Members of the
Cellular, Tissue and Gene Therapies Advisory Committee to the U.S. Food and Drug Administration convened for their 53rd meeting in Gaithersburg, Md., on Sept. 22-23 to advise the FDA on two issues: the biologics license application, or BLA, for umbilical cord blood, submitted by New York Blood Center, or NYBC, and the humanitarian device exemption, or HDE, for the CliniMACS CD34 Selection System of Miltenyi Biotec Inc.
BLA 125397, Umbilical Cord Blood, New York Blood Center, indicated for hematologic malignancies, bone marrow failure, primary immunodeficiency diseases, beta-thalassemia, Hurler syndrome, Krabbe disease and X-linked adrenoleukodystrophy
NYBC submitted a BLA for HemaCord, or hematopoietic progenitor cells-cord, HPC-C, for the use of hematopoietic stem cell transplantation for the treatment of patients with hematologic malignancies, Hurler syndrome, Krabbe disease, X-linked adrenoleukodystrophy, primary immunodeficiency diseases, bone marrow failure and beta-thalassemia.
briefing document provided to the committee included the efficacy document submitted by NYBC, a review by NYBC of safety outcomes, information available in the public domain and the summary of the FDA review of NYBC’s safety data.
The meeting began with a presentation by Celia Witten, MD, PhD, director of the Center for Biologics, Evaluation and Research’s Office of Cellular, Tissue and Gene Therapies (OCTGT), on the FDA’s regulation of cord blood. Witten commented that the CTGTAC meeting was the public forum for discussion of the BLA, which is the most critical step of the BLA approval process. Witten noted that the FDA was asking the committee to discuss the effectiveness of HPC-C for hematopoietic reconstitution in patients with certain diseases.
Andromachi Scaradavou, MD, NYBC’s National Cord Blood Program medical director, and Pablo Rubinstein, MD, NCBP program director, provided a detailed review of the NCBP cord blood program, which was founded in 1993, as well as the efficacy and safety data supporting the BLA application. NCBP distributes up to 1,000 cord-blood units per year. NYCB currently processes approximately 4,000 units of cord blood per year and currently stores more than 50,000 units.
Scaradavou and Rubinstein summarized the clinical results of 3,432 patients and 3,946 NCBP cord-blood units included in the BLA. The results of the comparison studies indicate that disease-free survival after transplantation of unrelated matched bone marrow or cord blood is similar and that the preliminatry results are very encouraging regarding improved leukemia-free survival after double-unit cord-blood grafts.
John Hyde, MD, PhD, medical officer, OCTGT, presented the FDA efficacy review of the indications being considered in the BLA. Donna Przepiorka, MD, PhD, medical officer, OCTGT, reviewed the safety data.
During the open comment session, Joanne Kurtzburg, MD, of Duke University and Carolinas Cord Blood Bank presented data from Duke concerning the transplantation of HPC-C for some of the indicated diseases. Kurtzburg also introduced three patients who had been transplanted with HPC-C and discussed their outcomes.
Committee Questions and Discussion
Regarding each claim listed in the BLA:
- Does the evidence of effectiveness in acute leukemia support the use of hematopoietic progenitor cells-cord, or HPC-Cs, for hematopoietic reconstitution in patients with other hematologic malignancies?
- What is the risk-benefit profile for the use of HPC-C to treat Hurler syndrome, or mucopolysaccharidosis I; Krabbe disease; and X-linked adrenoleukodystrophy?
- What is the evidence of effectiveness for primary immunodeficiency diseases, bone marrow failure and hematopoietic reconstitution in patients with beta-thalassemia?
The committee discussed the risk-benefit ratio of using cord blood as a treatment option, considering time constraints, dosage availability and transplantation antigen matches, and decided that cord blood should be an additional option in all cases where bone marrow therapy is indicated.
1. a. The product label can advise practicing physicians on dosing. For the purpose of labeling, please discuss any specific factors (e.g., the indication; degree of HLA matching) that you recommend that a practicing physician consider to determine the appropriate dose for a specific patient.
b. Any recommendation that you have for a minimum cell dose, either for a specific indication or for all indications.
The committee recommended that a practicing physician consider 4-5 HLA antigen matches when determining the appropriate dose for a patient and a minimum requirement of 2.5 x 107 total nucleated cells for the most positive outcome in all indications.
2. a. Please discuss any additional significant safety concerns associated with HPC-C transplantation, for any or all of the specified indications.
b. For the purpose of labeling, please discuss any actions (e.g., unit selection; patient selection; premedications or pre-emptive therapies; patient monitoring; instructions or warnings in the product label) that you recommend to mitigate the risk for the following:
- infusion reactions
- any additional safety concern (e.g., graft failure; graft-versus-host disease) identified above.
The committee recommended that the applicant should consider possibly including an infusion rate on the label. The committee suggested that a statement be included indicating that the HPC-C product should be handled only by physicians experienced in transplantations.
3. a. The model is constructed to assess an individual safety outcome. Please discuss which safety outcomes (e.g., graft failure; graft-versus-host disease; day-100 mortality) would be most important to model.
b. Please identify any issues (e.g., differences in era of transplantation; differences by diagnosis) that might limit the application of such a mathematical model.
The committee recommended that FDA use graft failure and day-100 mortality, with graft failure being more important.
HDE BH110018, CliniMACS CD34 Selection System, Miltenyi Biotec, for processing allogeneic HLA-matched hematopoietic progenitor cells-apheresis (HPC-A) from a related donor to obtain a CD34+cell population intended for hematopoietic reconstitution following a myeloablative preparative regimen without the need for additional graft-versus-host disease prophylaxis in patients with acute myelogenous leukemia in first or second morphologic complete remission
Witten presented the issue and questions to be discussed by the committee for the Miltenyi proposal to use the CliniMACS CD34 Selection System for processing HPC-A from an HLA-matched donor for hematopoietic reconstitution following a myeloablative preparative regimen without the need for additional graft-versus-host disease prophylaxis for patients with acute myelogenous leukemia.
Theodore Stevens, MS, RAC, associate director for information management at OCTGT, described the purpose of a humaniarian device exemption, or HDE, and the process required for HDE approval. The intent of an HDE is to provide an incentive for development of devices intended for treatment or diagnosis in small patient populations where otherwise a device manufacturer’s research and development costs could exceed market returns. To obtain approval for an HDE, the manufacturer must show that the device does not expose patients to unreasonable risk of illness or injury and that the probable benefit outweighs the risks of using the device, taking into account the probable risks and benefits of alternative therapies. Approval of an HDE authorizes the marketing of a humanitarian use device, or HUD. Approval by an institutional review board is required before the device can be used, and labeling must clearly identify the device as a HUD and state that effectiveness for that indication has not been demonstrated.
Kai Pinkernell, MD, head of clinical development at Miltenyi, summarized the safety and probable benefit of the CliniMACS system. Pinkernell explained that the function of the device is to deplete cells that may cause graft-versus-host disease, thus allowing for transplantation to proceed without the need for immunosuppressive drugs.
The data presented by Nancy Johansen, director of Regulatory Affairs at Miltenyi, included a brief introduction to Miltenyi Biotec Inc. and the CliniMACS CD34 Reagent System. Miltenyi was founded in 1989 and is composed of a diversified group of biotechnology companies with a business focus on cellular technologies. The CliniMACS CD34 Reagent System is a medical device system that is used in vitro to select and enrich CD34+ target cells from heterogeneous hematologic cell populations where clinically indicated.
Steven Devine, MD, from Ohio State University presented a summary of the data from the single-arm, multicenter study of T-cell depleted peripheral blood stem cells isolated by the CliniMACS system (BMT CTN 0303).
Marcelo Pasquini, MD, MS, from the Center for International Blood and Marrow Transplant Research, presented the
summary of the comparison of the outcomes of the CliniMACS system (BMT CTN 0303) versus the outcomes of the control cohort (BMT CTN 0101), a randomized, double-blind multicenter trial comparing two drugs for the prevention of invasive fungal infections in allogeneic blood and marrow transplant patients. Pasquini reported that the study compared engraftment, the incidence and severity of graft-versus-host disease, relapse, disease-free survival, transplant-related mortality and overall survival. Summary highlights included:
The cumulative incidence of neutrophil engraftment by day 30 was 100 percent (BMT CTN 0303) and 96.4 percent (BMT CTN 0101). There was no significant decrease in acute graft-versus-host disease; however, the risk of chronic graft-versus-host disease was significantly decreased in patients treated in the BMT CTN 0303 study.
In regard to relapse, there was no statistically significant difference between the two protocols. The risk of relapse estimates at six months and one year for all patients transplanted in the BMT CTN 0303 study were 6.8 percent and 20.6 percent, compared to 13.1 percent and 20.3 percent in the BMT CTN 0101 study.
The one-year cumulative incidence of transplant-related mortality did not demonstrate a statistically significant difference. The rates were 13.6 percent for the BMT CTN 0303 study and 16.7 percent for the BMT CTN 0101 study.
The disease-free survival rate at six months posttransplant was 81.8 percent in the BMT CTN 0303 study and 16.9 percent in the BMT CTN 0101 study. This result was not statistically significantly different.
The one-year overall survival rate for the BMT CTN 0303 study was 77.3 percent and 73.8 percent for the BMT CTN 0101 study.
Committee Discussion and Questions for Voting
1: Please discuss the safety of transplantation using CD 34-selected HPC-A using the CliniMACS CD34 Reagent System, especially related to graft failure, relapse, infections and treatment-related mortality at one year.
The committee agreed that the CliniMACS system is very safe in relation to graft failure and showed a lower rate for mortality at one year.
Question for voting:
1. Is there reasonable assurance that the CliniMACS CD34 Reagent System is safe for use in order to obtain a CD34+ cell-enriched population intended for hematopoietic reconstitution following a myeloablative preparative regimen without the need for additional graft-vs-host disease prophylaxis in patients with acute myeloid leukemia in first or second morphologic complete remission?
Comments: Benefits far outweigh the risk, and infection was slightly increased but manageable.
2. Considering the limitations of the data, please discuss whether the data support a finding of probable benefit for use of the CliniMACS CD34 Reagent System for processing allogeneic HLA-matched hematopoietic progenitor cells-apheresis (HPC-A) from a related donor to obtain a CD34+ cell-enriched population intended for hematopoietic reconstitution following a myeloablative preparative regimen in patients with acute myeloid leukemia.
The data show that the rate of graft-versus-host disease was no worse using the CliniMACS system and there also was no need to use immunosuppressive drugs. T-cell depletion is the primary reason for the decrease of graft-versus-host disease.
Question for voting:
2. Is there reasonable assurance that the CliniMACS CD34 Reagent System provides probable benefit by obtaining a CD34+ cell-enriched population for patients with acute myeloid leukemia in first or second morphologic complete remission undergoing a myeloablative preparative regimen?
3. The applicant has proposed to include patients in complete remission 1 (CR1) and complete remission 2 (CR2) in the indication for their device. Please discuss whether the totality of the data support a reasonable assurance of probable benefit for patients in both CR1 and CR2, or if the label indication should be restricted to patients in CR1.
The committee suggested that the label should reference the BMT CTN 0303 study and include the data from the CR1 and CR2 status. The explanation should include that the data for CR2 is small and that CR2 patients have a higher relapse rate at one year.
4. Please discuss whether there would be any limitation in generalizing the results of BMT CTN 0303 to a pediatric population.
The committee commented that because the presented data included no pediatric patients, it could not generalize the results.
5. a. Please discuss the adequacy of the user instructions and device performance data provided to demonstrate end users will be able to use the CliniMACS CD34 Reagent System, if approved, for processing HPC-A collected from an HLA-matched related donor for recipient hematopoietic reconstitution.
The committee agreed that the user instructions and device performance data are adequate for end users to use the CliniMACS system. The end users would be trained and experienced in transplantations.
b. Please discuss any recommendations for establishing device performance criteria.
The committee had no further recommendations.