per pig compare to control

与对照比每头猪增加的利润

¥21.39

¥189.62

¥113.41

¥0.00

¥20.00

¥40.00

¥60.00

¥80.00

¥100.00

¥120.00

¥140.00

¥160.00

¥180.00

¥200.00

Vaccine A Vaccine B Vaccine C

Extra Profit Per Pig

Trial Design 试验设计

• Remember 要记得––A well designed trial can provide good data with which you can

make better decisions.–合理的试验设计能够提供优质数据并帮助做出更好的决策

–A poorly designed trial at best wastes time and money, and at worst causes you to make bad decisions that waste more time and money.

–不合理的试验设计，轻则浪费时间和金钱，更糟的情况是，做了错误的决策并浪费更多的时间和金钱

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