1. Paul Kilgore, MPH, MD Monday, April 13, 2009 SNU Graduate School of Public Health How are licensed vaccines monitored: assessments of vaccine safety and vaccine effectiveness

2. Vaccine Introduction Vaccine testing: non-human subjects (pre-clinical) Vaccine testing: adults, children, special populations (clinical) Licensure of vaccine: special populations or universal (everyone) Introduction and Post-Licensure Evaluation: conducting surveillance and measuring impact of vaccination

3. Stages of Vaccine Trials Source: http://www.partnersforimmunization.org/pdf/Scientific_Studies.pdf

4. Definition: Vaccine Introduction The procurement, distribution and administration of vaccine according to the recommended schedule for the vaccine. Plus….. The conduct of disease surveillance and surveillance for adverse events following vaccination (safety surveillance).

5. Definition: Post-Licensure Evaluation Post-licensure: “after” licensure of vaccine, during/after introduction of vaccine for use in special population or as a universal immunization. Evaluation: measurement of disease- related or vaccination-related outcomes

6. Post-Licensure, Phase IV In some texts, you will find “Phase IV” written. Phase IV refers to the phases of clinical vaccine evaluation; moving from phase I, to phase II, III and ending with phase IV. Phase IV or post-licensure sometimes referred to as “post-marketing studies”

7. “Post-Marketing Studies” or “Post-Marketing Surveillance” Same meaning as “phase IV” or “post- licensure” studies or surveillance. These studies may be done by governmental agencies, vaccine manufacturers, independent scientists, others. Have become standard practice following introduction and use of new vaccines.

8. Definition: Post-Marketing Refers to period after licensure and publicizing a vaccine’s availability. In order to help doctors and consumers (i.e. parents, adults) understand that a new vaccine is available, vaccine manufacturers will publicize availability of vaccine. Publicity generally done between the time from licensure (by regulatory authorities) to time when vaccine is distributed to clinics, doctors’ offices.

9. Definition: Vaccine Uptake “Vaccine uptake” refers to events that allow or lead to increased use of a vaccine. Post-licensure or post-marketing surveillance assumes that there is some level of vaccine uptake. Phrase “vaccine uptake” sometimes used synonymously with “vaccine coverage”.

12. Definition: Vaccine Effectiveness The ability of a vaccine to prevent the disease- related outcomes for which the vaccine was licensed, when given to children or adults in private clinics, mass immunization campaigns, public vaccination clinics, etc… Even before vaccines are given routinely to target populations, we know they are not perfect…they will not prevent 100% of the outcomes for which they are created.

13. Interaction of Vaccine Uptake and Vaccine Effectiveness Does vaccine uptake affect vaccine effectiveness? Yes Vaccine effectiveness is measure of vaccine’s ability to prevent disease; to prevent disease, the vaccine must be used at some level…it must be taken up and administered to people.

14. What Factors will Increase or Decrease Vaccine Uptake? Public perception: will I get sick if I do not take the vaccine—am I at risk for the disease? Does the vaccine prevent a serious disease or even death? Provider perception: do doctors and nurses believe that the vaccine is safe and efficacious? Do they believe results of published vaccine trials? Do they believe that the public (e.g. parents) will accept the vaccine if they recommend its use?

15. Other Determinants of Vaccine Uptake Vaccine manufacturing capacity (is there a shortage of vaccine supply?) Vaccine distribution capacity Cold chain requirements Staff available to administer vaccine

16. Definition: Vaccine Safety Defined as the types, number and risk of adverse events that exist for a vaccine. If a medical complaint or problem arises after a vaccine is given, this is called an “adverse” event. Safety of a vaccine is determined by the types and number of adverse events that have been observed in both pre- and post-licensure vaccine trials.

17. Rationale for Vaccine Effectiveness and Safety Studies Pre-licensure study results may not always reflect what happens in “real-life”; phase III efficacy studies conducted under very controlled situations; phase IV, routine use: uncontrolled situations occur frequently. Phase III studies often involve several hundred up to several thousand patients….but even with these larger numbers, some adverse events may not occur with high frequency.

18. Post-Licensure Surveillance Screening and tabulation of persons who experience disease in question; “counting of cases”. Cases may be a clinical syndrome (clinically diagnosed only) or may be diagnosed with aid of laboratory tests. May be performed on indefinite basis (“forever”) or done as a special study for defined period of time.

19. Summary: Key Points “Post-licensure” = “Phase IV” = “Post-marketing”. The level of effectiveness for a given vaccine depends on “uptake” or use of the vaccine. Uptake of vaccine depends on both individual factors (e.g., perceptions) and programmatic factors (e.g., freezer space). Vaccine safety is the “sum total” of the adverse events following administration of a vaccine.

20. What Prompts Post-Licensure Surveillance? Policy-makers (i.e., politicians) may require information to “make the case” (rationalize) spending money on vaccines. Showing that a vaccine is reducing deaths or cases provides evidence that vaccine is doing what it is supposed to do. Post-licensure surveillance data also is used to guard against criticisms that vaccine is not effective—experience of “1” does not equal experience in a population.

21. “Doing” Post-Licensure Surveillance Screening and tabulation of persons who experience disease in question; “counting of cases”. Cases may be a clinical syndrome (clinically diagnosed only) or may be diagnosed with aid of laboratory tests. May be performed on indefinite basis (“forever”) or done as a special study for defined period of time.

22. Case Study 1 Measles in Bangladesh: Vaccine Effectiveness

23. Measles Burden “WHO estimates that almost 1 million measles- related deaths occur each year; the majority (85%) in Africa and Asia. In Bangladesh, measles remains a major cause of childhood morbidity and mortality. Population-based surveillance of 121 018 residents of a poor periurban area in Dhaka reported a measles incidence of 57 per 1000 per year among under-5-year-olds in 2001. A nationwide verbal autopsy study among a representative sample of under-5-year-olds who died between 1992 and 1996 reported that 6% of these deaths were due to acute measles and 15% to post- measles diarrhoea or pneumonia.”

24. Background

25. Expected Vaccine Effectiveness “As measles vaccine coverage increases, it becomes more important to identify risk factors for measles and target supplementary immunization strategies at high-risk groups. It is also important to provide high-quality immunization services. Vaccine effectiveness is expected to be at least 85% when measles vaccine is administered at 9 months of age, but cold chain and other programme failures have reduced effectiveness in rural and urban areas in developing countries.”

26. Case 1: Questions and Discussion

27. Case 1: Study Design How might you consider measuring measles vaccine effectiveness? What type of study design might be easiest to conduct in this developing country setting—Dhaka, Bangladesh?

28. Case 1: Case Identification What might be a case definition of measles that you could consider for this type of study? Would you want to have laboratory- confirmation? Is it necessary? Where would you look for cases?

29. Case 1: Measles Case Study Case Definition: Children living in urban Dhaka and presenting with a history of measles-like illness in the previous 6 weeks (generalized maculopapular rash of ≥3 days' duration with a history of fever and cough, coryza or conjunctivitis).

30. Case 1: Controls “We aimed to select four neighbourhood controls for each case, by visiting neighbouring households sequentially until four controls were identified. The controls were matched within age ranges (5–8, 9–11, 12–23, 24–35, 36–47, 48–59, 60–83, 84–107 and >108 months) and had no previous history of measles. We also attempted to recruit four age-matched controls from the same hospital, who lived at a similar distance from the hospital as the matched case. Children with pneumonia and pertussis were excluded because of the potential for nosocomial transmission. Poliomyelitis, tuberculosis, and surgical cases were not eligible as controls because our preliminary work suggested that their mothers' perceptions of severity and usefulness of medical care were different from those for measles.”

31. Case 2: Questions, Controls What is matching? Why is matching useful? Why did they attempt age matching? What is value in searching for “neighborhood controls”?

34. Case 1: Other Methods After obtaining their written informed consent, the parents of cases and controls were interviewed by health workers using pre-tested, structured questionnaires. Data collected included age, sex, socioeconomic status, parental education, number of children in the household, history of exposure to measles cases, and distance travelled and time taken to reach hospitals.

35. Case 1: Other Methods Immunization status was recorded from documents or from the verbal history given by the parent if no record was available. Respondents were asked whether the child had been to a health facility during the 3 months prior to enrolment, and if so, when the most recent visit had occurred and the reason for it. The same information was then requested for each previous visit, working backwards.

36. Case 1: Other Methods Laboratory assays were performed at ICDDR,B. Measles IgM antibody levels were measured using enzyme- linked immunosorbent assay kits (Enzygnost, Behring Diagnostics, Frankfurt, Germany). Each run of IgM assays included a positive and a negative control. The overall sensitivity of this test (for immunized and non- immunized subjects) for detection of measles IgM in measles cases confirmed by complement fixation test is 97.2%.

37. Case 1: Questions Why might they have used written informed consent in this study? What is meant by “pre-testing the questionnaire”? Why is it important to know how the immunization history was obtained? What is the value in knowing how far away the case or control lived from the hospital?

38. Key Messages Case-control studies are useful in conducting evaluations of vaccine effectiveness. Before starting a case-control study, it is important to understand the population where study will be done (e.g. patterns of health-care seeking) Methods can be implemented during patient screening, enrollment and data collection to minimize bias that may result in giving inaccurate estimates of vaccine effectiveness.

39. Case 2: Vaccine Safety

41. LANKINEN, Kari S., PASTILA, Satu, KILPI, Terhi et al. Vaccinovigilance in Europe: need for timeliness, standardization and resources. Bull World Health Organ, Nov. 2004, vol.82, no.11, p.828-835. ISSN 0042- 9686.

45. Large-Linked Databases The gaps that exist in the scientific knowledge of rare vaccine side effects prompted the CDC to develop the Vaccine Safety Datalink (VSD) project in 1990. This project involves partnerships with seven large health maintenance organizations (HMOs) to continually monitor vaccine safety. VSD is an example of a large- linked database (LLDB) and includes information on more than six million people. All vaccines administered within the study population are recorded. Available data include vaccine type, date of vaccination, concurrent vaccinations (those given during the same visit), the manufacturer, lot number and injection site. Medical records are then monitored for potential adverse events resulting from immunization. The VSD project allows for planned vaccine safety studies as well as timely investigations of hypotheses. At present, the VSD project is examining potential associations between vaccines and a number of serious conditions. The database is also being used to test new vaccine safety hypotheses that result from the medical literature, VAERS, changes in the immunization schedule or from the introduction of new vaccines. This project is a powerful and cost-effective tool for the on-going evaluation of vaccine safety.

46. Victims of Success? Pediatrics Chen et al. 99 (6): 765.

47. Vaccine Usage: Combinations Pediatrics Chen et al. 99 (6): 765.

48. Outcomes of Interest Pediatrics Chen et al. 99 (6): 765.

49. Case 2: Questions

50. Case 2: Surveillance for Safety Why are standard definitions used in safety surveillance? Are case reports of adverse events following immunization useful? Why or why not?

51. Case 2: Surveillance for Safety If you are designing a surveillance system for vaccine safety, when might you consider starting surveillance activities? What issues related to analysis might arise when you want to assess adverse events following immunization with a “combination vaccine”?

52. Case 2: Surveillance for Safety How might a large-linked database be used to study vaccine safety? List a few examples. What are potential methodologic limitations you might find when you analyze data from a large-linked database?

53. Key Messages As vaccine preventable disease frequency, vaccine safety surveillance becomes increasingly important. Standardized definitions for events are critical and education of those who will report events is important so that accurate data can be recorded. Large-linked databases in which cases are automatically captured and where vaccine histories can be linked to cases in a population- based manner are very powerful tools to assess vaccine safety—but they require substantial planning and investment in resources to start and maintain.