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Summary Basis for Regulatory Action, May 30, 2013 - ALLOCORD

Date:  May 30, 2013

From: Brent McCright, Ph.D., Chair of the Review Committee 

BLA/ STN#: 125413

Applicant Name: SSM Cardinal Glennon Children’s Medical Center, St. Louis Cord Blood Bank

Date of Submission: October 19, 2011 (original submission); December 13, 2012 (response to FDA Complete Response letter dated August 16, 2012)

PDUFA Goal Date: June 15, 2013

Proprietary Name: ALLOCORD

Non-Proprietary name:  HPC, Cord Blood

Indication:  ALLOCORD is an allogeneic cord blood hematopoietic progenitor cell therapy intended for use in unrelated donor hematopoietic progenitor cell transplantation procedures in conjunction with an appropriate preparative regimen for hematopoietic and immunologic reconstitution in patients with disorders affecting the hematopoietic system that are inherited, acquired, or result from myeloablative treatment.  The risk benefit assessment for an individual patient depends on the patient characteristics, including disease, stage, risk factors, and specific manifestations of the disease, on characteristics of the graft, and on other available treatments or types of hematopoietic progenitor cells.

Recommended Action:  Approval

Signatory Authorities Action:

Offices Signatory Authority:

Celia Witten, PhD, MD, Office Director, Office of Cellular, Tissue, and Gene Therapies  

X I concur with the summary review.
□ I concur with the summary review and include a separate review to add further analysis.
□ I do not concur with the summary review and include a separate review.

Mary Malarkey, Director, Office of Compliance and Biologics Quality 

X I concur with the summary review.
□ I concur with the summary review and include a separate review to add further analysis.
□ I do not concur with the summary review and include a separate review.

Material Reviewed/ Consulted Specific Documentation Used in Developing the SBRA

Material Reviewed/ Consulted 

Reviewer Name – Document(s) Date

CMC Review

16- Aug-2012 McCright, Niland, Karandish, Ghosh
22-May-2013 McCright, Niland, Karandish, Ghosh

CBER Lot Release

22-May-2013 Campbell

Facilities Review

11-Feb-2013 and 14 Aug 2012 Waites

Environmental Assessment

08-Apr-2013 Waites

Establishment Inspection Report

20-Aug-2012 Waites

Nonclinical Pharmacology/Toxicology Review

21-June-2012 Hoque

Clinical Review

12-Aug-2012 Xu

Statistical Review

12-Aug-2012 Rees

Advertising and Promotional Labeling Review

27-Mar-2013 and 15-Feb-2013 Nguyen

Division Director’s Secondary CMC Review

23-May-2013 Benton, Puri


 

Table of Contents

1. Introduction
2. Background
3. Chemistry Manufacturing and Controls (CMC)
a)     Product Quality
b)     CBER Lot Release
c)     Facilities review/inspection
d)     Environmental Assessment
4. Nonclinical Pharmacology/Toxicology
5. Clinical Pharmacology
6. Clinical / Statistical
a)     Clinical Program
b)     Pediatrics
c)     Other Special Populations
7. Safety
a)     Infusion Reactions
b)     Adverse Reactions other than Infusion Reactions
8. Advisory Committee Meeting
9. Other Relevant Regulatory Issues
10. Labeling
11. Recommendations and Risk / Benefit Assessment
a)     Recommended Regulatory Action
b)     Risk / Benefit Assessment
c)     Recommendation for Postmarketing Risk Management Activities
d)     Recommendation for Postmarketing Activities


 1. Introduction

Biologics License Application (BLA) STN#125413 is for ALLOCORD (Hematopoietic Progenitor Cells (HPC), Cord Blood) manufactured by the St. Louis Cord Blood Bank (SLCBB) of the SSM Cardinal Glennon Children’s Medical Center.  ALLOCORD is an allogeneic cord blood hematopoietic progenitor cell therapy indicated for use in unrelated donor hematopoietic progenitor cell transplantation procedures in conjunction with an appropriate preparative regimen for hematopoietic and immunologic reconstitution in patients with disorders affecting the hematopoietic system that are inherited, acquired, or result from myeloablative treatment.

The risk-benefit assessment for an individual patient depends on the patient characteristics, including disease, stage, risk factors, and specific manifestations of the disease, on characteristics of the graft, and on other available treatments or types of hematopoietic progenitor cells.

The applicant followed FDA guidance recommendations, and cited data in the dockets (FDA-1997-N-0010 and FDA-2006-D-0157) as primary evidence of the efficacy and safety of ALLOCORD.  The applicant also submitted its own observational dataset, which is used as supplementary data to support the efficacy and safety of the product.

This document summarizes the basis for the approval of ALLOCORD.  All findings identified during the review of the BLA have been adequately addressed.  The review team recommends marketing approval of the product.

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 2. Background

HPC, Cord Blood is rich in hematopoietic progenitor cells, and has been used in the treatment of a variety of disorders, including hematologic malignancies, metabolic disorders, and immunodeficiencies.

Regulatory History
FDA developed and finalized guidance for industry entitled Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications (October 2009).  This guidance provides recommendations for the submission of a BLA for placental/umbilical cord blood.  In an October 2009 Federal Register notice, FDA announced that manufacturers of cord blood will be required to have an approved BLA or IND in effect for unrelated cord blood shipped after October 20, 2011.  

On October 19, 2011, the SSM Cardinal Glennon Children’s Medical Center submitted a BLA application to request licensure of HPC, Cord Blood manufactured at both the St. Louis Cord Blood Bank manufacturing site located in St. Louis, Missouri and the St. Luke’s Cancer Institute manufacturing site located in Kansas City, Missouri.  The original application was not granted approval because of CMC and facility-related deficiencies identified during the review process and the pre-license manufacturing site inspections.  A Complete Response (CR) letter was sent to the SSM Cardinal Glennon Children's Medical Center on August 16, 2012.  On December 13, 2012, the applicant submitted a complete response to our CR letter comments.  As part of their response they decided to withdraw the St. Luke’s Cancer Institute (SLCI) manufacturing site from the application.  The December 13, 2012 amendment and subsequent amendments addressed adequately all of the outstanding issues from the FDA CR letter.   

The BLA proposed the following indication: for use in unrelated donor hematopoietic progenitor cell transplantation procedures in conjunction with an appropriate preparative regimen for hematopoietic and immunologic reconstitution in patients with disorders affecting the hematopoietic system that are inherited, acquired, or result from myeloablative treatment. 

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 3. Chemistry Manufacturing and Controls (CMC)

  1. Product Quality

Product Description

HPC, Cord Blood is manufactured by the St. Louis Cord Blood Bank (SLCBB) of the SSM Cardinal Glennon Children’s Medical Center.  The proprietary name ALLOCORD was reviewed by CBER and found to be acceptable.  The manufacture of ALLOCORD at the SLCBB manufacturing site is consistent with recommendations made in the FDA licensure guidance.

Mothers who consent to donate their newborn’s cord blood for public banking are screened and tested for communicable infectious diseases per regulations in 21 CFR 1271 Subpart C. ALLOCORD is processed from cord blood collected from mothers who screen and test negative for the relevant communicable disease markers.  A positive CMV result is allowed, and the CMV result will be reported to the transplant center when the lot of ALLOCORD is selected.  The applicant has arrangements with approximately 30 hospitals in Missouri and Illinois to collect cord blood.  The collected cord blood units are transported to the SLCBB manufacturing site by dedicated couriers using validated and temperature-monitored shipping containers.

ALLOCORD is processed using the PrepaCyte-CB kit which is FDA cleared (510(k) BK070067) for cord blood processing (510(k) BK070067.  PrepaCyte-CB processing reduces the cord blood unit’s red blood cell (RBC) count and plasma volume.  The volume of the final product is approximately 35 mls and contains 10% DMSO, 1% Dextran 40, approximately 42% PrepaCyte-CB, and approximately 10% citrate-phosphate-dextrose.  Each lot is frozen using a -------(b)(4)------ freezing process and then stored in either vapor or liquid phase of liquid nitrogen (≤ -150oC).  The final product is tested for purity, identity, sterility, and potency.  ALLOCORD will have a 3-year dating period from the date of cryopreservation.

ALLOCORD is shipped frozen in special shipping containers (dry-shippers) designed to maintain a controlled environment and a very low temperature (≤ -150oC).  Shipping must be completed within (b)(4) and temperature is electronically monitored and recorded for the entire transit time.

The thawing and preparation procedures have been validated.  Directions for thawing are appended to the end of the prescribing information in the section “Instructions for Preparation for Infusion”, and will be included with each shipped lot of ALLOCORD.

Manufacturing Controls

Process and product controls are in place to assure the quality of ALLOCORD. There are specified time limits for all manufacturing process steps; cord blood is processed and frozen within 48 hours of collection.  --------------------------------------------------(b)(4)-----------------------------------------------------------.  A summary of the lot release tests performed on each lot of ALLOCORD is shown in Table 1.  Infectious disease testing is performed on a maternal blood sample; hemoglobin analysis, HLA typing, and ABO/Rh typing are performed on (b)(4)processing cord blood samples; sterility testing is performed on the -------------------------------(b)(4)-------------------------; and the rest of the testing is performed on (b)(4)processing cord blood samples.  All lot release tests must meet specifications for the product to be released into the search inventory.  Confirmatory HLA typing is performed on an attached segment at the time of release for transplantation.

Table 1: Lot release acceptance criteria for ALLOCORD

Product CharacteristicsTestingHPC, Cord Blood (pre-cryopreservation) acceptance criteriaTest Method
SafetyInfectious disease -21CFR 1271.45 thru 1271.90On maternal blood sample within 7 days of birth. 21CFR1271.80(a)(b) All tests negative(CMV results are recorded)Performed using FDA licensed or approved test kits.
Sterility – Bacterial/fungal culturesNo growth-----------------------------------(b)(4)--------
HemoglobinNo homozygous hemoglobinopathy-----------------------------------(b)(4)--------
  Purity and PotencyTotal nucleated cells (TNC)≥ 5.0 x 108 TNC/unitCalculated using the    -----(b)(4)-----
Viability nucleated cells≥ 85%---------(b)(4)--------
Viable CD34+ cell count≥ 1.25 x 106 / unitDetermined by ----------(b)(4)------
Colony Forming Units (CFU)-----------------------------------(b)(4)-------------------------------------------(b)(4)--------
  IdentityHLA typing (Confirmatory HLA typing Required*)   Maternal HLAHLA-A, B, C Antigens –               -------(b)(4)---------------------- HLA-DRB1, HLA-DQB1 Antigens –    ---(b)(4)---- Haplotype match-----------------------------------(b)(4)---------------------  
ABO and RhMust match pre and post processing---------------(b)(4)-----------------------

*Prior to release for transplantation

Manufacturing Risks

The greatest risks associated with the manufacture of ALLOCORD are 1) the risk of transmitting infectious diseases, 2) the risk of product contamination, particularly during collection of the cord blood and also during processing, and 3) the potential for loss in product potency during cryostorage or thawing.  These risks are mitigated by various approaches.

To address infectious disease risks, medical records are reviewed for high-risk exclusions, and mothers of the newborn donors are also screened and tested for infectious diseases according to 21 CFR 1271 regulations.  Cord blood collection is performed in delivery suites.  The collection staff are trained to use aseptic technique and appropriate gowning, and collect one cord blood unit at a time.

Each collected cord blood unit is given a unique bar code ID number (ISBT 128) which is both machine and manually readable.  This bar code is associated with all test results (maternal and cord blood) as well as the matched patient data.

To address contamination risks, collection and processing personnel are trained appropriately.  The processing methods have been validated to ensure aseptic processing, and the cryoprotectant is added to the processed cord blood using aseptic technique within a   ------(b)(4)-------.  Post-processing samples are tested for microbial contamination and must be negative.

To preserve cell potency, ALLOCORD is frozen using a ------(b)(4)----- freezing process and then stored in either vapor or liquid phase of the liquid nitrogen freezer (≤ ‑150oC).  ALLOCORD is placed in an ----(b)(4)---- bag before being placed in the metal canister for freezing.

The applicant has provided data to validate the freezing and thawing procedures and to establish the product dating period.  Based on the stability data submitted to the BLA, the current dating period for ALLOCORD is 36 months (3 years).

  1. CBER Lot Release

An exemption has been granted from CBER Lot Release testing, including no requirement for submission of product samples to CBER.  The basis for this decision is the fact that each lot is a single HPC, Cord Blood unit that will treat a single patient.  Lot release testing would negatively impact the limited quantity of cells available to the patient, and failure of a single lot will have a minimal potential impact on public health.

  1. Facilities review/inspection

The Center for Biologics Evaluation and Research (CBER) conducted Pre-License Inspections (PLI) of the St. Louis Cord Blood Bank manufacturing site in St. Louis, Missouri (FEI number 3003937585) from April 16 - 20, 2012 and the St. Luke’s Cancer Institute manufacturing site in Kansas City, Missouri (FEI number 005059679) from April 23 - 27, 2012.  As stated in the Background section, the St. Luke’s Cancer Institute site was withdrawn from the BLA in the December 13, 2012 resubmission; thus the inspection of that site will not be addressed.  The PLI focused on the following: Quality Systems, Facility and Equipment Systems, Materials Management Systems, Production Systems, Packaging and Labeling Systems, and QC Laboratory Control Systems used to manufacture and provide quality controls for ALLOCORD, in addition to the process and control for Donor Eligibility.  The inspection team reviewed and verified the documents related to donor eligibility, facility and equipment qualification, process validation, aseptic process validation, environmental monitoring, quality systems, QC laboratory controls, production, shipping validation, computer systems, and training.  In addition, the inspection team observed the entire operation for processing ALLOCORD, which included receipt, accessioning, processing, cryopreservation, QC testing, storage, packaging, and shipping.

On April 20, 2012, at the conclusion of the PLI of the St. Louis Cord Blood Bank facility, a nine-item Form FDA 483 was issued.  The nine objectionable conditions noted on the Form FDA 483 documented deficiencies in quality systems, product segregation, process validation, aseptic process validation, and batch record documentation.  

On Dec 13, 2012, a response to the Form FDA483 was submitted documenting the implementation of corrective actions to adequately address the nine objectionable conditions found at the St. Louis Cord Blood Bank manufacturing site in St. Louis, Missouri.

  1. Environmental Assessment 

St. Louis Cord Blood Bank requested a categorical exclusion from an environmental assessment pursuant to 21 CFR 25.31(c), which applies to a biologic product containing substances that occur naturally in the environment when the introduction of the product does not alter significantly the concentration or distribution of the substances, their metabolites, or degradation products in the environment.  The request for categorical exclusion is justified because the product meets the applicable exclusion criteria in 21 CFR Part 25, and there is no information indicating that extraordinary circumstances exist.  

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4. Nonclinical Pharmacology/Toxicology

No preclinical pharmacology/toxicology studies were conducted with ALLOCORD due to the minimal manipulation of the product and the previous human experience with HPC, Cord Blood (from multiple cord blood banks).

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5. Clinical Pharmacology

 No studies of drug interactions have been performed with HPC, Cord Blood.

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6. Clinical / Statistical

  1. Clinical Program

This BLA was submitted by SSM Cardinal Glennon Children’s Medical Center, St. Louis Cord Blood Bank and proposes to use ALLOCORD in unrelated donor hematopoietic progenitor cell transplantation procedures in conjunction with an appropriate preparative regimen for hematopoietic and immunologic reconstitution in patients with disorders affecting the hematopoietic system that are inherited, acquired, or result from myeloablative treatment.  The applicant did not conduct any clinical trials to study the efficacy or the safety of ALLOCORD.  To support its BLA, the applicant submitted its own observational dataset (ALLOCORD data), and referenced data in the dockets (FDA-1997-N-0010 and FDA-2006-D-0157) and data available from the public domain.  Based primarily on the docket data, supplemented by the ALLOCORD data, and considering the publically available data, the joint clinical and statistical review team determined that the BLA submission is sufficient for assessment of the safety and efficacy of ALLOCORD.

Clinical efficacy review:

The efficacy of ALLOCORD for hematopoietic reconstitution has been established by FDA analyses of the docket data as well as the COBLT study and other published observational studies.  Assessment of hematopoietic reconstitution was based primarily on analyses of neutrophil and platelet recovery (see Table 2) of patients who received a total nucleated cell dose ≥2.5 x 107/kg.  Neutrophil recovery is defined as the time from transplantation to an absolute neutrophil cell (ANC) count more than 500 per microliter (ANC >500/μl).  Platelet recovery is the time to a platelet count more than 20,000 per microliter (> 20,000/µl). Erythrocyte recovery is the time to a reticulocyte count greater than 30,000 per microliter (> 30,000/µl).  The docket data demonstrate that the TNC dose and degree of HLA match are inversely associated with the time to neutrophil recovery.  Transplantation of ALLOCORD also resulted in hematopoietic reconstitution, indicated by neutrophil, platelet and erythrocyte recovery.  Table 2 summarizes the efficacy data.  The cumulative incidence of neutrophil recovery of ALLOCORD appears comparable to HPC, Cord Blood products that contributed to the docket data and the COBLT study.  The cumulative incidence of platelet recovery appears to be better for patients who received ALLOCORD than for subjects in the COBLT study.  However, the ALLOCORD data are incomplete, and the incidence of platelet recovery is based on a relatively small subset of the patients who received ALLOCORD. Therefore, the data are insufficient to support a claim of superior effectiveness of ALLOCORD over other HPC, Cord Blood products.

Based on the docket data, and considering the publically available data, ALLOCORD has also demonstrated efficacy for immunologic reconstitution, as demonstrated by neutrophil recovery (Table 2).

Table 2: Summary of Efficacy Demonstrated by Hematopoietic Reconstitution for Patients Transplanted with HPC, Cord Blood, Total Nucleated Cell (TNC) Dose ≥ 2.5 x 107/kg

 

COBLT Study*

Docket* and
Public Data*

ALLOCORD**

 

Design

Single-arm prospective

Retrospective

Retrospective

 

Number of Patients

324

1299

1086***

 

Median Age (years)
(range)

4.6
(0.07 – 52.2)

7.0
(<1 – 65.7) 

6.4
(2.5 – 67.0)

 

Median TNC Dose
(x 107/kg)

6.7

6.4

6.4

Neutrophil Recovery by Day 42
(ANC>500/μl)

76%

77%

88%

Platelet Recovery by Day 100
(>20,000/μl)

57%

-

87%

Erythrocyte Recovery by Day 100
(> 30,000/µl)

65%

-

-

* HPC, Cord Blood from multiple cord blood banks
** Patients who received transplant with a ≥ 4/6 human leukocyte antigen (HLA) match
*** Only a subset of these patients was used in the analysis of neutrophil and platelet recovery, and the amount of data missing is different for each variable.

  1. Pediatrics

Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable.  This application does not trigger PREA.

  1. Other Special Populations

Clinical studies of HPC, Cord Blood (from multiple cord blood banks) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.  In general, administration of ALLOCORD to patients aged 65 and over should be cautious, reflecting their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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 7. Safety

The safety review of this BLA focuses on transplantation-related adverse events, including early death, infusion reactions, graft-versus-host disease (GVHD), and graft failure.  The assessment of these adverse events is based primarily on the docket data, supplemented by the ALLOCORD data, and considering the publically available data.

  1. Infusion Reactions

The data described in Table 3 reflect exposure to 442 infusions of HPC, Cord Blood (from multiple cord blood banks) in patients treated using a total nucleated cell dose >2.5 x 107/kg on a single-arm trial (The COBLT Study).  The population was 60% male, and the median age was 5 years (range 0.05-68 years), and included patients treated for hematologic malignancies, inherited metabolic disorders, primary immunodeficiencies, and bone marrow failure.  Preparative regimens and graft-vs-host disease prophylaxis were not standardized.  The most common infusion reactions were hypertension, vomiting, nausea, and bradycardia.  Hypertension and any grades 3-4 infusion‑related reactions occurred more frequently in patients receiving volumes greater than 150 milliliters and in pediatric patients.  The rate of serious adverse cardiopulmonary reactions was 0.8%.

Table 3: Incidence of Infusion-Related Adverse Reactions Occurring in >1% of Infusions (The COBLT Study)


Adverse Reaction

Any Grade

Grade 3-4

Any reaction

65.4%

27.6%

Hypertension

48.0%

21.3%

Vomiting

14.5%

0.2%

Nausea

12.7%

5.7%

Sinus bradycardia

10.4%

0

Fever

5.2%

0.2%

Sinus tachycardia

4.5%

0.2%

Allergy

3.4%

0.2%

Hypotension

2.5%

0

Hemogloburia

2.1%

0

Hypoxia

2.0%

2.0%

Information on infusion reactions was available from voluntary reports for 737 patients who received ALLOCORD.  Preparative regimens and graft-vs.-host disease prophylaxis were not standardized.  The reactions were not graded.  An infusion reaction occurred in 13% of the 737 patients.  The most common infusion reactions, occurring in ≥ 1% of patients, were hypertension (54%), vomiting (12%), dyspnea (9%), bradycardia (6%), nausea (4%), chest pain (2%), hemoglobinuria (2%), fever (2%), and hives (2%). 

  1. Adverse Reactions other than Infusion Reactions

For other adverse reactions (i.e., other than infusion reactions), the raw clinical data from the docket were pooled for 1299 patients (120 adult and 1179 pediatric) transplanted with HPC, Cord Blood (from multiple cord blood banks) with total nucleated cell dose >2.5 x 107/kg.  Sixty-six percent (n=862) underwent transplantation as treatment for hematologic malignancy.  The preparative regimens and graft-vs-host disease prophylaxis varied.  The median total nucleated cell dose was 6.4 (range, 2.5 - 73.8) x 107/kg.  Data on other adverse reactions were also available for 501 patients treated with ALLOCORD, at a total nucleated cell dose >2.5 x 107/kg. 

  • Deaths (Day-100 mortality)

For the 1299 patients in the pooled dataset, Day‑100 mortality from all causes was 25%.  Primary graft failure occurred in 16%.  For the 499 patients in the ALLOCORD dataset, Day-100 mortality from all causes was 17%.  The cumulative incidence of Day-100 mortality appears to be better for patients who received ALLOCORD than for patients  in the pooled dataset.  However, the ALLOCORD data are incomplete, and the incidence of Day-100 mortality is based on a relatively small subset of the patients who received ALLOCORD.  Therefore, the data are insufficient to support a claim of superior effectiveness of ALLOCORD over other HPC, Cord Blood products.  The incidences of the most common causes of death with ALLOCORD were primary disease (43%), infection (25%), organ failure (12%), pulmonary causes (9%), and graft failure (3%).

  • Graft-versus-Host Disease (GVHD)

For patients in the pooled docket dataset who received a TNC dose >2.5 x 107/kg, the incidence of grades 2-4 GVHD was 42%, and of grades 3-4 GVHD was 19%.  

  • Engraftment Syndrome (ES)

The data in the docket do not address the risk of ES.  In addition, the BLA does not provide any reports of ES associated with ALLOCORD.  However, ES occurred in 15% (11.7-18.0%) of the 364 patients in the COBLT study.  Median time to onset of the event was 10 days after transplantation (range, 5-35 days).  In literature reports, the incidence of ES varies from 30% to 78%.

  • Donor Cell Leukemia, Transmission of Serious Infection, and Transmission of Rare Genetic Disorders

Data from published literature and from observational registries, institutional databases, and cord blood bank reviews reported to the docket revealed nine cases of donor cell leukemia, one case of transmission of infection, and one report of transplantation from a donor with an inheritable genetic disorder.  The data are not sufficient to support reliable estimates of the incidences of these events.  The BLA did not provide any reports of donor cell leukemia, transmission of serious infection, or transmission of rare genetic disorders associated with ALLOCORD. 

Due to differences in the size and quality of the datasets, the review team assessed the safety data from the pooled docket and other publically available data as the best indicator of the likely postmarketing performance of ALLOCORD.  Therefore, the package insert gives precedence to this pooled, publically available safety data over the ALLOCORD safety data.

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8. Advisory Committee Meeting

This application was not referred to an Advisory Committee because the product is not the first-in-class and the review committee did not identify novel concerns.  

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9. Other Relevant Regulatory Issues

Considering the extensive prior clinical experience with HPC, Cord Blood (from multiple cord blood banks), the review team determined that a pharmacovigilance plan was not necessary.  In addition, review of the BLA did not identify any safety concerns that were not already known for this class of product.  Therefore, the BLA review does not include a Pharmacovigilance Plan Review from the Office of Biostatistics and Epidemiology.  However, to monitor the postmarketing safety of the product, the review team recommends a postmarketing safety outcomes monitoring and analysis plan, and expedited reporting of serious infusion reactions. 

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 10. Labeling

The package insert (PI) originally submitted to the BLA and all subsequent amendments related to the label were reviewed by members of the BLA review team.  Labeling for HPC, Cord Blood is primarily class labeling.  Therefore, the labeling of ALLOCORD follows the format of labeling of approved HPC, Cord Blood products.  

Multiple discussions about the PI were held between review team members and the applicant.  These discussions resulted in multiple rounds of revisions until final agreement was reached.  The most significant discussions and changes related to incorporating a class labeling approach for HPC, Cord Blood products, are summarized below:

  • Detailed procedures for “The Wash Method” were added to the product preparation instructions.
  • The amount of time the product may be stored after thawing and reconstitution was changed to an upper limit of 4 hours.
  • “Expected Results” and “Limitations” sections were removed from the Instructions for Preparation in the Package Insert that was originally submitted. 

The Advertising and Promotional Labeling Branch reviewed the package insert, patient labeling, and carton and container labels.  Changes to container and package labels were required in order to be in full compliance with regulations.  After discussions with the applicant, all of these submissions were found to be acceptable.

The sponsor will submit the label in Structured Product Labeling format after product licensure.

The proposed label provides adequate directions for the safe and effective use of ALLOCORD in the indicated population.

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11. Recommendations and Risk / Benefit Assessment

a. Recommended Regulatory Action

The review team recommends approval of ALLOCORD as indicated for use in unrelated donor hematopoietic progenitor cell transplantation procedures in conjunction with an appropriate preparative regimen for hematopoietic and immunologic reconstitution in patients with disorders affecting the hematopoietic system that are inherited, acquired, or result from myeloablative treatment.  The risk benefit assessment for an individual patient depends on the patient characteristics, including disease, stage, risk factors, and specific manifestations of the disease, on characteristics of the graft, and on other available treatments or types of hematopoietic progenitor cells.

The recommended minimum dose is 2.5 x 107 nucleated cells/kg at cryopreservation.

b. Risk / Benefit Assessment

The benefit of ALLOCORD is based on hematopoietic and immunologic reconstitution in patients with disorders of the hematopoietic system.  Considering the substantial risks associated with ALLOCORD, the risk benefit assessment is highly individualized.

The quality, efficacy, and safety of this product have been thoroughly reviewed and have been determined to be acceptable for use of this product as indicated in the label.

c. Recommendation for Postmarketing Risk Management Activities

 There was no safety issue identified that warrants a Risk Evaluation and Mitigation Strategy (REMS).  ALLOCORD is expected to have a favorable risk-benefit profile.

d. Recommendation for Postmarketing Activities

There are no safety issues that warrant postmarketing requirements or commitments.

The review team recommended, and the applicant agreed to do, the following:

  1. Implement a safety outcomes monitoring and analysis plan.  This plan will include a) maintenance of an observational database to include, for all ALLOCORD units released, information including but not limited to, time to neutrophil recovery, graft failure, survival, cause of death, infusion reactions, and other adverse experiences,  b) aggregate analyses of interval and cumulative adverse experience reports, and c) safety outcomes analyses of interval and cumulative data that address early mortality, graft failure-related mortality, graft failure, time to neutrophil recovery, infusion-related events, and other adverse experiences.  Reports will include a description of the population analyzed, results of the analyses, whether outcomes indicators were triggered and, if so, what actions were implemented as a result.
  2. Submit a 15-day “alert report” for each serious infusion reaction associated with administration of ALLOCORD.