Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Quality and Regulatory Issues in Cellular Therapy
Cellular therapy is the use of viable cells and tissues for the treatment of disease. Modern cell-based therapies include regenerative medicine, which is the process of replacing or regenerating human cells, tissues, or organs to restore or establish normal function. With these advances, a need existed to incorporate quality systems and regulatory oversight. While the basics of quality and quality systems are the same for blood banking/transfusion services and cellular therapies, there are some distinct differences. This is seen both in standards created for cellular therapy and in the applicable US Food and Drug Administration (FDA) regulations. Accreditation of cellular therapy laboratories is through the Foundation for the Accreditation of Cellular Therapies (FACT), AABB, the College of American Pathologists (CAP) and other nongovernmental agencies, which are primarily in the United States but also accredit internationally. Since 2005, the FDA has regulated cellular therapies based on 21 CFR 1271, which contains the current good tissue practice (cGTP) regulations and the regulations pertaining to use of an investigational new drug (IND). Certain laboratory tests performed on cells or tissue intended for transplantation are regulated under the Clinical Laboratory Improvement Amendments (CLIA) under the auspices of Centers for Medicare and Medicaid Services (CMS). State health departments may also have local regulations relevant for cellular therapy. As additional uses for cell therapies are found, it is expected that there will be further expansion of regulatory oversight ( Table 89.1 ). Individuals and organizations or institutions involved in cellular therapy processing must be familiar with the requirements of these agencies.
Table 89.1
Overview of Key Events in the Regulations of Cellular Therapies
| 1912 | Public Health Service Act—blood defined as a biologic |
| 1938 | Federal Food, Drug, and Cosmetic Act—products must be safe |
| 1972 | FDA granted jurisdiction over human biological products, therapeutics, and blood banking diagnostics |
| 1986 | First clinical trials with nonhematopoietic cells |
| 1997 | First FDA license for autologous chondrocytes |
| 1998 | Regulation of unrelated allogeneic peripheral and umbilical cord blood hematopoietic progenitor cells |
| 2001 | Establishment registration and product listing finalized |
| 2004 | Donor eligibility requirements finalized |
| 2005 | 21 CFR 1271 in effect |
| 2010 | First licensed cellular immunotherapy product |
| 2011 | First FDA license for cord blood granted |
| 2017 | First CAR T-cell product licensed to treat children and young adults with B-cell acute lymphoblastic leukemia—first licensed immunotherapy |
| 2017 | First CAR T-cell product a licensed to treat non-Hodgkin lymphoma |
There are many potential forms of cell therapy. Human cells, tissues, or cellular or tissue-based products (HCT/Ps) are defined as articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient. Examples of HCT/Ps include, but are not limited to, bone, ligament, skin, dura mater, heart valve, cornea, hematopoietic stem/progenitor cells derived from peripheral and cord blood and bone marrow, manipulated autologous chondrocytes, epithelial cells on a synthetic matrix, and semen or other reproductive tissue.
Accreditation Standards
FACT, AABB, and CAP have created sets of standards for quality systems applicable to organizations that manufacture HCT/Ps and accredit organizations that meet these standards.
Foundation for the Accreditation of Cellular Therapy
FACT Standards promote improvement and progress in cellular therapy. Because cellular therapy products often are exchanged internationally, the requirements help to ensure consistency in product quality worldwide. The Standards are the cornerstone of the FACT accreditation program. The Standards address both clinical and laboratory practices and are applicable to HCT/Ps and therapeutic cells (TCs), which are obtained from the bone marrow, peripheral blood, or umbilical cord blood. FACT accreditation is awarded to organizations following successful documentation of compliance with the Standards. On-site inspections are conducted by inspectors who are qualified by training and experience and who have working knowledge of the industry. The inspection is quality-oriented and in line with the FDA current good tissue practice (cGTP) regulations. FACT inspections focus on all areas of manufacturing, including donor eligibility, collection, processing, storage, distribution, administration, clinical outcomes, and other clinical parameters. With the expansion of cellular therapies, FACT has developed different sets of standards to address different needs of cellular therapy facilities to include the following:
- 1.
FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration. For these standards, FACT joined with the Joint Accreditation Committee (JACIE) of the International Society for Cellular Therapy (ISCT), and the European Group for Blood and Bone Marrow Transplantation (EBMT) to publish standards for hematopoietic progenitor–derived cellular therapy. These Standards cover all aspects of collection, processing, storage, and administration of the bone marrow and cells derived from peripheral blood. For umbilical cord blood products, these Standards only apply to the administration of the cellular product.
- 2.
Common Standards for Cellular Therapies that represent the basic fundamentals of cellular therapy that can be applied to any cell source or therapeutic application and are intended to be used throughout product development and clinical trials. These Standards apply to cells collected from nonhematopoietic sources (e.g., adipose tissue) or cells collected from hematopoietic sources for nonhomologous use (e.g., mesenchymal stromal cells for cardiac repair).
- 3.
Immune Effectors Standards , which apply to immune effector cells, are used to modulate an immune response for therapeutic intent, such as dendritic cells, natural killer cells, T cells, and B cells. This includes, but is not limited to, genetically engineered chimeric antigen receptor T cells (CAR-T cells) and therapeutic vaccines.
- 4.
NetCord-FACT International Cord Blood Standards that cover all phases of cord blood collection, processing, testing, selection and release, and distribution. These NetCord-FACT Standards are organized into sections, which cover the following:
-
Operations, including quality management; Donor management and collection; Processing; Listing, search, selection, reservation, release, and distribution.
-
American Association of Blood Banks
The first edition of AABB Standards for Cellular Therapy Product Services was published in 2004. The Standards for cellular therapy products are similar to those for blood banks and transfusion services with an emphasis on a quality system composed of 10 elements ( Table 89.2 ). The accreditation process is also similar in that accreditation is voluntary and involves assessments by trained AABB assessors. Accreditation is based on compliance with the Standards and is focused on donor eligibility, collection, processing, storage, distribution, and certain clinical components.
Table 89.2
AABB Quality System Essentials for Cellular Therapy
|
College of American Pathologists
CAP accredits laboratories and has deemed authority by CMS. It also offers an accreditation service to help laboratories earn accreditation under ISO 15189 Medical Laboratories.
Regulation
The number of uses of HCT/Ps has increased rapidly, and as the field has expanded, regulations have been promulgated, which govern the procurement, manufacture, and transplant of HCT/Ps. Regulation is focused on safety and efficacy: safety issues include sterility, purity, identity, segregation, and tracking, whereas efficacy includes potency and stability.
Unmanipulated bone marrow cell transplants are regulated by the Health Research and Services Administration (HRSA). This organization also oversees the marrow and cord blood (HPC, Bone Marrow and HPC, Cord Blood, respectively) donations under the National Marrow Donor Program (NMDP). Other HCT/Ps, such as HPC, Apheresis, were regulated under 21 CFR 1270 until May 2005 when 21 CFR 1271 came into effect and superseded 1270. The purpose of these regulations is to create a unified registration and listing system for establishments that manufacture HCT/Ps and to establish donor eligibility, cGTP, and other procedures to prevent the introduction, transmission, and spread of communicable diseases by HCT/Ps. The Office of Cellular, Tissue and Gene Therapies (OCTCT) within the Center for Biologics Evaluation and Research (CBER) regulates HCT/Ps under section 361 of the Public Health Service Act (PHS Act/42 U.S.C. 262). Regulation solely under section 361 (designation as a 361 HCT/P) requires establishments to adhere to regulations designed to prevent the transmission of communicable disease but do not require premarket review or notification for such products. The criteria for regulation solely under section 361 are as follows:
- 1.
HCT/P is minimally manipulated;
- 2.
HCT/P is intended for homologous use only;
- 3.
Manufacture of the HCT/P does not involve the combination of the cell or tissue component with a drug or device, except for a sterilizing, preserving, or storage agent, if the addition of the agent does not raise new clinical safety concerns with respect to the HCT/Ps; and either
- 4.
HCT/P does not have a systemic effect and is not dependent on the metabolic activity of living cells for its primary function; or
- 5.
HCT/P has a systemic effect or is dependent on the metabolic activity of living cells for its primary function, and
- a.
is for autologous use,
- b.
is for allogeneic use in a first or second degree relative, or
- c.
is for reproductive use.
- a.
Any cell-based product that contains cells or tissues that “are highly processed, are used for other than their normal function, are combined with nontissue components, or are used for metabolic purposes” would also be subject to the Public Health Safety Act, Section 351 (designation as a 351 HCT/P), which regulates the licensing of biologic products and requires the submission of an IND application to the FDA before studies involving humans are initiated. 21 CFR Parts 210 and 211 apply to the manufacture of these cellular products as well as the applicable parts of 21 CFR Part 600. The FDA is allowed to inspect facilities, announced or unannounced, where HCT/Ps are manufactured at reasonable times and in a reasonable manner.
The Clinical Laboratory Improvement Amendments
Laboratories that perform testing on cells and/or tissue intended for implantation, transplantation, or infusion are subject to CLIA regulations under CMS. The tests regulated are FDA-required tests for communicable diseases, FDA-required testing for emerging infectious diseases, and sterility testing in cases where donor notification is necessary (e.g., stem cells).
Investigational New Drug
With certain exceptions, clinical investigations in which a drug is administered to human subjects must be conducted under an IND as required in 21 CFR Part 312. The definition of the term drug in section 201(g)(1) of the Food, Drug, and Cosmetic Act (FD&C Act) includes, among other things, “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease…” and “articles (other than food) intended to affect the structure or any function of the body of man or other animals.” Biological products subject to licensure under section 351 of the PHS Act may also be considered drugs within the meaning of the FD&C Act ( Table 89.3 ).
Table 89.3
Regulations Applicable to Investigational New Drugs (INDs)
| Regulation | Content |
|---|---|
| 21 CFR 312.23 | IND content and format |
| 21 CFR 312.42 | Clinical holds |
| 21 CFR 312.50– 21 CFR 312.69 |
Responsibilities of sponsors/investigators |
| 21 CFR 50 and 56 | IRB ad consents |
| 21 CFR 58 | Good laboratory practice |
| 21 CFR 1271 | Human cells, tissues, and cellular and tissue-based products (includes current good tissue practice) |
Each IND has a sponsor, which is the individual or organization that takes responsibility for and initiates a clinical investigation, and one or more investigators, who conduct the clinical investigation. The sponsor and investigator may be the same person. An IND submission contains a specified set of documents and information ( Table 89.3 ). IND submissions are reviewed, approved or disapproved, and monitored by the FDA. There are four types of IND studies: phase I evaluates safety of the drug; phase II studies efficacy and dose; phase III confirms efficacy and provides statistical evidence of effectiveness; and phase IV includes postmarketing studies designed (1) to compare a drug with other drugs already in the market; (2) to monitor a drug’s long-term effectiveness and impact on a patient’s quality of life; and (3) to determine the cost-effectiveness of a drug therapy relative to other traditional and new therapies.
Current Good Tissue Practice
The core requirements of the cGTPs are most directly related to preventing the introduction or transmission or spread of communicable disease ( Table 89.4 ).
Table 89.4
Current Good Manufacturing Practices (cGMPs) Versus Core Current Good Tissue Practices (cGTPs)
| cGMPs | cGTPs |
|---|---|
|
|
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here