Update: Lowering Measles Antibody Lot Release Specification in IGIV/IGSC Blood Products Advisory Committee May 1, 2008 Dorothy Scott, M.D. Division of Hematology/OBRR/CBER

Background Measles antibody titers serve as a potency test for lot release of all immune globulins licensed in the U.S. Measles antibody levels in products have been declining in recent years due to diminished titers in plasma donors Failure of potency testing at lot release results in lot rejection (21 CFR (f)) Potential large negative impact on Immune Globulin products availability for Primary Humoral Immune Deficiency Diseases (PIDD) CBER proposed to lower the minimum measles antibody titer of IGIV and IGSC to levels still expected to be effective in pre-exposure protection in patients with PIDD.

Clinical Impact of Lowering Measles Specification Measles uncommon in U.S.; no endemic disease present; exposure unlikely Measles in U.S. residents is usually due to transmission from infected travelers returning from endemic regions of the world PIDD patients with measles – rarely observed PIDD patients with combined B and T cell defects are at most risk of serious complications

Clinical Impact of Lowering Measles Specification Protective antibody level against clinical measles = 120 mIU/ml in normal subjects Sterilizing immunity ~ 1,000 mIU/ml Protective level unknown in PIDD patients –Likely to vary depending on specifics of immune deficiency FDA-proposed specification based on PK modeling – at 0.48 x CBER standard (adjusted for IgG concentration) –At this specification level, IGIV given at 400 mg/kg, should provide serum trough levels of at least 240 mIU/ml. Data from CSL Behring for IGIV and IGSC affirmed likelihood of achieving trough levels greater than 240 mIU/ml with standard doses of Privigen (IGIV) and Vivaglobin (IGSC)

Questions for the Committee: 1.Do Committee members concur with the FDA proposal to lower the minimum measles antibody specification for IGIV and IGSC from 0.60 x CBER standard, to 0.48 x CBER standard? Yes: 13No: 1 (more data needed)

Question 1 - Discussion Risk to supply of rejecting lots exceeds the current risk of serious measles infections in PIDD patients When exposure is possible due to travel or contact with an infected person in U.S. –Travelers with PIDD should receive IGIV/IGSC before going to an endemic area –Need for clinician education concerning patient treatment in setting of possible or actual measles exposure Surveillance would be important to identify and investigate breakthrough cases in IGIV/IGSC recipients –Measles is a nationally notifiable disease (required by all states; reported to CDC)

Question 2 2. CBER is considering requesting additional studies to confirm that PIDD patients will achieve trough levels of measles antibodies above 120 mIU/mL if treated with IGIV and IGSC products that meet the proposed revised potency standard of > 0.48 x CBER standard. Do the Committee members agree that this information is needed? Yes: 13No: 1

Question 2 Committee Discussion More data would be useful to support conclusions of PK extrapolations –Trough levels of measles antibodies in IGIV/IGSC-treated patients, correlated with dose of anti-measles antibody administered –Data similar to CSL Behring data could supply additional assurance that patients will achieve a reasonable minimum titer of measles antibodies

Committee Comments Requested Please comment on the need for and feasibility of any alternative strategies that CBER should consider to reduce the likelihood of failed lots of IGIV and IGSC based on potency testing for measles antibodies in order to ensure availability of product for PIDD patients.

Additional Committee Comments on Alternative/complementary strategies PIDD patients traveling to measles-endemic areas should be infused prior to travel, preferably with high titer product. Education of physicians may be needed so that PIDD patients who have been exposed or may be exposed to measles can have dosing and/or dose timing adjustments. If exposed to measles, PIDD patients with profound T cell deficiencies should receive doses that achieve "sterilizing immunity" i.e. > 1000 mIU/mL.

Regulatory Pathway Manufacturers may voluntarily propose to change the measles antibody specification to 0.48 x CBER standard (adjusted for IgG concentration), as a Prior Approval Supplement Agree to report measles in a PIDD patient as a 15-day report to FDA Agree to labeling change that reflects the potential need for dosing alterations (timing, total dose) for a PIDD patient with potential or actual exposure to measles Post-marketing commitment to determine measles trough level titers in PIDD patients receiving a known dose of measles antibodies In context of upcoming, ongoing, or completed trial (with retention samples) for PIDD Alternatively, a separate stand-alone trial would also be acceptable Measles titers measured by functional assay

Regulatory Pathway - Outcomes Provides expedited path to changing measles antibody lot release specification –Abrogates loss of IGIV/IGSC lots due to specification failures Enhances likelihood of surveillance and investigation of measles cases in PIDD patients Provides information about measles exposure considerations in package insert Provides means of data collection to support that at least minimum protective titers would be attained –Although actual protective titers not known on a per-patient basis, failure to achieve > 120 mIU/ml would dictate that higher doses of IGIV or IGSC should be considered, especially in the setting of measles exposure.