Blood Products Advisory Committee

August 16, 2007

Bethesda, MD

ISSUE SUMMARY

 

Topic II:  Measles Antibody Levels in U.S. Immune Globulin Products

 

Issue:   FDA seeks the advice of the Committee on a proposal to lower the minimum titer for measles antibodies in Immune Globulin Intravenous (Human) (IGIV) and Immune Globulin Subcutaneous (Human) (IGSC) recommended for lot release.

 

Background:

 

Measles antibody titers serve as potency tests for lot release of all immune globulins licensed in the U.S.   However, measles antibody titers in Immune Globulin products[1] have been declining over recent years, probably as a result of fewer donors having experienced natural infection, with resultant failure of some product lots.  Based on available scientific evidence, CBER proposes lowering the minimum titer for measles antibodies for IGIV and IGSC products recommended for lot release, consistent with a level expected to be effective in pre-exposure protection against measles in patients with Primary Humoral Immunodeficiency Diseases (PIDD).  CBER is not proposing to lower the recommended minimum measles antibody titer for lot release of Immune Globulin Intramuscular (IGIM), which is specifically indicated for post-exposure measles prophylaxis.[2]

 

Lot release testing for Immune Globulin Product potency

 

Regulatory requirements

 

            Potency testing is required for all biologic products.  Potency is defined as “the specific ability or capacity of the product, as indicated by appropriate laboratory tests…to effect a given result.” [3] Laboratory controls [of product] must “include the establishment of scientifically sound and appropriate specifications, standards, sampling plans and test procedures designed to assure that…drug products conform to appropriate standards of identity, strength, quality, and purity.”[4]  Failure to meet a final container specification results in rejection of the entire product lot.[5]  These potency tests not only provide assurance of functional antibody activity, but also provide evidence for lot-to-lot manufacturing consistency.

            Every vial of U.S.-licensed Immune Globulin Product contains a minimum level of antibodies for measles, diphtheria, and at least one type of poliomyelitis.   Minimum levels are defined for IGIM in the CFR for all three of these specificities.  IGIM must demonstrate adequate levels of potency for measles antibodies compared with a CBER reference standard.  The CBER Director advises manufacturers of an appropriate antibody level for IGIM.[6]  Although CFR-required measles antibody potency testing applies to IGIM,[7] industry and FDA practice has been to apply these criteria to all Immune Globulin Products indicated for treatment of PIDD.

           

Development of measles antibody specification levels

 

            The potency assay for anti-measles antibody has been specified for IGIM in the CFR (21 CFR 640.104) since 1965.  Prior to that, the Division of Biologics Standards, NIH, recommended that “several lots…be shown by clinical trials to be effective in the prophylaxis of measles.”[8]  By the 1960’s, in vitro assays for measles antibodies became widely available.  Immune Globulin Product measles titers are determined by hemagglutinin inhibition or infectivity neutralization assay, and compared to a CBER standard tested in parallel.  IGIM, but not IGIV, is labeled for use in measles prophylaxis because the original studies that demonstrated effectiveness were performed using IGIM.  Similar studies have not been conducted using IGIV or IGSC, although there are no scientific reasons to doubt that products meeting the minimum potency requirement for measles antibody would provide an adequate level of protection against wild type measles virus infection. 

 

Measles potency is defined relative to a CBER standard which was first promulgated in 1961.  The first CBER standard (Measles Reference Serum 1) was a pooled serum prepared from 100 rhesus macaques who had undergone natural infection with wild-type measles virus previously and who were boosted with measles virus antigen in Incomplete Freund’s Adjuvant and then exsanguinated 1-2 weeks later.  This Reference Serum had a neutralization titer of ~1:1024 in the assay in use at that time.   In 1961, it was assumed that all IGIM lots tested contained sufficient measles antibody to provide protection to healthy individuals during a measles outbreak.  Sixty lots of IGIM were assayed as a part of a FDA study to set a minimum potency for measles antibody.  The cut-off of 0.25 x Measles Reference Serum 1 was chosen in order to set a limit at which 95% of lots would be deemed acceptable.  Thus, for a 16.5% solution of IgG, IGIM minimum potency for anti-measles antibody was defined as 0.25 x the Bureau of Biologics Reference Serum #1. The minimum titer for release of Measles Immune Globulin, which was a licensed product at that time, was higher and was set at 0.5 times the Measles Reference Serum #1.   Measles Reference Serum 1 was subsequently replaced by IGIM Lot 175 in 1971, followed by the current reference Lot 176 (in 1992).  The potency of each reference material was related back to the prior reference material by testing in parallel and the minimum potency specification adjusted accordingly.  Based on this determination, the current recommendation is that Immune Globulin lots shall have at least 0.60 x relative potency compared to reference Lot 176, when compared at the same IgG concentration.

 

Clinical need for measles prophylaxis in patients with Primary Immune Deficiency

 

Currently, reported measles incidence is rare in the U.S., with only 66 confirmed cases reported to the CDC in 2005.[9]  Since 2001, measles outbreaks have been rare, and usually attributable to exposures outside the U.S., suggesting little or no measles circulation domestically.  Seroprevalence surveys suggest that 93% of the U.S. population has measles antibodies, providing sufficient herd immunity and making epidemics unlikely.[10]  However, measles remains an important pathogen worldwide, and is responsible for 21% of deaths from disease in children < 5 years.[11]  

Anecdotally, reports of measles infection in PIDD patients are rare.  Two factors are likely responsible: protection due to treatment with immune globulin products, and lack of exposure to measles.  Additionally, some PIDD patients may have successfully developed T cell immunity through vaccination.  Measles/Mumps/Rubella (MMR), a live attenuated vaccine, is not intentionally given to PIDD patients, but some PIDD patients may have been immunized prior to diagnosis. The rate of successful  vaccination  in this population is unknown.  Non-human primate studies suggest that B cell immunity and serum antibodies are necessary to prevent measles virus infection while measles clearance depends mainly upon CD8+ T cells. 

 Despite the rarity of recent clinical cases, the potential for measles exposure in PIDD patients continues to exist, and larger measles outbreaks could still occur if vaccination wanes, or if vaccination compliance declines.  Although measles has rarely occurred in the U.S. in the past decade, large outbreaks have occurred as recently as 1989-91 (> 55,000 cases reported).[12]  PIDD patients are unlikely to be exposed to measles unless traveling to an endemic area.   PIDD patients, especially those with T cell deficiencies as well as humoral immune deficiencies, are susceptible to severe measles disease.   While measles infection is not a current clinical concern for PIDD patients, it remains a potential clinical problem that could become manifest in the absence of antibody protection.  Failure to clear measles virus can result in giant cell pneumonia or measles inclusion body encephalomyelitis, often without a rash, making diagnosis more difficult.

 

Protective titer against measles infections and relation to IGIV specifications and dosing

 

            A serum titer of 120 mIU/mL, has been associated with protection against clinical measles disease in healthy immunocompetent, previously vaccinated individuals while a titer of approximately > 1,052 mIU/mL was associated with protection against infection in one small study.[13] The protective titer for immune deficient patients is not known.  The IGIV dose for most PIDD patients is 200-800 mg IgG/kg, given every 3-4 weeks.  The calculated theoretical minimum anti-measles antibody potency of IGIV, given at 200 mg/kg, to achieve a trough level of 120 mIU/mL, would be 1200 mIU/mL or 0.47 x CBER Standard Lot 176.[14] 

 

Decline in measles antibody potency in Immune Globulin Products in the US

 

            The decline in measles antibody potency in Immune Globulin products has been gradual, and is occurring in tandem with the decline in donor antibody levels in the United States. There are two main explanations that likely account for the decline in measles antibody potency in Immune Globulin products. The main cause of declining donor measles antibody levels is the increase in proportion of donors who received measles vaccine, compared to donors born prior to the 1960’s, who experienced natural measles infection.  Wild-type measles infections result in higher and longer lasting measles antibody titers than vaccination.[15]  Measles vaccine was first licensed in the U.S. in 1963, and was implemented in all states due to school immunization laws by the mid-1980’s.  Data on measles titers in relation to donor age suggest that donors born prior to the 1960’s indeed have higher measles antibody titers.[16] Second, it is known that measles antibody titers decline as the time from infection or immunization increases.  The success of the two dose measles vaccination program, initially implemented in the US around 1989, has also provided a high level of herd immunity and limited the spread of wild type measles virus in the general population.  In the absence of circulating measles virus, there are fewer natural opportunities for antigenic boosting which may also contribute to lower measles antibody titers in the general population.

             

 

CBER proposal to lower the minimum measles antibody potency in IGIV and IGSQ

 

Consequences of maintaining the current lot release specification

            The consequences of maintaining the current lot release specification for IGIV and IGSC product lots could include a significant reduction of the IGIV supply, which has been considered tight in recent years.  A significant proportion of current product lots are at or near the minimum measles titer recommended for lot release, suggesting that, in the absence of remedies, an increasing number of lot release failures could occur within the next 5 years and possibly within the coming year.

 

Strategies to address declining titers

            Two strategies have been considered within CBER to address declining measles antibody levels.  The first of these, to lower the recommended measles antibody titer in IGIV and IGSC products, is feasible providing that adverse clinical impacts are not expected.  A different approach would be to revaccinate plasma donors in an attempt to increase measles antibody levels.  However, the likelihood of achieving substantially higher and durable levels is estimated to be low in adults.[17]  In a study conducted by Charles LeBaron et al in children in Marshfield, Wisconsin, the geometric mean measles neutralizing antibody titer rose two to three fold one month after 4 to 5 year old or 11 to 12 year old children were given a second dose of measles containing vaccine and no measles seropositive children had a four fold or greater rise in measles antibody titer.[18]  Increased titers tend to be of short duration, lasting around 6 months on average.[19] For this reason, CBER has focused on the possibility of lowering the potency titer in IGIV and IGSC if this can be accomplished without increasing the risk of measles in the PIDD population.

 

Rationale for a new measles antibody specification for Immune Globulin Products

            Chen et al reported enhanced immunity to measles in healthy exposed people with antibody titers > 1,052 mIU/mL based on the low level of clinical symptoms, absence of characteristic rash, and lack of rise in measles antibody titers after exposure.[20]   In the same study, titers of < 120 mIU/mL were not protective, and titers > 120 mIU/mL were associated with protection from clinical disease but rising measles antibody levels were sometimes observed in those with levels < 1,052 mIU/mL, indicating subclinical infection.   For PIDD patients, the level needed for measles protection is less certain, but probably ranges between 120 – 1,052 mIU/mL.  Based on a survey of IGIV lots manufactured between 1998 – 2003, CBER researchers estimated that trough antibody titers achieved by patients receiving 400 mg/kg IGIV every 4 weeks, would range between 250 – 718 mIU/mL. Unfortunately, there are no published pharmacokinetic data analyzing the IGIV product administered and the consequent measles neutralizing antibody levels achieved pre and post IGIV infusions, in PIDD patients.    

            Estimating the protective dose of measles antibodies for PIDD patients is complicated by the lack of specific data on protective levels in this population.  The heterogeneity of  PIDD (comprised of more than 100 distinct syndromes, with varying degrees of cellular immune and humoral deficiencies) adds a further complication, since protective levels in one type of PIDD may be different than in another.  Some assurance that current titers are adequate is provided by the anecdotal lack of measles cases reported in PIDD population cohorts, although exposure rates to measles are likely to have been low.[21]

            A proposed minimum potency of 0.24 x CBER Standard Lot 176 would result in calculated trough measles antibody levels of 120 mIU/mL post-infusion, if the IgG dose is at least 400 mg/kg.[22]  Uncertainties attend the use of a lowermost estimate, such as the possibility that some patients receive < 400 mg/kg IGIV, and the inherent likelihood that trough levels in individual patients will not each precisely simulate the calculated theoretical levels.  CBER therefore proposes an adjustment of the estimated minimum measles antibodies titer, for a specification of 0.48 x CBER standard in lieu of the present requirement of 0.60 x CBER Reference Lot 176, to account for dosing differences and biological variation.  At this level, patients receiving a 200 mg/kg dose of IGIV would still be predicted to achieve trough levels of 120 mIU.

 

Questions for the Committee:

 

1.      Considering both the supply concerns in the setting of current lot release requirements and the uncertainties concerning protective levels of measles antibodies in PIDD patients, do Committee members concur with the FDA proposal to lower the minimum measles antibody potency specification for IGIV and IGSC from 0.60 x CBER standard, to 0.48 x CBER standard? 

2.      Please comment whether additional studies are needed to confirm that PIDD patients will achieve trough levels of measles antibodies above120 mIU/mL if treated with IGIV and IGSC products that meet the proposed revised potency standard of 0.48 x CBER standard.

 

3.   Please comment on the need for and feasibility of any alternative strategies that CBER should consider to evaluate the potency of measles antibodies in lots of IGIV and IGSC.


 

Appendix to BPAC Issue Summary: Calculation of Trough Titer Specific Antibody Concentration

 

Formulae:

 

P = peak value (mIU/ml) after intravenous infusion.

N = dose, in total mIU, infused into patient.  

 

P = N/[(40 ml plasma/kg) x patient mass in kg]

 

Equilibrium value (4-5 days after intravenous infusion) = 0.4[23] x P

 

Estimated trough value = 0.5 x level at equilibrium[24]

 

 

Simplified Formula:

 

Estimated Trough value = 0.005N/patient weight (kg)

 

 

 

 

 

   

 

 

 

 

 

 

 

 

 

 

 

 

 



[1] Abbreviations used in this document: IGIM (Immune Globulin (Human), administered intramuscularly), IGIV (Immune Globulin Intravenous (Human)), IGSC (Immune Globulin (Human), administered subcutaneously).  “Immune Globulin Products” refers to all forms of IgG products (intravenous, intramuscular, and subcutaneous).

[2] GamaSTANTM S/D package insert, 2007

[3] 21 CFR 600.3(s)

[4] 21 CFR 211.160(b)

[5] 21 CFR 211.165(f).  Under some circumstances, reprocessing may be performed.

[6] 21 CFR 640.104(b)(2)

[7] 21 CFR 640.101(e)(2)

[8] Minimum Requirements: Immune Serum Globulin, Division of Biologics Standards, Department of Health, Education, and Welfare, NIH.   April 9, 1953.

[9] MMWR 55(50): 1348-51, December 22, 2006

[10] Hutchins, SS et al.  Population immunity to measles in the United States. JID 189(Suppl 1): S91-7, 2004, and MMWR 53(31): 713-6, 2004. 

[11] MMWR 55 (18):511-15, 2006

[12] MMWR Recommendations and Reports 47(RR-8): 1-57, May 22, 1998.

[13] Chen, RT et al.  Measles antibody: reevaluation of protective titers.  JID 1990; 162: 1036-42.

[14] Audet, S et al.  Measles virus-neutralizing antibodies in Intravenous Immune Globulins.  JID 194: 781-9, 2006.

[15] Markowitz, LE and Katz, SL.  Measles Vaccine.  In: Plotkin SA, Mortimer EA Jr., editors.  Vaccines, 2nd ed. Philadelphia: WB Saunders.  P. 229-76, 1994.

[16]Audet, ibid,  and  CSL Behring data presented at IGIV workshop http://www.fda.gov/cber/summaries/ig042507ts.pdf (accessed 7/05/07)

[17] Wong-Chew et al.  Cellular and humoral immune responses to measles in immune adults re-immunized with measles vaccine.  J. Med. Virol. 70:276-80, 2003.

[18] LeBaron et al.  Persistence of measles antibodies after 2 doses of measles vaccine in a postelimination environment.  Arch. Pediatr. Adolesc. Med. 161: 294-301, 2007.

[19] Ibid.

[20] Chen et al.  Measles antibody: reevaluation of protective titers.  JID 162: 1036-42, 1990.

[21] Transcript of FDA Workshop: Immune Globulins for Primary Immune Deficiency Diseases: Antibody Specificity, Potency and Testing - 4/25-26/2007, April 26, 2007, at http://www.fda.gov/cber/minutes/ig042607t.htm#pan. (accessed 7/05/07) 

[22] Audet, S et al. ibid.

[23] Assumption that for equilibrium, 45% of IgG is intravascular, and 55% is extravascular

 

[24] Assuming that t1/2 is 22 days; time of trough level would be 26-27 days after last infusion