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EXPERIENCE WITH BRIDGING STUDIES IN THE CENTER FOR BIOLOGICS EVALUATION & RESEARCH Susan S. Ellenberg, Ph.D. Office of Biostatistics and Epidemiology Center for Biologics Evaluation & Research, U.S. FDA Kitisato University-Harvard School of Public Health Symposium October 28, 2003 1 ACKNOWLEDGEMENTS • A. Dale Horne, Dr. P.H., Chief, Vaccines Evaluation Branch, Division of Biostatistics • Karen L. Goldenthal, M.D., Director, Division of Vaccines and Related Biological Applications 2 BRIDGING STUDIES IN VACCINE DEVELOPMENT • Bridging studies are commonly performed in vaccine research • Outcomes usually evaluated – Immune responses – Safety-related events • Bridging studies may evaluate – – – – – Effect of manufacturing change Effect of formulation change Effect of dose/schedule change (Effect of other vaccines given concomitantly) Validity of assumption that observed effect can be generalized to other populations 3 IMMUNE RESPONSE • Vaccines work by stimulating the development of protective antibodies that can protect vaccinated individuals when they are exposed to disease-causing bacteria and viruses • “Immune response” refers to the rise in the relevant antibody levels • In many (but not all) cases, immune response is a reliable surrogate for clinical efficacy (protection from disease) 4 DESIGN OF VACCINE BRIDGING STUDIES • For studying effects of changes in manufacturing, composition or method of administration, randomized noninferiority studies are generally conducted • Examples: – Randomize participants to receive vaccine manufactured with original process or with new process – Randomize participants to receive vaccine on original schedule or on new schedule • Analyze results to determine if immune responses are similar in randomized groups 5 RATIONALE FOR RANDOMIZED BRIDGING STUDIES • Changes made in manufacturing, or administration, could possibly affect vaccine efficacy or safety • Consistency of immune responses expected to predict consistency of prevention of clinical disease • Occasionally, bridging studies identify problems with new approach – Combining acellular pertussis vaccine with Hib vaccine had adverse effect on Hib immune responses for some products 6 SAFETY EVALUATION • Safety is always assessed in bridging studies, but usually without formal “bridging” criteria • Changes in manufacturing are of particular concern – Worst case: Cutter incident, 1950’s – Cutter was one of several manufacturers of Salk polio vaccine, using killed virus – Changes in manufacturing process for Salk polio vaccine resulted in inadequate killing process; Cutter vaccine caused hundreds of polio cases 7 BRIDGING ACROSS POPULATIONS • These bridging studies differ from those to assess changes in manufacturing, formulation or delivery • Not possible to randomize country/ethnic group! • Generally done as non-randomized but controlled studies, comparing immune responses in the region where clinical efficacy was demonstrated, to these outcomes in a different region 8 RATIONALE FOR BRIDGING ACROSS POPULATIONS • Inefficient to do multiple large clinical efficacy trials of new vaccines • Often clinical efficacy trials are possible only in certain regions – Disease endemic in limited areas – Existing vaccines in some areas • High likelihood that vaccine effective in one population will also be effective in other populations 9 EVIDENCE FOR “ETHNIC FACTORS” IN VACCINE EFFECTS • Haemophilus influenzae b (PRP-D) – Vaccine shown to be highly effective in Finland – Poor efficacy shown in Alaskans – Possible explanations: • Risk of Hib disease higher in Alaska • Occurs at earlier ages • Stronger and more rapid immune response required for protection in Alaska 10 APPROACH TO BRIDGING STUDIES FOR VACCINE LICENSURE IN THE U.S. • Often not feasible to evaluate clinical efficacy in the U.S. • Licensed vaccines still needed for travelers, military, certain occupational categories • Usual approach: perform clinical efficacy study where disease rate is relatively high, then “bridge” to U.S. population with single-arm study of new vaccine 11 DESIGN OF POPULATION BRIDGING STUDIES • Comparison of immune responses is fundamental objective • Primary outcomes: – Per cent “responders” (immune response above threshold predicting clinical protection from disease) – Ratio of geometric mean concentration of antibodies • Study designed to have good power to rule out important difference in parameters of immune response • Safety outcomes also measured 12 OTHER CONSIDERATIONS • Since study must be observational, try to make study in U.S. as similar as possible to that in country where primary study was performed – – – – – – Manufacturing considerations Age of participants Concomitant vaccines administered Schedule and route of administration Surveillance for adverse events Timing of blood draws for response assessment 13 VACCINES LICENSED IN U.S. WITH NON-U.S. EFFICACY DATA (NOT COMPLETE LIST) • Acellular pertussis-containing vaccines (DTaP) • Oral polio vaccine • Typhoid Vi Polysaccharide • Japanese encephalitis • Hepatitis A 14 COUNTRIES PROVIDING PRIMARY CLINICAL EFFICACY DATA FOR U.S. LICENSURE • • • • • • Sweden Italy Finland Germany Indonesia Thailand • • • • • • South Africa Nepal England Chile Japan Soviet Union 15 KEY CONSIDERATION: STRAINS OF INFECTIOUS AGENT • Prevalent strains may differ from country to country • If vaccines protecting against all strains prevalent anywhere cannot be developed, different vaccines may have to be developed in different regions; in such cases, would not try to “bridge” • Not routinely an issue, but likely will be important for HIV vaccines in future 16