Considerations in Testing Vaccines in Developing Countries

1. Considerations in Testing Vaccines in Developing Countries Zhi-yi Xu, MD, Wei Liu, MD International Vaccine Institute

2. Definition of Phases PhaseStudy PopulationPrincipal Goal(s) 1 Healthy adults Safety; Preliminary evaluations of immunogenicity; Dose-response; Shedding 2A Target population Safety; Immunogenicity; Dose-response; Shedding; Transmissibility 2B Healthy adults Preliminary assessments of clinical protection and immune correlates of protection; Safety; Immunogenicity 3 Target population Protective efficacy; Safety; Immune correlates of protection

3. Complexities in DesigningTrials in Developing Countries • Choosing the right study site • Data management • Ethical issues • Protection against bias • Loss to follow-up • Non-compliance • Intention-to-treatment

4. Choosing the Right Site • Informed and firm commitment from national and local authorities • Informed and firm commitment from local population • Local research infrastructure • Investigators • Other personnel • Laboratories • Propitious geography • Political stability • Demographic stability

5. Data Management-“Incompleteness” • Missing of required questionnaires • Missing of the value of a variable in the data set

6. Data Management-“Replication Error” • An entity is entered more than once; two or more entities share the same identity

7. Data Management-“Range Error” • The value of a variable does not fall within the expected range (“outlier”)

8. Data Management-“Inconsistencies” • The value of the inter-related variables does not fall within expected range

9. General Considerations: Clinical and Ethical Issues • Clinical trials should be conducted in accordance with ethical principles that have their origin in the declaration of Helsinki • Nonclinical and clinical information on an investigational vaccine should be adequate to support conduct of the trial • Clinical trials should be initiated and continued only if the anticipated benefits justify the risks

10. General Considerations: Clinical and Ethical Issues • Rights, safety, and well-being of the individual take precedence • Trials should be scientifically sound and described in a clear protocol • Trial protocols should be approved by an appropriately constituted IRB

11. General Considerations: Clinical and Ethical Issues • Trial investigators and care givers must be qualified • Freely given informed consent must be obtained • Confidentiality of information is essential

12. General Considerations: Clinical and Ethical Issues • Tested agents should be produced in accordance with GMP • Procedures must be implemented to assure quality • Information must be collected, stored, and handled in a way that allows accurate reporting, interpretation, and verification

13. Complexities in DesigningTrials in Developing Countries • Choosing the right study site • Data management • Ethical issues • Protection against bias • Loss to follow-up • Non-compliance • Intention-to-treatment

14. Other Major Issues in developing countries • Failure to randomize subjects • Failure to use blinding techniques • Violation of the protocol (example, fail to meet inclusion/exclusion criteria) • Inappropriate statistical methods

15. Advantages of Asia as Research Site for Clinical Trial • Rapid study subject recruitment • Lower cost • Generation of Asian data to address ethnic diversity, need for bridging data, and acceleration of local product approvals.

16. Final note Dear Rich, The data computerised at the study sites should be transmitted electronically on daily basis to the data center where the data will be checked and validated again, and frozen for analysis. Then, nobody can change the original data deliberately.  We have 4 major considerations: Selection of study sites, Ethical issues Data management and transmission Protection against bias. We did not touch general issues, such as sample size, data and safety monitoring board, statistical analysis and others. I  wish a success of your conference! Zhi-Yi 

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18. “Loss to follow up”-RCT of Havrix in Thailand One –year surveillance for clinical hepatitis A cases after treatments among school children was suspended for 2 months due to summer vacation. Number of hepatitis A cases in the vaccine and placebo groups during the 2 months was unknown.

19. “Non- compliance”- RCT of Hantaan Virus Vaccine • More than 10,000 study subjects randomized to vaccine or control group were unwilling or unable to receive vaccine or placebo. • However, these subjects had similar incidence rate of the disease as the control group. • The vaccine was considered efficacious (Table).

20. “Intention-to-treatment”- long term follow-up for HB vaccine protection • HBsAg seropositivity in vaccinated children of carrier mothers was 6.2% compared to 0.6% in children of non-carrier mothers. • But children of carrier mothers were more likely to pay multiple visits (131/743, 17.6%) than children of non-carrier mothers (13/1705,0.8%). • The Bias led to under-estimation of vaccine effectiveness.

21. Complexities in DesigningRCT Trials in Developing Countries • Choosing the right study site • Data management

22. HFRS Attack Rate Vaccine vs. Control: p=0.00006, Efficacy:100%; 95% lower CI: 76.15% Vaccine vs. Unvaccinated: p=0.0000.6, Efficacy: 100%; 95% lower CI: 75.0%

23. “Intention-to-treatment”HBsAg Seropositivity in Vaccinated Children - long term follow-up for HB vaccine protection

24. 30-day Safety Review Phase I Phase II Phase III A C B • Developmental Stage • Pre-clinical research and development • Notice of claimed investigational exemption for a new drug • Clinical research and development Phase I, Phase II, Phase III • Licensing Stage • Post-licensure Stage Stages Involved in Regulation of Biological Products a b c

25. Group A (Experimental) Target Infection No Target Infection Target Population Study Population R Target Infection Group B (Comparison) No Target Infection Assembly Allocation Surveillance Figure 1 A schematic of the sequence of events in a two-group, randomized controlled trial. In this sequence, the study population is assembled from a target population and is then randomized to constitute the experimental vaccine and comparison groups, which are then followed longitudinally and concurrently for ascertainment of the occurrence of target infections.

26. Evaluation of Vaccine Efficacy • Goal: To measure the full protection directly conferred upon a healthy, vaccinated individual, when vaccine is administered in an appropriate fashion • Question addressed: “ Can the vaccine reduce the occurrence of the target infection in an acceptably safe fashion, under ideal conditions?”

27. Decisions that Determine the Research Perspective • Choice of a target population • Choice of a vaccine formulation and of methods of storage and administration • Choice of a comparison agent • Choice about whether or not additional agents or interventions are to be received • Choice of the unit to be allocated • Choice of an approach for assessing vaccine safety • Choice of target outcomes for assessing protection • Choice of an index of vaccine protection • Choices about the participants and events to be included in analyses of vaccine performance

28. Features of an Efficacy Trial • Target population • At high risk for infection • Likely to respond to vaccination: Exclude subjects with significant comorbidity • No preexisting immunity: Exclude if previously infected or if previously vaccinated

29. Features of an Efficacy Trial • Vaccine formulation • Primary goal: Maximize immunogenicity (practicality is secondary) • Vaccine storage and administration • Storage under optimal conditions • Rigid scheduling • High level of training and supervision to ensure correct administration

30. Features of an Efficacy Trial • Control group: Persons receiving an agent without activity against the target infection • Receipt of other vaccines and drugs prohibited • Unit of allocation • Determined by goals of: • Measuring only the direct effect of vaccine in reducing susceptibility to infection • Minimizing sample size requirements • Usually individuals rather than groups

31. Features of an Efficacy Trial • Assessment of side-effects: • Those expected on basis of earlier studies • Those that occur shortly after vaccination • Those that occur with reasonable frequency • Target outcomes defined with restrictive biological criteria

32. Features of an Efficacy Trial • Index of vaccine protection: Protective Efficacy (PE) • PE = {1 – (Incidence in vaccinees)/(Incidence in non-vaccinees)} X 100% • Measures the proportionate reduction of the target outcome attributable to vaccination • Magnitude not affected by whether the incidence in non-vaccinees is high or low

33. Features of an Efficacy Trial • Analysis of protection • Group under analysis: Participants who received complete amount of assigned vaccine or comparison agent • Outcomes under analysis: Target infections that occur after “immunogenic window” • Duration of follow-up: Minimum interval required to obtain precise estimate of protection

34. Havrix Example • Havrix- inactivated hepatitis A vaccine developed by Smithkline Beecham in conjunction with the U.S. Army was tested in a trial in Thailand. • Hepatitis B vaccine was used as placebo on 40,000 children aged 1-16.

35. Havrix Example • Thailand was chosen for many reasons • Long standing collaboration on vaccines beginning with US Army research on Japanese encephalitis after World War II • Hepatitis A is endemic to the area • Transmission rate: 119/100,000 population

36. Havrix Example • Vaccine would not be made readily available in Thailand due to: • Large number of people to be vaccinated • High cost for the vaccine • Unavailability of health care resources

37. Havrix Example • There were hundreds of meeting with the local population and teachers. The local population supported the research trial apparently because they really wanted their children to receive the Hepatitis B Vaccine

38. Havrix Example • A leading Thai vaccine researcher opposed the trial. His argument against the trial: • No Thai need for the vaccine while a priority for the US army • Insufficient technology transfer to Thailand • Insufficient benefit to the community • Lack of respecting for collaborating Thai researchers

39. Complexities in DesigningRandomized Controlled Trials (RCT) in Developing Countries • Choosing the right study site

40. Complexities in DesigningRCT Trials in Developing Countries • Choosing the right study site • Date management and tracking • Ethical issues

41. Ethical Issues • Injustice in treatment of control group

42. AZT Example • Short course of AZT treatment was tested for preventing maternal-infant transmission of HIV. Placebo group did not get standard treatment. • If pregnant women in control group could be provided with standard treatment with AZT, fewer children in this group could have been born with HIV.

43. Ethical Issues • Injustice in treatment of control group • Injustice in conduct of trial in developing countries

44. Ethical Issues • Injustice in treatment in control group • Injustice in conduct of trial in developing countries • Informed consent

45. Informed consent • No written informed consent obtained • No signature by study subjects • Inappropriate timing (consent obtained after study initiation) • Inadequate information on the study risk given to the study subject

46. Ethical Issues • Injustice in treatment in control group • Injustice in conduct of trial in developing countries • Informed consent • IRB approval

47. Major Violations against IRB • No IRB approval • Starting the study before IRB Approval • Inappropriate IRB Committee members • Inappropriate monitor by IRB or study investigator