ISSUE SUMMARY

Blood Products Advisory Committee

Gaithersburg, MD

July 21, 2005

 

 

Topic # 2:  Scientific Basis for Review of Varicella Zoster Immune Globulin

 

 

Issue:  FDA seeks the advice of the Committee on options for determining the efficacy of Varicella Zoster Immune Globulin (VZIG) that could accelerate the development of new VZIG products.  Additionally, we seek the opinion of the Committee whether IGIV or acyclovir can serve as a substitute for VZIG.

 

Background:

 

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FDA is seeking ways to expedite the approval of new VZIG products.

 

Varicella (chickenpox) is usually a self-limited disease, occurring mainly in children.   Vaccination using live attenuated varicella zoster virus (VZV) has decreased the rate of infections in children.  However, wild type VZV still causes severe infections in non-immune adults, pregnant women, neonates, and immune compromised individuals.  Severe VZV complications include pneumonia, encephalitis, hepatitis, pancreatitis, and bone marrow suppression.  VZIG is indicated for prophylaxis of severe varicella infections in:

 

 Pediatric Populations

 

-         Immunocompromised children exposed to VZV.

-         Neonates, if maternal VZV infection occurs within 5 days before to 2 days after birth

-         Exposed premature babies of 28 weeks or less gestation if maternal history of VZV is uncertain, or negative

-         Selected exposed infants < 1 year of age

 

Adult Populations

 

-         Immunocompromised, VZV exposed adults without evidence of prior VZV infection (by history, or serology)

-         Healthy susceptible (e.g. non-immune) exposed adults on a case-by-case basis, because VZV infections have a higher complication rate in adults than in children

-         Exposed pregnant women deemed likely to be non-immune, to prevent severe infection in the mother.

 

VZIG is manufactured from selected donor plasma that has high titers of anti-varicella antibodies.  The donors are random qualified donors, and are not actively vaccinated with the intent to produce hyperimmune plasma.  Plasma pools are fractionated using alcohol precipitation.  Viral inactivation is by solvent-detergent treatment.    VZIG is a 10-18% solution of IG, and is administered intramuscularly.

 

VZIG was licensed in the U.S. in 1981, based on a double blind, randomized trial that compared VZIG to ZIG (Zoster Immune Globulin, prepared from plasma donors convalescing from shingles).  The subjects were immune compromised children with no history of varicella, and recent exposure to varicella from a household member.   The outcomes measured were varicella attack rate, pox count, complications, and mortality.[1] 

 

Results:                         ZIG                  VZIG               Expected[2]

 

Pox Count > 100                  13/835 (16%)  12/81 (15%)  87%

 

Pneumonia                                3/83 (4%)    3/81 (4%)    25%

 

Hepatitis                                   0                      0                      10%

 

Encephalitis                              0                      0                      5%

 

Death                                       0                      0                      7%

 

 

VZIG dosing, according to the package insert is 125 units/10 kg for the first 10-40 kg of weight.   For children and adults > 40 kg, the dose is 625 units.  Vials are supplied as

125-unit or 625-unit vials. 

 

The number of patients treated with VZIG is difficult to estimate.  Although the number of units distributed/year is known, the number of patients is not certain (because treatment is weight-based).   It is believed that at least several thousand patients receive VZIG annually.    

 

Discussion:

 

A.  Are there surrogate markers for prevention of severe varicella disease?

 

Surrogate markers for efficacy, if well understood and validated, may be used to shorten clinical trial times, or to decrease the number of subjects needed for a study.  In the case of VZIG, surrogate markers of efficacy could include correlates of protection such as serum antibody levels, or equivalent pharmacokinetic profiles to the licensed product.  In varicella vaccine trials, anti-varicella antibody titers of > 5 units, measured by glycoprotein ELISA (gpELISA), were correlated with protection from clinical primary infections in healthy people.  However, this cutoff should be interpreted with caution, as the vaccine also induces cell-mediated immunity not measured by the gpELISA assay.   The gp ELISA is not commercially available.   Other assays that could be used to measure anti-varicella binding include fluorescent antibody to membrane antigen (FAMA), indirect immunofluorescence (IFA), complement fixation, RIA, latex agglutination, and in vitro neutralization, but these have generally not been used in studies of protection.   Levels of antibody that provide protection in healthy children may not be the same as those needed for protection of immune compromised children and adults. 

 

B.  What are the most appropriate target populations for VZIG study?

 

The number of patients given VZIG in each at-risk group is not known.  Since visceral VZV involvement has been described in all of the patient types for which there are indications, it could be argued that one of these groups would be sufficient for testing clinical efficacy.  It is expected that immune deficient patients and neonates would be the most difficult patients to protect against severe infection.  In clinical trials, VZIG was not completely effective in preventing VZV disease in these immune compromised children. Cellular immune deficiencies are often associated with VZV susceptibility.  Immune deficient people include those with HIV-1, congenital immune deficiencies, and patients on chemotherapy. 

 

C.  Can IGIV substitute for VZIG?

 

Potential substitutes for VZIG include antiviral drugs and Immune Globulin Intravenous (Human) (IGIV).  IGIV is made from plasma that is not specifically selected for anti-varicella antibody titers and IGIV lots are not routinely tested for anti-varicella antibodies.  Published studies demonstrate that IGIV and IG contain anti-varicella antibodies, but at a lower level than VZIG.[3]  Small and/or uncontrolled studies have compared ZIG to IG and VZIG to IGIV.  Published reports have described patients that developed VZV infection in spite of IGIV prophylaxis, or VZIG prophylaxis, although most such infections have been mild.[4]    There are no published controlled trials comparing acyclovir prophylaxis directly with VZIG, however there are studies that demonstrate acyclovir activity in VZV prophylaxis.[5] 

 

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 population(s) 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 whether the available scientific data support the use of IGIV or acyclovir as a substitute for VZIG for prophylaxis of severe VZV infection in any clinical settings.

 



[1] Zaia, JA et al. Evaluation of varicella-zoster immune globulin: protection of immunosuppressed children after household exposure to varicella.  JID 147(4): 737-43, 1983.

[2] Feldman, S et al  Varicella in children with cancer: seventy-seven cases. Pediatrics 56: 388-97, 1975 .  [60 children receiving active anticancer treatment]

 

[3] Gershon, AA et al, Antibody to varicella-zoster virus after passive immunization against chickenpox.  J. Clin. Micro. 8(6): 733-5, 1978; Paryani SG et al, Comparison of varicella zoster antibody titers in patients given intravenous immune serum globulin or varicella zoster immune globulin.  J. Pediatr. 105(2): 200-5.

[4] Gershon, AA, ibid; Zaia, JA, ibid; Ferdman, RM, Failure of intravenous immune globulin to prevent varicella-zoster infection.  Ped. Inf. Dis. J. 19(12): 1219-20, 2000;  Huang, Y-C, et al.  Prophylaxis of intravenous immune globulin and acyclovir in perinatal vaccinia.  Eur. J. Pediatr. 160: 91-4..

[5] Asano et al.  Post exposure prophylaxis of varicella in family contacts by acyclovir.  Pediatrics 92: 219-22, 1993; Saga et al.  Effect of oral acyclovir against primary and secondary viraemia in incubation period of varicella. Arch. Dis. Child 69: 639-42, 1993/