Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans: Guidance for Industry | Guideline Explorer

Description

The Food and Drug Administration (FDA) is issuing this guidance to provide sponsors and applicants of xenotransplantation products with updates concerning the production, testing, and evaluation of products, during protocol development and during the preparation of submissions to FDA, e.g., Investigational New Drug Applications (INDs) and Biologics License Applications (BLAs). This guidance also includes updated references and Agency practices intended to prevent the introduction and spread of infectious agents of animal origin into the human population. This guidance amends the guidance of the same title dated April 2003 (April 2003 guidance).

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

5

Xenotransplantation Products

Use of Xenotransplantation Products in Humans

Heterogeneous Xenotransplantation Products

Products containing many varieties of cells or extraneous tissues.

Human Embryonic Stem Cell Lines

hES cell lines that used murine feeder layer cells.

Combination Product

Products combining drug, device, or biological constituents; Generally recommended for Enhanced Documentation; Requires 14971-based framework incorporating ICH Q9; A drug-device combination where the device constituent part detects ingestion.

Xenotransplantation Product

May meet the definition of a regenerative medicine therapy

Stakeholders

8

Sponsor

Entity responsible for submitting applications under section 524B

investigators

Knowledge by investigators can impact trial integrity

Intimate contacts

Persons who have engaged in activities resulting in exchange of body fluids with a recipient

Health care providers

Prescribers who may require particular training or certification; health care providers' attitudes about the risk and safe-use interventions

Applicant

Entity submitting development data and knowledge; Entity performing the work process for change

Institutional Animal Care and Use Committee

Requires approval and oversight of applicable animal research

Institutional Biosafety Committee

Reviews and oversees basic and clinical research to assess safety.

Institutional Review Board

Governs top dose in clinical studies

Regulatory Context

Regulatory Activities

9

Investigational New Drug Applications

Regulatory submissions for clinical trials.; General requirements for INDs apply to development programs

FDA application

submit a plan for clinical follow-up of recipients in a xenotransplantation protocol in the FDA application

Clinical trials

Development program for drugs intended for sGERD treatment

Investigational application

Submission of preclinical data to FDA.

License application

summaries of data resulting from validation execution included in application

Biologics License Applications

BLA application type eligible for reduced fees.

BLA

Biologics License Application

IDE

Investigational Device Exemption submissions; Submission Documentation for Investigational Device Exemptions; Investigational Device Exemption submission recommendations

IND

Investigational New Drug submissions

Document Types

8

Clinical Protocol

The template defines the structure and content of clinical protocols; The document provides a template for clinical electronic structured harmonised protocols; Ensure alignment with every other section of the protocol.; The primary document being structured and amended.

Health records

Records to be maintained for at least 50 years

Death reports

Records maintained on recipients including cause of death

Informed consent document

must describe reasonably foreseeable risks

SOPs

Standard Operating Procedures must identify circumstances of potential plasma dilution.

SOP

Standard Operating Procedures for evaluating suppliers; Based on the manufacturer's established SOP for evaluating suppliers.; Standard Operating Procedures for regulatory compliance

Informed Consent

Process by which a subject voluntarily confirms his or her willingness to participate in a particular trial; Integral feature of the ethical conduct of a trial

Master File

Documentation artifact related to NDI notifications

Attributes

8

Designated Pathogen Free

Status of facilities and animals (DPF) free of designated pathogens.

50 years

Retention period for health records beyond transplantation

4 degrees Celsius

storage temperature for specimens

Biocompatibility

impact the biocompatibility of the device

Class 100

Air classification of manufacturing rooms

Potency

Measurement of potency for biological products

Purity

specifications for the purity, strength, and composition of dietary supplements

-70 degrees Celsius

Storage temperature condition for archived samples of source animal tissues and body fluids.; You should archive tissue and fluid samples at -70 degrees Celsius or lower

Technical Details

Substances

9

Leukocytes

Viable cells archived for subsequent isolation of nucleic acids and proteins.

Source Leukocytes

including Source Plasma and Source Leukocytes

Source Plasma

including Source Plasma and Source Leukocytes

PBMC

PCR of recipient's PBMC for PERV DNA sequence

Viral transport medium

medium for storing specimens at 4 degrees Celsius

Bioactive molecules

Cytokines or hormones synthesized by the product.

Immunosuppressive drugs

Used to manage host response but may affect pharmacokinetics and toxicity.

WFI

Water for Injection used for final rinses in washing; WFI is used for the final rinses

porcine endogenous retrovirus(es)

PERV sequences present in pig genomes

Testing Methods

10

Microbiological Testing

Use of data from assessing process control

Autopsy

Post-mortem examination requested in informed consent

RT-PCR

Example of a highly sensitive molecular comparator method

Serologic analysis

serologic analysis for PERV-specific antibodies

Enzyme-Linked Immunosorbent Assay

Analytical test for binding properties

Clonogenic assays

In vitro assays of tumorigenic potential for cell lines.

Histopathology

The standard of truth for measuring diagnostic performance.; Typically used as a truth standard for optical imaging drugs.

Media fills

Failure to conduct media fills that closely simulate aseptic production operations

RT assay

reverse transcriptase assay for PERV detection

EM

visualization of co-cultures to identify morphologic changes

Processes

10

Aseptic Processing

implied manufacturing process under QS regulation

Postmortem examination

You should request a complete postmortem examination, including histopathology and cultures of all recipients.

Sterilization

Required for contaminated equipment and media before disposal

Extracorporeal hemoperfusion

Use of devices outside the body for blood treatment.

Air Handling Systems

HVAC systems designed to provide adequate air quality

Changeover Procedures

designed to prevent contamination between harvests of xenotransplantation products

environmental monitoring

program for monitoring air and surfaces in processing areas

Necropsy

Procedure where worms are identified and counted for effectiveness calculations.

Aseptic techniques

Required for parenteral interventions and biopsies.

Validation and Qualification

Required for manufacturing and processing of xenotransplantation products.

Clinical Concepts

7

Immunosuppressed

Condition of the recipient that increases risk of infection.

Zoonotic Infection

Reference 29

Adverse events

Safety findings including deaths and post-mortem examinations

Cytomegalovirus

CMV disease in patients who have undergone transplantation; CMV disease in transplant recipients is considered serious and life-threatening; disease to be treated or prevented in transplantation patients; Developing drugs to treat or prevent disease

Zoonotic infections

potentially serious public health risks

GVHD

Graft-versus-host disease potentially caused by immunologically active cells.; immunological risk associated with xenogeneic cells

Graft versus host disease

early-phase studies can be informative with regards to the risks of GVHD; modified to reduce the risk of GVHD; major concern for recipients of allogenic CAR T cells

Identified Hazards

Hazards

10

Transmission of infectious agents

Potential public health risk from xenotransplantation products.

Bovine Spongiform Encephalopathy

Causative agent requiring inactivation controls

Tumorigenesis

Risk of tumor formation associated with xenotransplantation

Zoonotic infections

Potential infectious risks from source animal species

PERV

assess all recipients of xenotransplantation products involving the use of porcine cells, tissues, or organs for evidence of infection by PERV.; Porcine endogenous retrovirus that can be transmitted from pig cells to human cells

TSEs

category of infectious agents of concern; Infectious diseases with protracted incubation periods

Tumorigenicity

Risk associated with intended pharmacology or off-target effects

Cross-contamination

Risk associated with construction, traffic flow, and shared equipment.; Risk from raw food to RTE food or from insanitary objects; Personnel handling RTE foods touch contaminated surfaces

latent viruses

viruses known to occur in a latent state that may be activated

Zoonoses

Infectious agents known to cause diseases transmissible from animals to humans.

Standards & References

External Standards

8

USP <1231>

Water for Pharmaceutical Purposes

PHS Guideline on Infectious Disease Issues in Xenotransplantation

Reference 1

USP<1231>

monograph on Water for Pharmaceutical Purposes

USP <85>

Endotoxin should be assessed following USP <85> Bacterial Endotoxins Test.

PHS Guideline

Public Health Service guideline providing recommendations for sample archiving and storage duration.; Public Health Service Guideline on infectious disease issues in xenotransplantation.; recommends clinical xenotransplantation procedures be performed in transplantation centers; Section 4.1.1.2 of the PHS Guideline suggests an active screening program.

USDA-approved postmortem diagnostic tests

Tests used for BSE detection.

Guide for the Care and Use of Laboratory Animals

Standard for animal husbandry practices in PER studies.; Standard for the ethical treatment and housing of lab animals

AAALAC

Accreditation body for animal facilities.

Specifications

3

Lot release criteria

Includes identity, potency, and safety (microbiological sterility).

Negative Gram stain

Set as a lot release criterion for the final product.

Lot release specification

Results of purity, endotoxin, and viability tests used as criteria for release.; endotoxin assay results used for product release

ICH References (8)

ICH S6(R1)

Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals; guidance regarding nonclinical immunotoxicity assessment of biopharmaceuticals

ICH Q6B

Specifications for biotechnological/biological products; Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products

ICH Q6A

Referenced regarding specifications and solid state forms.

ICH Q5D

Recommendations for cell bank stability

ICH guidance document on safety preclinical evaluations in biotechnology

Reference for additional guidance on bioactive substance identification.

ICH

International Council for Harmonisation cited for scientific standards

ICH Q5A(R1)

Viral Safety Evaluation of Biotechnology Products

ICH Guideline

Relevant international guidelines for characterization of cell lines.

Related CFR Sections (9)

21CFR312.32§ 312.32 IND safety reporting.
(a) Definitions. The following definitions of terms apply to this section:Read full regulation →
21CFR312.23§ 312.23 IND content and format.
(a) A sponsor who intends to conduct a clinical investigation subject to this part shall submit an “Investigational New Drug Application” (IND) including, in the following order:Read full regulation →
21CFR610.9§ 610.9 Equivalent methods and processes.
Modification of any particular test method or manufacturing process or the conditions under which it is conducted as required in this part or in the additional standards for specific biological products in parts 620 through 680 of this chapter shall be permitted only under the following conditions:Read full regulation →
21CFR610.13§ 610.13 Purity.
Products shall be free of extraneous material except that which is unavoidable in the manufacturing process described in the approved biologics license application. In addition, products shall be tested as provided in paragraphs (a) and (b) of this section.Read full regulation →
21CFR211.25§ 211.25 Personnel qualifications.
(a) Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. Training shall be in the particular operations that the employee performsRead full regulation →
21CFR589.2001§ 589.2001 Cattle materials prohibited in animal food or feed to prevent the transmission of bovine spongiform encephalopathy.
(a) Purpose. The purpose of this section is to prohibit the use of certain cattle origin materials in the food or feed of all animals to further reduce the risk of the spread of bovine spongiform encephalopathy (BSE) within the United States.Read full regulation →
21CFR589.2000§ 589.2000 Animal proteins prohibited in ruminant feed.
(a) Definitions —Read full regulation →
21CFR600.11§ 600.11 Physical establishment, equipment, animals, and care.
(a) Work areas. All rooms and work areas where products are manufactured or stored shall be kept orderly, clean, and free of dirt, dust, vermin and objects not required for manufacturing. Precautions shall be taken to avoid clogging and back-siphonage of drainage systems. Precautions shall be taken Read full regulation →
21CFR600.10§ 600.10 Personnel.
(a) [Reserved]Read full regulation →

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Quality control unit failed to exercise its responsibility

101

Failure to conduct at least one test to verify the identity of each component

95

Failure to establish adequate written procedures for production and process control

88

Failure to have appropriate laboratory determination of satisfactory conformance to final specifications

56

Failure to thoroughly investigate any unexplained discrepancy or failure of a batch

56

Failure to establish an adequate quality control unit

49

Failure to test samples of each component for identity and conformity

47

Failure to establish laboratory controls

35

Failure to thoroughly investigate any unexplained discrepancy

28

Failure to test samples of each component for identity

25

Recent Cases

Related Warning Letters (10)

Related MFDS Guidelines

Korean regulatory guidelines covering similar topics