FDA has issued two guidance documents on minimally manipulated, unrelated cord blood. One guidance is intended to assist manufacturers of cord blood in obtaining a biologics license, and the other is intended to assist potential sponsors in the submission of an Investigational New Drug application (IND) for cord blood that is not licensed (approved).
The agency has received questions from manufacturers, health care professionals and others, and hopes the following information will be helpful in understanding FDA’s guidance and IND requirements for minimally manipulated, unrelated allogeneic placental/umbilical hematopoietic progenitor cells-cord (HPC-C) for hematopoietic and immunologic reconstitution in patients with disorders affecting the hematopoietic system that are inherited, acquired, or result from myeloablative treatment.
How can HPC-Cs be made available for clinical use?
HPC-Cs can be made available under an approved Biologics License Application (BLA) or an IND. Manufacturers of HPC-Cs may submit a BLA.
FDA also recommends an IND pathway to facilitate availability of unlicensed HPC-Cs that a physician has selected for a particular patient. FDA describes this pathway in its guidance on IND submissions for these products. An IND may be submitted by the manufacturer, the physician, the transplant center, or a national or international cord blood registry involved in coordinating the distribution or other qualified sponsor.
Unlicensed HPC-Cs for hematopoietic and immunologic reconstitution in patients with disorders affecting the hematopoietic system that are inherited, acquired, or result from myeloablative treatment can be distributed under an IND, as described in the guidance. Additionally, FDA regulations allow expanded access to unlicensed (unapproved) drugs, including biological drugs such as HPC-Cs, for treatment use in patients with serious diseases or conditions who lack therapeutic alternatives (21 CFR 312.300). Under these regulations, the HPC-Cs are made available under an IND for the primary purpose of treating the patient’s disease or condition (21 CFR 312.300(a)) and are not supplied to generate scientific data to characterize the HPC-Cs. Units distributed in this way are being used for treatment and not to address research questions.
Why are some cord blood products for hematopoietic and immunologic reconstitution in patients with disorders affecting the hematopoietic system that are inherited, acquired, or result from myeloablative treatment, available under an IND and other cord blood products available under a license?
HPC-C units are available under an IND for several reasons. In some cases, banks may hold a license but have unlicensed HPC-C units in inventory. For example, a unit may have been collected and processed before the licensing controls were in place, or the cell dose in the HPC-C unit may be smaller than the value specified in the HPC-C licensure guidance. In other cases, the HPC-C unit is in a bank where a license application has not yet been submitted or is pending.
FDA understands that the continued availability of such unlicensed units is essential in order to enhance the diversity of HLA phenotypes of units in inventory and increase the likelihood that individuals with less common HLA types will be able to find suitably matched HPC-Cs for transplantation. In many cases, an unlicensed unit may be the best match for a patient and therefore the best treatment for the patient. FDA’s IND guidance explains how these units can be distributed under an IND to treat, by hematopoietic and immunologic reconstitution, patients with disorders affecting the hematopoietic system that are inherited, acquired, or result from myeloablative treatment.
What is the status of the HRSA-funded National Cord Blood Inventory (NCBI) HPC-C units collected prior to finalization of the BLA guidance document and NCBI units that continue to be collected under IND since finalization of the guidance?
The U.S. Health Resources and Services Administration (HRSA) began funding the collection of HPC-C units for the National Cord Blood Inventory prior to finalization of the BLA guidance document. NCBI HPC-C units are collected according to criteria established by HRSA in consultation with transplant physicians and experts in umbilical cord blood banking. These criteria have been reviewed by the HHS Advisory Council on Blood Stem Cell Transplantation. NCBI HPC-C units distributed under IND continue to be available for use for the treatment of patients. In many circumstances, IND HPC-C units, whether NCBI units or others, remain the best match for searching patients.
Can HPC-C units from an ineligible donor or from a donor who did not undergo complete screening and testing be made available under an IND?
Yes. An HPC-C unit that is from a donor who did not undergo complete screening and testing or from an ineligible donor(s) can be made available under an IND if appropriate criteria are met. For example, an ineligible donor is one who has gone through a complete donor eligibility determination, but has an identified risk factor or a reactive/positive test result. In the event that the HPC-C unit is from an ineligible donor, it may not be used unless there is a documented urgent medical need as defined in 21 CFR 1271.3(u), and the requirements described in 21 CFR 1271.65 are met. Similarly, an HPC-C unit from a donor for whom the donor eligibility determination is not complete may be used if there is a documented urgent medical need as defined in 21 CFR 1271.3(u), and the requirements in 21 CFR 1271.60 are met. Additional labeling requirements for HPC-Cs from ineligible or incompletely screened and tested donors are explained in the labeling section of the IND guidance.
Will FDA allow distribution of cord blood units under IND indefinitely?
The IND guidance does not specify a duration or time limit for use of these unlicensed units under IND.
How does the indication described in the Licensure and IND guidances differ from the indication approved by FDA in November 2011?
In November 2011, FDA granted marketing approval to New York Blood Center for HPC-Cs intended to be used for hematopoietic and immunologic reconstitution in patients with disorders affecting the hematopoietic system that are inherited, acquired, or result from myeloablative treatment This indication is based on reevaluation of data from the legacy docket and other sources, and consideration of the proceedings at the September 2011 meeting of the Cellular, Tissue, and Gene Therapy Advisory Committee.