1. Scientific Basis for Review of Varicella Zoster Immune Globulin Products Blood Products Advisory Committee July 21, 2005 Dorothy Scott, M.D. OBRR/CBER

2. Varicella Zoster Immune Globulin (VZIG) Licensed in 1981 Intramuscular preparation sourced from selected high anti-VZV plasma units Indications – Prevention/Modification of severe varicella disease in: –Immune compromised children and adults –Premature infants –Infants < 1 year age –Selected non-immune pregnant women and healthy adults Should be administered within 96 hours of varicella exposure

3. VZIG Licensure 1981 Study subjects: immune compromised children with household exposure to varicella Trial design: randomized, double-blind Comparators: –Historical controls (Feldman et al, Pediatrics 56: 388-97, 1975) –Zoster Immune Globulin (unlicensed IG prepared from plasma of donors convalescing from shingles)

4. VZIG Pivotal Trial for Licensure 1 VZIGZIG Historical controls 2 Pox count > 100 12/81 (15%) 13/83 (16%)87% Pneumonia3/81 (4%)3/83 (4%)25% Hepatitis0010% Encephalitis005% Death007% 1 Zaia et al, JID 147: 737-43, 1983. 2 Feldman et al, Pediatrics 56:388-97, 1975

5. VZIG Supply Sole manufacturer – Massachusetts Public Health Biological Laboratories (MPHBL) MPHBL plasma fractionation facility scheduled to close VZIG Supply (MPHBL report) Are there alternative, effective therapies to prevent severe VZV disease? What scientific evidence is needed to support licensure of another VZIG product?

6. Possible alternatives to VZIG – no controlled trials Antiviral medications, e.g. acyclovir IGIV

7. Anti-Varicella gp ELISA titers for currently licensed IGIV’s compared to licensed VZIG Data courtesy of Scott Schmid, Ph.D., NCID, CDC

8. VZIG/VZIGIV Licensure Possible target population(s) for study – exposed, non-immune subjects –Immune compromised children/adults –Pregnancy (for prevention of severe infections in the mother and/or neonatal infection) –Non-immune otherwise healthy individuals Which population(s) would be most informative/useful to study? Are surrogate markers useful predictors efficacy?

9. Why surrogate markers? One Potential option for licensure via Accelerated Approval (21 CFR 601.40-46) Approval may be granted on the basis of adequate and well controlled clinical trials establishing that the product has an effect on surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence to predict clinical benefit, or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity. Note: as a condition, the applicant must study the product further to verify its clinical benefit post- licensure)

10. Possible Surrogate Markers for VZIG Efficacy (PK study) Serum anti-VZV antibody tests: –Solid-phase assays – ELISA, FAMA, IFA, complement fixation, etc. –gpELISA: correlates with protection in vaccine studies Levels needed for protection in immune compromised patients unknown –In vitro neutralization –Animal models

11. Questions to the Committee 1.Please discuss what laboratory and clinical data would be sufficient to demonstrate efficacy of a new anti-varicella antibody preparation, for prophylaxis of severe varicella infection. In particular, please comment on a.Which target populations would be most informative to study b.What surrogate markers would be appropriate for assessment of efficacy c.Other considerations for clinical trials 2.Please comment on whether the available scientific data support use of IGIV or acyclovir as a substitute for VZIG for prophylaxis of severe VZV infection in any clinical settings

12. Speakers 1. Donna Ambrosino, M.D., and Catherine Hay, Ph.D., MPHBL. VZIG manufacture, potency testing, and current supply status. 2.Philip LaRussa, M.D., Professor of Clinical Pediatrics, Columbia University. Severe Varicella Zoster disease, correlates of protection, and post-exposure prophylaxis options. 3.Mona Marin, M.D., NIP/CDC. ACIP and Red Book recommendations for post-exposure prophylaxis of severe varicella zoster infections