The 110th meeting of the Blood Products Advisory Committee (BPAC) to the Food and Drug Administration (FDA) was convened in Silver Spring, Md., on July 31, 2014 to advise the FDA on the benefit to risk profile of Baxter Healthcare Corp.’s biologics license application for HyQvia [Immune Globulin Infusion 10% (Human) combined with Recombinant Human Hyaluronidase (rHuPH20)]] for the treatment of patients with primary immune deficiency disorders. In the afternoon, the Committee discussed reentry of blood donors who had been deferred on the basis of Chagas’ disease screening test results.
Topic 1 – Baxter Healthcare’s HyQvia
Primary immunodeficiency disease (PIDD) is a collection of hereditary immune system defects. This family of rare diseases is treated with life-long, repeated administration of immune globulin derived from human plasma. Current standard of care for many patients with PIDD is either intravenous (IV) therapy carried out every 3-4 weeks or subcutaneous (SC) therapy carried out weekly or biweekly. IV therapy must be performed by a health care provider, usually in a hospital, and can take 2-4 hours to administer. Systemic side effects are common with IV therapy, including aseptic meningitis. SC therapy is administered by the patient at home, requires 3-5 infusion sites and 1-2 hours per infusion. Baxter’s novel SC infusion therapy, currently under FDA review, is intended to be administered every 3-4 weeks at a single infusion site.
Review of product submitted for licensure
Baxter Healthcare presented HyQvia [Immune Globulin infusion 10% (Human) with Recombinant Human Hyaluronidase] for the treatment of PIDD. The addition of rHuPH20 increases the permeability and decreases the viscosity of the immune globulin infusion, allowing improved dispersion and absorption when administered SC. Patients need only use one infusion site once every 3-4 weeks. The FDA previously concluded that the efficacy of HyQvia had been established.
The FDA requested that the Committee review the benefit to risk profile of HyQvia, particularly as it related to the development of antibodies to rHuPH20 in some patients. Baxter, the FDA and experts on the antibody specific to Hyaluronidase (PH20) presented data. Current literature, preclinical models and non-clinical data were examined in detail. Much of this information is available on the BPAC Website.
FDA noted that rHuPH20 was immunogenic in 17 percent of patients with PIDD. These antibodies were not associated with specific adverse events, yet there was concern that the antibodies may bind to PH20 in native tissue, primarily in the testis but also in the brain, with an unknown safety impact. Antibodies to PH20 may be able to cross the blood-testis and blood-brain barriers in patients with PIDD due to their condition, allowing the antibodies to bind with native PH20. Other FDA concerns included:
- A subset of patients, who appear to be predisposed to rHuPH20 immunogenicity and breaking tolerance
- The tissue expression profile of PH20 in people has not been systematically collected. Therefore it is difficult to estimate the safety impact of immune targeting of native PH20 in tissue.
- Animal models may not be sufficient to predict safety of chronically-elevated anti-PH20 in patients with PIDD.
During the open public portion of the hearing, a number of patients and patient advocacy organization representatives addressed the benefits of having another option for the treatment of PIDD. This could allow patients and their caregivers the authority to balance their personal benefits and risks.
Committee discussion and vote
The Committee actively discussed two questions presented to them by the FDA.
“Do the available data indicate a favorable Benefit:Risk ratio for HyQvia, taking into consideration the antibodies detected against PH20 which bind human tissues namely, reproductive tract, neurological and gastrointestinal tract tissues?”
Much of the discussion related to prior commercial experience with rHuPH20, specific clinical trial information and post-marketing follow-up required for the European release of HyQvia. Hylenex, the commercially available form of rHuPH20, has been on the market since 2005. Hylenex is administered in a lower dose than that proposed for HyQvia. To date, more than 400,000 individual doses have been administered and 32 patients are being followed through a post-marketing safety study with chronic exposure data available for two years.
Postmarketing studies have been proposed to evaluate the safety profile of HyQvia in the US. These studies parallel the postmarketing surveillance protocols underway in Europe. Six months into the European surveillance study no events have been reported that would address any theoretical safety risk due to antibodies to PH20.
Patient enrollment in the proposed US postmarketing study was discussed briefly. The surveillance program will include data collection on pregnancy ratios among patients. It is expected that it will take at least five years of product use to generate adequate data to determine whether HyQvia may have an effect on fertility.
In summary, the Committee felt that there was clinical benefit to this product, in addition to patient convenience. Regarding FDA concerns, the focus should shift to what could be done to improve the Benefit:Risk ratio. They noted that drugs with significant side effects have been approved for marketing in the US. The product sponsor will need to ensure that any accepted risks would be communicated consistently to patients.
Vote: 15 Yes, 1 No. The nonvoting industry representative participated in the discussion but did not indicate a preference.
“If approved, would the Benefit:Risk assessment be influenced by risk mitigation strategies, including:
- restricted labeling for certain Primary Immunodeficiency population subsets, e.g., pregnant women, male children, patients with inflammatory conditions involving the nervous system or gastrointestinal tract;
- implementation of risk communication strategies to help subjects and physicians make informed decisions about whether to use HyQvia;
- monitoring for emergency and/or increasing levels of anti-PH20 antibodies?”
Strategies discussed to mitigate risk included educational labeling — such as suggesting that men consider freezing sperm prior to starting treatment — and postmarketing surveillance. There was a lack of data to support restrictive labeling, which would preclude postmarketing data collection in the populations of concern.
Antibody monitoring of all patients was also discussed. Concern was voiced that antibody monitoring was not indicated for patient follow-up and would be difficult without a routine test available for antibodies to PH20. The sponsor indicated that the postmarketing study would monitor antibody levels and that patients desiring that level of follow-up would be encouraged to enroll.
2a. Restrictive labeling: 5 Yes, 9 No, and two abstention. The nonvoting industry representative indicated Yes.
2b. Risk communication strategies: 16 Yes. The nonvoting industry representative indicated Yes.
2c. Active monitoring of antibody levels: 6 Yes, 10 No. The nonvoting industry representative indicated No.
Topic 2 – Reentry of blood donors deferred on the basis of screening test results for antibodies to Trypanosoma cruzi
Screening of blood donors for Trypanosoma cruzi (T. cruzi), the causative agent for Chagas’ disease began on a voluntary basis in the US in 2007. FDA recommendations in 2010 concurred with what had become the industry practice of one-time testing of each donor for antibodies to T. cruzi. Currently, donor testing is performed using either of two automated screening assays, the ORTHO T. cruzi enzyme-linked immunosorbent assay (ELISA) or the ABBOTT PRISM Chagas assay. Both are licensed for screening blood donors for antibodies to T. cruzi. Donor samples with repeat reactive (RR) results are confirmed either with the unlicensed T. cruzi radioimmune precipitation assay (RIPA) or with the ABBOTT Enzyme Strip Assay (ESA) Chagas test, which was licensed as an additional, more specific test for antibodies to T. cruzi in 2011. Currently, blood donors who test repeatedly reactive on a licensed screening assay are indefinitely deferred from donating.
Data reported by the AABB Chagas’ Biovigilance Network indicate that more than 75 percent of RR donations are not confirmed as positive. As of June 2014, more than 7,000 donors remain indefinitely deferred due to unconfirmed repeat reactivity on a licensed screening assay.
At the time of the 2010 FDA guidance, there was no licensed supplemental test available to consider for use in a reentry algorithm. FDA has now analyzed data from donor follow-up studies performed by the American Red Cross and developed candidate algorithms to reenter blood donors with falsely reactive screening results. Of particular concern to the FDA in drafting the algorithms is the fact that reentered donors will not be tested at future donations.
Abbott Enzyme Strip Assay (ESA) Chagas Test
Representatives from Abbott Laboratories presented information on the FDA-licensed Abbott in vitro ESA Chagas test. The test uses the same four hybrid recombinant proteins used in the ABBOTT PRISM Chagas assay. These four proteins contain 14 distinct antigenic regions, which are recognized by antibodies present in persons with acute and chronic T. cruzi infections. The ESA test strip contains seven active regions: the four test proteins, two onboard calibration marks and a control stripe. The ESA is a manual test kit that is subjectively read by a technician, who determines the intensity of the test stripes compared with the low and high calibration marks.
If two or more bands are present, and at least one band is graded as having intensity greater than or equal to 1+, the test is considered positive. If no bands are visible, or if only one band is visible with faint intensity (+/-), then the test is considered negative. A single band graded as greater than 1+ or multiple faint (+/-) intensity bands are considered indeterminate.
American Red Cross experience with Chagas screening, supplemental testing and donor follow-up
Susan Stramer, Ph.D., of the American Red Cross presented the Red Cross’ experience testing for antibodies to T. cruzi in a seven-year period during which the organization used all four of the research and licensed tests described above. The Red Cross initiated universal blood donation screening for antibodies to T. cruzi in 2007. Universal testing was replaced in 2009 by selective testing, in which each donor is qualified for future donations by a single nonreactive test result. Three testing algorithms have been employed during the past 7 years.
- Before August 2011, samples were tested using the ORTHO ELISA, and any RR samples were tested using the RIPA.
- From September 2011 through July 2012, samples were tested using the ABBOTT PRISM. Any RR samples were tested using the ORTHO ELISA, and only concordant RR samples were further tested using the RIPA.
- From August 2012 through January 2014, samples were tested with the ABBOTT PRISM, and any RR samples were tested with both the ORTHO ELISA and ABBOTT ESA.
Current ABBOTT ESA labeling has sample suitability criteria which limits sample storage to a maximum of 14 days from collection. [Abbott representatives indicated that a request to the FDA to extend maximum frozen (-20 degrees) sample storage to two months is in process.]
Over a period of seven years, the American Red Cross screened more than 24 million donations. 5,447 units were RR for a rate of 0.023 percent, and 678, or 12 percent, of those were confirmed positive. The overall specificity of the testing was 99.98 percent. The positive predictive value varied by algorithm and was greatest for the ORTHO ELISA/RIPA group at 20 percent.
In order to establish comparable data for a subset of donors, plasma unit and follow-up samples from selected confirmed and unconfirmed donors were tested with all three licensed assays. Secondary analysis was performed using only ESA-negative RR donors regardless of primary screening test used, with follow-up samples tested using all three licensed assays. [The data was supplied to FDA and used to support development of donor reentry algorithms.] Dr. Stramer noted in her presentation that less than 100 percent of RR, confirmed positive donors at index were RR when retested, indicating false positivity within each algorithm. Less than 50 percent of RR-confirmed negative donors were RR when retested and none confirmed positive by RIPA/ESA, indicating that many donors should be able to be reentered and confirming the need for a reentry algorithm.
The American Red Cross experience demonstrated that supplemental T.cruzi testing algorithms are enhanced by the use of a second licensed screening test. Since no RR samples in any unconfirmed group confirmed positive when further tested, non-reactivity on both screening tests — ORTHO ELISA and ABBOTT PRISM — in a follow-up sample should be sufficient for reentry following an index ABBOTT ESA negative test result. Proposed FDA scenario 4, described below, offers broad antigen representation by using both companies’ assays and provides accessibility via the automated aspect of the assays. FDA was asked to consider allowing reentry of donors with indeterminate RIPA or ESA results on index samples, as data was presented for donors that showed no further serologic activity upon repeat testing of the index or follow-up samples.
Review of possible reentry algorithms
The FDA proposed five reentry algorithms — one of which was indicated as the FDA preference — for the reentry of blood donors deferred because of RR results on a screening assay. The five scenarios below, based on analyses of donor follow-up studies performed by the American Red Cross, are described in Topic 2: Issue Summary and summarized in Table 5. Donors eligible for reentry would have a RR screening test and either a negative RIPA or ESA Chagas supplemental test, or no confirmatory test performed on their index donation. Deferred donors would provide a follow-up blood sample no less than six months after the index donation. This is expected to be sufficient time to allow for seroconversion in recently exposed donors or to allow resolution of any cross-reacting medical conditions that may have caused the repeat reactivity.
- FDA Preferred Scenario: A follow-up sample would be tested with BOTH licensed screening tests. If non-reactive (NR) on BOTH screening tests, the ESA supplemental test would be performed and also would need to be negative. Repeat reactivity on either screening test or a positive or indeterminate result on the ESA would result in a permanent deferral. The FDA provided data from a study completed by the American Red Cross, in which 238 donors, who were RR on a screening test and negative on the ESA Chagas supplemental test, were evaluated for reentry. Forty-eight percent of donors met the reentry requirements. This proposal was perceived to provide the lowest chance of reentering a donor with any risk.
- Scenario 1: A sample from the index donation, which was RR on one of the screening tests, is tested using the alternate screening test (had not been used to test the index sample). If NR on the alternate screening test, the donor would be reentered. Ninety-nine percent of donors met the reentry requirements. A portion of the donors provided follow-up samples and of those, approximately 50 percent were reactive on at least one of the licensed tests (usually the primary screening assay that was used with the initial index donation) and were considered by FDA to be reentered with possible risk.
- Scenario 2: A follow-up sample would be tested with the alternate licensed screening test (had not been used to test the index sample) and the ESA supplemental test. Results for both tests performed on the follow-up sample would need to be NR or negative for reentry. Ninety-five percent of donors met the reentry requirements. Forty-nine percent of those donors were RR when tested again with the primary screening test (had been used to test the index donation) and were considered by FDA to be reentered with possible risk.
- Scenario 3: A follow-up sample would be tested with the licensed screening test that had been used to test the index sample — the primary assay— and the ESA supplemental test. Results for both tests used for the follow-up sample would need to be NR or negative for reentry. Forty-nine percent of donors met the reentry requirements. Two percent of those donors were RR, when tested using the alternate screening test and were considered by FDA to be reentered with possible risk.
- Scenario 4: A follow-up sample would be tested with both licensed screening tests. Results from both tests used for the follow-up sample would need to be NR for reentry. Forty-nine percent of donors met the reentry requirements. Supplemental testing was completed with the ESA and less than 2 percent of reentered donors were considered by FDA to be reentered with possible risk.
- There was some discussion during the open public hearing on whether a confirmatory or supplemental test would be required for reentry if the index donation occurred prior to licensure of the supplemental assay.
Dr. Louis Katz, MD, Chair of the AABB Transfusion Transmitted Diseases Committee presented a joint statement from AABB, America’s Blood Centers, and the American Red Cross.
“Our organizations support the use of alternative reentry scenario 4. Donors with repeat reactivity on a screening test and a negative licensed confirmatory test at index (or a negative research RIPA at index or untested with a supplemental assay) are retested at an interval of several months after the index donation using both licensed screening tests. If nonreactive on both, they may be reentered into the eligible donor pool. Scenario 4 has optimal sensitivity based on the use of two screening tests containing both parasite-derived lysate antigens and recombinant antigens configured in automated assays using an objective interpretation. This scenario is accessible to most testing labs in the US (vs. the ESA which is not and which poses logistical challenges based on testing a follow-up sample within the time frame specified within the product insert).
The FDA has classified as “less safe” two donors who were screened repeat reactive and ESA negative at index. These donors were negative on both screening tests when the index samples were retested, and again demonstrated no reactivity by both screening tests at follow-up, but had borderline reactivity with the ESA, a subjective assay. There is no evidence that such donors are infected or infectious. Such components, negative on screening tests, are transfused daily in the US, based on clinical specificity studies summarized in Tables II and III of the licensed ESA package insert; no transmissions have ever been documented from such units. Based on published lookback studies in the United States summarized by Dr. Susan Stramer, transmission rates are less than 1 percent, even from confirmed-positive donors. Further, fewer than 10 percent of confirmed-positive donors have detectable parasitemia when examined by hemoculture.
The agency’s preferred algorithm requires the use of the licensed ESA, in addition to both screening tests, on a follow-up sample, regardless of negative ESA results at index. This assumes that there are cases in which screening reactivity at index will disappear at follow-up, but supplemental reactivity will be preserved or enhanced. The rationale for the use of the ESA following two negative screening tests at follow-up appears to be based on the FDA’s assertion that ‘the relative analytical sensitivity of the ABBOTT ESA Chagas assay was shown to be greater than that of the two licensed screening tests’. Although this is stated in the FDA issues summary, we can find no data to support that statement. It appears the assertion is based on the results obtained from dilution series of highly reactive sera that are not characteristic of the donor samples of interest in this discussion. It also has been discussed at this and prior BPAC meetings that no recent seroconverting US blood donor has yet to be documented. Along these lines, donors with an indeterminate ESA or prior indeterminate RIPA result should not be discarded as potentially infected, if follow-up data demonstrate otherwise. These donors should not be permanently deferred but should have an opportunity to be re-entered based on testing of subsequent samples.
He and other public session speakers noted that the most important issue of the day was for the BPAC to support FDA’s efforts to make available a reentry algorithm. They noted that the ESA is an important tool in confirming initial results and counseling blood donors; as a reentry tool it is less vital.
Committee discussion and vote
The Committee held active discussion on the three questions presented to them by the FDA.
- Please discuss whether the available scientific data support a conclusion that the FDA proposed reentry algorithm could be used to safely reenter deferred donors who on follow-up testing are found non-reactive on screening tests and negative on the licensed supplemental test for antibodies to T. cruzi.
- Please discuss whether FDA should consider any of the suggested alternative reentry algorithms in preference to its current proposal.
- Do the members concur with the FDA proposed algorithm?
The members of the BPAC recognized the FDA’s efforts in this matter and confirmed that there was an obligation to try to bring donors with false positive test results back into the donor pool. There was general support that a reentry algorithm is needed and that the available assays could provide adequate risk reduction.
The FDA’s protocol was considered to provide the greatest risk reduction by requiring NR or negative results on all three assays at the time of reentry. Support was also voiced for both reentry scenarios 3 and 4, which would require a follow-up sample to be tested either by the primary screening test again and the ESA (3) or by both licensed screening tests (4).
There was general agreement within the Committee that a follow-up sample collected some months after the index donation was required; that donors should not be reentered based on their index sample.
There was no vote held on question 3. FDA representatives noted that they had heard adequate discussion on the various scenarios and did not need a vote on Question 3.