1. 2019 Joint Statistical Meetings at Denver
Using the retrieved dropout approach for estimating a treatment policy estimand
Ruvie Martin* and Bjoern Bornkamp
30 July 2019, Denver, Colorado
2019 Joint Statistical Meetings

2. Outline ICH E9(R1) Addendum
Study Information and Estimand for the Primary Objective
Using the Retrieved Dropout Approach
Implementation
Conclusion

3. ICH E9 (R1) Addendum

4. ICH E9 Addendum on estimands and sensitivity analysis in clinical trials
More detailed description of the treatment effect of interest and the trial objective is required. Intercurrent events have to be taken into account at the estimand/"trial objective" level not the statistical analysis/missing data-handling level.
The difference of intercurrent events and missing data

5. Estimand Estimand description Together these attributes describe the
defining the target of estimation
Intercurrent event strategies
Treatment policy strategy
Composite strategy
Hypothetical strategy
Principal stratum strategy
While on treatment strategy
Bretz (2017) How the ICH E9 addendum around estimands may impact our clinical trials. Cancer Drug Development Forum

6. Study Information and Estimand for the Primary Objective

7. Background
A 2-year open label study to compare Treatment A versus Treatment B
Endpoint of Interest – imaging endpoint done by independent readers measured at Week 104
The primary objective is to demonstrate the proportion of subjects on Treatment A with successful response at Week 104 is superior to subjects on Treatment B

8. Estimand of the Primary Objective
The primary objective is to demonstrate the proportion of subjects on Treatment A with successful response at Week 104 is superior to subjects on Treatment B.
Population – defined through appropriate inclusion/exclusion criteria to reflect the targeted disease population
Variable of Interest – binary response variable indicating successful response
Intercurrent event – details on the next slides
Population-level summary – treatment difference in proportions of responders between Treatment A and Treatment B
FAS is the analysis set, what will be used for analysis while population is the group of patients
Business Use Only

9. Expected Intercurrent Events
Subject switching to commercial drug (non study drug)
Subject not taking the study drug nor commercial drug because of tolerability issues
Subject discontinuing study drug nor taking commercial drug because of the following:
adverse event/s, pregnancy, physician decision, subject/guardian decision

10. Which intercurrent event handling strategy?
Health Authority suggested using the treatment policy strategy since it will be reflective of clinical practice and thus will provide a clinically meaningful estimate
Treatment policy strategy will be used for all intercurrent events
The occurrence of the intercurrent event is irrelevant; the value for the variable of interest is used regardless of whether or not the intercurrent event occurs

11. Treatment Policy Strategy and Study Conduct
Treatment policy strategy can only be implemented when values for the variable after the intercurrent events exist
To help minimize missing data
(1) protocol and ICF clearly differentiate treatment discontinuation from study withdrawal
(2) site investigators are trained to understand the importance of subject retention and the prevention of missing data
(3) consent forms include a statement educating subjects about the continued scientific importance of their data even if they discontinue study treatment early
(4) the protocol recommends that attempts be made to contact subjects who fail to actively maintain contact with the investigator

12. Breakdown of subjects
Subjects who will finish the study and provide Week 104 data
Retrieved Dropout Subjects
Subjects who will discontinue study drug but will remain in the study and provide Week data
Subjects who will discontinue the study drug and the study and will not provide Week data
Both groups experienced intercurrent event
Subjects in yellow box have data
Subjects in green box have missing data

13. Using the Retrieved Dropout Approach

14. Why “retrieved dropout approach”?
From the ICH E9 Addendum under treatment policy strategy “For example, missing data may be imputed based on similar subjects who remained in the trial. Similarity may be established based on the same baseline covariates, the same randomised treatment arm, the same measurement history and information on the intercurrent event.”
Imputation based on the retrieved dropout subjects for the subjects with missing Week 104 data would get us close to the handling of the intercurrent events under the treatment policy strategy

15. EMA Guidance on Missing Data in Confirmatory Clinical Trials

16. EMA Guidance Section 5.1

17. Handling of Missing Data
Missing Week 104 data for a given subject who discontinued in the study will be imputed using an imputation model based on the observed data of subjects in the same randomized arm who also discontinued study treatment but for whom Week 104 data are available (‘retrieved dropout approach’, EMA 2010) and based on the observed data of the given subject.

18. Implementation

19. Implementation
A logistic regression model will be fitted to the Week 104 data for the retrieved dropout subjects, while adjusting for treatment, baseline score and post- baseline slope in the score.
The post-baseline slope is defined as the last available post-baseline change in score divided by study day on which the assessment was taken
PROC MCMC will be used for fitting the logistic regression model and multiple imputation of the Week 104 value with weakly informative priors

20. Conclusion

21. Conclusion
Even if a study is implementing the “treatment policy strategy” we still need to do imputation for the subjects with missing data.
The choice of handling intercurrent event have an impact on the trial conduct.
Imputation based on the retrieved dropout subjects for the subjects with missing data is an appropriate way to the handle the intercurrent events under the treatment policy strategy.

22. The 17th century 64-gun warship Vasa (Stockholm, Sweden)