Safety and Efficacy Evaluation of Preventive Vaccines

1. Safety and Efficacy Evaluation of Preventive Vaccines Cynthia Kleppinger, M.D. Center for Biologics Evaluation and Research Food and Drug Administration December 7, 2000

2. Preventive Vaccines • Preparation containing a modified pathogen to induce an immune responseto protect against an infectious disease • Given largely to healthy individuals • Among the most powerful tools for disease prevention

3. Two Immune Systems • Innate-first line of defense, non-specific, phagocytic cells • Adaptive-specific, memory, lymphocytes

4. Vaccination • Relies primarily upon the adaptive immune system

5. Types of Vaccines Live, Attenuated • Derived from “wild” strains/types • Must replicate to be effective • Mimics natural infection • Circulating antibody may interfere with response • May revert to a virulent form

6. Types of Vaccines ( cont. ) Inactivated Vaccines • Cannot replicate • Minimal interference with circulating antibody • May be adjuvanted • Mostly induce a humoral (antibody) response • May require periodic booster doses

7. Types of Inactivated Vaccines Killed • Relatively safe and easy to produce • Do not cause infection in vaccinee ( with proper manufacturing and controls ). • Immunity may be less complete and shorter lasting than live vaccine/natural infection

8. “ Fractional” • Toxoid • Subunit Protein - Purified or Recombinant • Pure Polysaccharide • Polysaccharide Conjugate

9. Combination Vaccines Two or more antigens in a physically mixed preparation for administration as a single immunization • Multi-disease combination • Multi-valent combination Mixed by manufacturer or health care worker

10. Animal Virus Vaccines • Does not cause severe disease in healthy humans • Shares some proteins with its more virulent cousin • Stimulates the human immune response-especially the production of memory cells.

11. Factors that influence the immune response to vaccines • Maternal antibody • Nature/type of vaccine & dose • Route of administration • Adjuvants • Host factors ( age, nutritional status, genetics, coexisting disease, prior exposure to agent )

12. History and attitudes • 1798- Jenner Inquiry - no mention of second vaccinee John Baker’s death • 1911-1922 in the UK: 103 deaths/4 million vaccinations- merely a coincidence/ procedure free of risk • 1959- “There is virtually no danger from smallpox vaccination if proper precautions are taken”

13. How CBER came to be • Death and Disasters

14. CBER Regulatory Philosophy • Use sound scientific principles • Common sense • Flexibility • Case-by-case approach based on rational science • Risk vs. Benefit assessment

15. Safety -Vaccines are primarily for healthy individuals • Is determined case by case • Reflects the product’s risk vs. benefit relationship • Needs an “adequate” safety data base • Is ordinarily studied together with efficacy in the patient population at risk or with the condition to be treated.

16. Analysis of Safety Pre-clinical • Product characterization • Safety/Toxicity Studies ( in vitroor in vivo ) • Immunogenicity • Animal Protection Model • Rationale for Human dose and route • Assays to evaluate immune response • Lot information

17. Consider vaccine-specific features for safety assessment • Shedding • Level of attenuation • Reversion to virulence • Neurovirulence

18. Clinical Safety Analysis • Identify potential specific adverse events • Type of vaccine/ extent of inactivation • Target population • Intended use • Previous human experience for reactogenicity for closely similar products

19. Safety Data Monitoring • Active vs. Passive • Subject Diary Cards • Case Report Forms • Local reactions • Method • Measuring • Frequency • Grading • Definitions

20. Safety Data Monitoring ( cont. ) • Systemic adverse events • Active vs. Passive • Measure • Grading • Definition and body system • Frequency • Immediate vs. late/long term • Duration of reaction-information on recovery and any sequelae

21. Serious Adverse Drug Experience • Death • A life threatening experience • In-patient hospitalization or prolongation of existing hospitalization • A persistent or significant disability/incapacity • A congenital anomaly/ birth defect

22. Analyzing the Safety Data • Is there a reasonable possibility that the experience may have been caused by the drug ? • Was event described in risk information in the Investigator’s Brochure ? • Were there similar, but milder events ? • Were animal studies predictive ?

23. Analyzing Safety Data ( cont. ) • Any differences in serious adverse events in population groups ? • Any identification of any risk factor ? • Is there a way to prevent or ameliorate the severity ? • Is the reaction due to overdose ? • Do laboratory findings reflect the event ?

24. Safety “Triggers” • IND Safety Reports • Subject Deaths • Subjects who dropped out if associated with an adverse event • Information from preclinical studies that are in progress or completed • Significant manufacturing changes

25. Adverse event(s) happen What FDA does: • Depends on state of clinical development • Depends on strength of causal relationship • Reviews current, prior human safety data and non-clinical data • Reviews same products, similar products or related protocols in other INDs • May request additional data

26. Possible Regulatory Actions • Protocol modifications- changes in eligibility criteria, dose, route, schedule, monitoring, stopping rules • Change informed consent to reflect new toxicity, re-consent current study participants

27. Potential Regulatory Actions • Update Investigator’s Brochure • Consider need for new non-clinical studies • Place study on clinical hold

28. Grounds for Phase I Clinical Hold • Unreasonable & significant risk • Clinical Investigator(s) not qualified • Inadequate Investigator’s Brochure • Insufficient Information to assess risk

29. Phase 2/3 Clinical Hold • Same as reasons for Phase 1 • Protocol Design Inadequate to Meet Objectives

30. Post Licensure • Trials to assess long-term safety as a condition of marketing approval- usually address a specific aspect of safety/efficacy

31. Post Licensure ( cont. ) • Voluntary study • Commitment • VAERS • Pregnancy Registry

32. Public Health Service Act The Secretary of Health and Human Services can refuse to approve a new drug application if he/she finds that “There is a lack of substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of used prescribed, recommended or suggested in the proposed labeling thereof...”

33. “Substantial Evidence” Defined: Evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports…in the labeling.

34. Efficacy- early information • Epidemiology data needed from intended population prior to efficacy trial • Immunogenicity differences may exist among populations- genetics, nutritional status, background infections

35. Efficacy- information • Phase 2 immunogenicity data • Early evaluation of proposed efficacy endpoints • Correlate of protection

36. Efficacy ( cont. ) • Product should be defined • Final product formulation completed • Assay validation

37. Efficacy • Appropriateness of the study design(s) • Randomized, well-controlled ( best ) • Selection of patients/ well-defined • Duration of studies • Choice of endpoints • Choice of control group (s)

38. Efficacy Study Endpoints • Prospective primary and secondary endpoints • Clinical relevance of efficacy case definitions • Specificity of case definitions emphasized • SOPs for specimens, interpretation, centralized readers

39. Statistical Methods • Reliance on unapproved endpoints • Multiple endpoints • Support for any unplanned analyses • Interpretation of efficacy data

40. Efficacy Assessment ( CBER/ CDER ) • Two efficacy trials are the “standard” • One trial may be adequate if the results are compelling • Robust data, e.g., multicenter

41. Therefore- • Must obtain safety and immunogenicity data using the candidate vaccine in the specific population in which the efficacy trial will be performed.

42. Special Clinical Studies • Immunogenicity-correlate of immunity • Human challenge studies • Bridging studies • Concomitant administration

43. Final Analysis • Do the results of well-controlled studies provide substantial evidence of effectiveness ? • Do the results show the product is safe under the conditions of use in the proposed labeling ?

44. Safety Evaluation • Prospective and Persistent • If in doubt, leave data in

45. Efficacy Evaluation • Prospective and Protocol Subsistence • Garbage in, garbage out

46. Remember The plural of anecdote is : DATA

47. Much thanks to fellow CBERees • Dr. Karen Goldenthal • Dr. Donna Chandler • Dr. Julianne Clifford • Dr. Karen Weiss • Dr. Rebecca Sheets • Dr. Frederick Miller

48. Reference Resources • Advisory Committee on Immunization Practices, 1996. Update: Vaccine Side Effects, Adverse Reactions, Contraindications, and Precautions MMWR 45:1-35 • http://www.fda.gov/cber/products.htm • http://www.fda.gov/cber/vaers/vaers.htm • http://www.fda.gov/cber/safety/safety.htm

49. References (cont.) • http://www.ifpma.org/ich5.html • http://www.fda.gov/cber/guidelines.htm • Draft Guidance for Industry: Considerations for Reproductive Toxicity Studies for Preventive Vaccines for Infectious Disease Indications - 9/8/00 • ICH Guidance on Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human or Animal Origin - 9/24/98

50. References (cont.) • Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drugs and Biological Products- 5/15/98 • Guidance for Industry for the Evaluation of Combination Vaccines for Preventable Diseases: Production, Testing and Clinical Studies - 4/10/97