Biologicals regulatory framework changes from 1 July 2018

Including changes to regulation of autologous human cell and tissue products and classification of biologicals

2 July 2018

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New definitions related to classification

The definitions and guidance below relate to any HCT covered by the biologicals regulatory framework, in addition to the exemption and exclusions proposed for autologous HCT products.

Classification of biologicals

The definitions for Class 2, 3 & 4 biologicals have been modified, and we do not expect that the changes will affect any previous decisions on classifications of biologicals. The definitions improved clarity and international harmonisation.

The new definitions are below.

Class 2 biological

Class 2 biological means a biological that:

  • has been subject to a process that is minimal manipulation and is for homologous use
  • OR
  • is mentioned in Schedule 16 as a Class 2 biological.

Class 3 biological

Class 3 biological means a biological that:

  • has been subject to a process that is more than minimal manipulation and/or is not for homologous use
  • OR
  • is mentioned in Schedule 16 as a Class 3 biological

Class 4 biological

Class 4 biological means a biological that:

  • is mentioned in Schedule 16 as a Class 4 biological

High risk products must be specified in the Schedule 16 instrument to be classified as Class 4 biologicals. This list includes viable animal HCT products and human HCT products that are considered to pose a high risk, due to the level of manipulation and/or the current lack of safety data to appropriately classify them. As the level of safety data and experience with a specific group of HCT products increases, it is possible that they could be removed from the list.

Defined in Schedule 16

Class 4 biologicals are defined in the Schedule 16 instrument as:

  • Things that comprise or contain live animal cells, tissues or organs.
  • An HCT that has been modified to artificially introduce a function that was not intrinsic to the donor cell or tissue.
  • Pluripotent stem cells and products that were derived following ex vivo differentiation of pluripotent cells to a defined lineage.
'Artificial' altering of function

The 'artificial' altering of the function or functions of the HCT is intended to capture only modifications that are not intrinsic to the HCT in vivo.

Examples of intrinsic modifications that are considered to artificially alter the function include:

  • Genetic modification of cells (e.g. CAR T cells, iPSCs)
  • Induction of pluripotency in cells (iPSCs).

The techniques used to alter the function may include the use of recombinant nucleic acid technologies, liposome modification, nanoparticles and/or pharmaceutical treatment, or equivalent technology.

Examples of intrinsic modifications that are not considered to artificially alter the function include:

  • Many compounds and growth factors are used to expand, maintain or induce differentiation of cells in culture, but these only influence the intrinsic functions, ability and plasticity of the HCTs
  • Cells where exogenous proteins or peptides (non-pharmaceutical) have been taken up by normal endocytic processes (e.g. tumour antigen-pulsed dendritic cells) would not be considered to have artificially altered the function of the HCTs.
Pluripotent cells, including ex vivo differentiation

By definition pluripotent cells are able to give rise to cells found in all tissues of the embryo, except for germ cells, so the use of these cells raises significant safety concerns. The in vitro differentiation of these cells may address some safety concerns, but raises others over the ability to control the quality and safety of the defined population. Other biologicals that contain or are derived from stem cells may still have multipotent potential, but the safety concerns are not as great as for pluripotent cells. These other stem cell derived products will generally be treated as Class 3 biologicals.

Minimal manipulation

Minimal manipulation is defined as:

  • cells and tissues are subjected to a process of minimal manipulation if the process does not result in the alteration of any of the biological characteristics, physiological functions or structural properties that are relevant to the intended use of the cells or tissues.

This definition:

  • introduces a link between the processes to which the cells and tissue are subject and the intended clinical function of the product, which is crucial for assigning an appropriate risk classification
  • is generally consistent with that used in the EU and by the FDA. (However, the FDA definition differentiates between structural and non-structural tissue, which is a complexity not considered relevant in the Australian regulatory context.)
  • removes definitional issues around the listed actions.

Importance of the link between processing and intended use

Where relevant characteristics of the HCT are altered it raises issues around the product consistency and quality, safety and efficacy of the processed HCT, as product function in the recipient cannot be predicted.

In determining whether any processing step(s) altered the characteristics of the HCT, the properties of the HCT in the donor should be considered. Not all functions may be preserved during processing, but the manufacturer must be able to show that the activity of relevant characteristics related to the intended use is sufficiently maintained. This may require a reasonable understanding of the mechanism(s) of action.

The following list of actions would usually be considered minimal manipulation (i.e. processes that do not result in alteration of the biological characteristics, physiological functions or structural properties relevant to the intended use of the human cell or tissue therapy):

  • centrifugation
  • trimming, cutting or milling
  • flushing or washing
  • refrigeration
  • freezing
  • freeze drying
  • the use of additives such as cryopreservatives, anticoagulants, antimicrobial agents
  • irradiation for the purpose of bioburden reduction.

However, the intended use of the HCT may dictate whether or not any of the above listed actions would amount to only minimal manipulation.

Actions that would generally be considered to be more than minimal manipulation include, for example:

  • cell culture
  • in vitro differentiation of cells or tissues
  • genetic modification
  • mixing demineralized bone with a gelatinous carrier, e.g. glycerol
  • mixing demineralized bone with a medicine e.g. recombinant bone morphogenetic proteins (BMPs)
  • seeding of cells on to a medical device
  • enzymatic dissociation of tissue.

Examples to demonstrate minimal manipulation

  1. Musculoskeletal tissue example:
    1. A manufacturer performs mechanical machining to shape bone during total knee replacement. This would generally be considered to be minimal manipulation as the structural element is maintained and is the crucial characteristic of the tissue relating to its intended use.
    2. A manufacturer grinds the bone to form morselised chips and particles for filling of bone voids. The structural element of the bone is no longer maintained, but this would still generally be considered to be minimal manipulation as the strength and resistance to compression is maintained, which is the crucial characteristic of the tissue relating to its intended use.
    3. A manufacturer demineralises morselised bone sufficiently to increase the malleability of the bone, with the intended use restricted to void filing. This is considered minimal manipulation as it maintains the utility to support bodily structures.
    4. A manufacturer demineralises the bone sufficiently to increase the exposure of the bone morphogenetic proteins, for use in bone grafts where osteoinductive potential is desired. This may still be considered to be minimal manipulation, as osteoinductivity is an inherent property of mineralised bone. However, the manufacturer must be able to demonstrate that the manufacturing process does not substantially diminish the osteoinductive potential (to a clinically relevant level). Note that due to batch variation in osteoinductive potential (presumably due to variation between donors), most demineralised bone matrix (DBM) preparations would require batch testing where an osteoinductive claim is made. Mixing the DBM with a carrier is considered more than minimal manipulation.
  2. Skin example:
    1. A manufacturer processes skin to decellularise it, leaving the collagen matrix, for use in covering burns. The utility of the skin to provide a protective covering is not substantially compromised by the processing, so this is considered minimal manipulation.
  3. Adipose tissue example:
    1. Adipose tissue is collected from one area of the patient and used for transplantation into the subcutaneous areas of breast for reconstruction or augmentation procedures. This is minimal manipulation because the processing does not alter the cushioning and support of the adipose tissue.
    2. A manufacturer processes adipose tissue (enzymatic or physical dissociation) with the aim to dissociate cell-cell contacts and isolate the cellular portion. The resultant product (such as stromal vascular fraction (SVF)) is injected back in to patients for reputed anti-inflammatory uses. In this case the cells responsible for the intended use and to which the determination of minimal manipulation applies (e.g. mesenchymal stem cells) would be considered the autologous HCT product. Such methods used to disrupt adipose tissue would be considered beyond minimal manipulation. The process applied to isolate the cells is likely to result in changes to their properties, e.g. activation state or surface molecule expression, which could significantly impact the cells characteristics or functions.
  4. Amniotic membrane example:
    1. A manufacturer processes amniotic membrane to preserve it and package it in sheets, for use in wound covering. This is considered minimal manipulation as the barrier function of the membrane is not altered by the processing.
    2. A manufacturer processes amnion and then grinds it in to particles for injection into a wound to improve healing. This may be considered to be minimal manipulation, as long as the manufacturer can demonstrate to the satisfaction of the TGA that the mechanism of action for the clinical claim is a result of the intrinsic characteristics and functions of amniotic tissue, and that the manufacturing process does not alter these relevant characteristics. Note that although the processing step may be considered minimal manipulation, the intended use may not be considered to be homologous.
  5. Platelet-rich plasma and conditioned serum example:
    1. Preparation of platelet-rich plasma from a single uninterrupted venipuncture, for injection in to damaged tissue. Generally the processing involved does not alter the functions of the platelets so is considered minimal manipulation.
    2. Culturing blood to produce a conditioned serum for injection in to damaged tissue. The serum is cultured to induce the white blood cells to produce anti-inflammatory compounds in to the serum, so this processing is considered more than minimal manipulation. In addition, the culturing raises safety concerns around the growth of microorganisms.

Homologous use

Homologous use refers to:

  • The repair, reconstruction, replacement or supplementation of a recipient's cells or tissues with cells or tissue that perform the same basic function or functions in the recipient as the donor

Where this definition is not met, compared with a homologous use, there would be increased safety and efficacy concerns with the use of the HCT as there is less information on which to predict the behaviour of the product.

For clarity, distinguishing between homologous or non-homologous use also applies to autologous use of HCTs, with the donor and recipient being the same person.

In determining whether the use of the HCT is homologous, the intended clinical treatment will be carefully considered, including review of the manufacturer's labelling and advertising material.

When the use of HCT is identical in the donor and the recipient, e.g. skin grafts collected from one area and used to replace damaged skin in another location, this is accepted as a homologous use.

The determination of homologous use may be complex in some circumstances where the donor HCT is not identical to the cells or tissue that will be repaired, reconstructed, replaced or supplemented in the recipient, but it performs the same basic functions. Generally, in this situation it would be considered to be homologous use if the manufacturer provides sufficient evidence to support the claim. Where treatment involves an unproven clinical use it is likely to be considered to be a non-homologous use.

Defining basic functions of human cells and tissues

When defining the basic function or functions of HCTs we mean those that are well understood (scientifically) to apply to the donor tissue, and where functionality can be assumed in the recipient in the absence of a need to perform testing. It is not necessary for all functions of the HCT to be maintained and performed in the recipient, only those claimed in the intended use.

The HCT may perform the same basic function or functions even when it is not used in the same anatomic location where it occurred in the donor.

Examples to demonstrate homologous use

Some of the examples provided are taken from the FDA guidance on the definitions and interpretation of homologous use, but others differ in interpretation from their guidance and represent TGA's current interpretation.

  1. HPC examples: Sources of hematopoietic stem/progenitor cells (HPCs) include cord blood, peripheral blood, and bone marrow. The basic functions of HPCs include forming and replenishing the lymphohematopoietic system.
    1. HPCs from mobilized peripheral blood are intended for transplantation into an individual with a disorder affecting the hematopoietic system that is inherited, acquired, or the result of myeloablative treatment. This is homologous use because the peripheral blood product performs the same basic function of reconstituting the hematopoietic system in the recipient.
    2. HPCs from bone marrow are intended for infusion into an artery with a balloon catheter for the purpose of limiting ventricular remodelling following acute myocardial infarction. This is not homologous use because limiting ventricular remodelling is not a basic function of bone marrow.
    3. HPCs from cord blood are intended for intravenous infusion to treat cerebral palsy purportedly through the repair of damaged tissue in the brain through paracrine signalling or differentiation into neuronal cells. This is not homologous use because there is currently insufficient evidence to support that repair of neurologic tissue through paracrine signalling or differentiation into neuronal cells is a basic function of these cells in the donor.
  2. Amniotic membrane example. Some basic functions of amniotic membrane include:
    • serving as a selective barrier for the movement of nutrients between the external and in utero environment, and
    • protecting the foetus from the surrounding maternal environment, and
    • serving as a covering to enclose the foetus and retain fluid in utero.

FDA also recognise potential functions for the tissue including reducing scarring, angiogenesis, and inflammation, but advise that they are not basic functions of the amniotic membrane when associated with the foetus. Therefore, where any of potential functions are claimed as the intended they are considered to be non-homologous uses of amniotic membrane by the FDA.

In contrast, where these additional functions can be demonstrated (experimentally) by a manufacturer to also be active in the donor, we will consider these functions to be homologous. Therefore, the following represents our current position on homologous use of amnion.

  1. An amniotic membrane product is applied to the surface of the eye to cover or offer protection from the surrounding environment in ocular repair and reconstruction procedures. This is homologous use because serving as a covering and offering protection from the surrounding environment are basic functions of amniotic membrane.
  2. Amniotic membrane is used to support bone regeneration following surgery to repair or replace bone defects. This is not a homologous use because bone regeneration is not a basic function of amniotic membrane.
  3. An amniotic membrane product is to be used for wound healing and/or to reduce scarring and inflammation. The barrier function of the membrane is considered homologous use. However, based on current evidence, the other functions are not considered to be homologous use, unless these additional functions can be demonstrated by a manufacturer to also be active in the donor.
  1. Adipose tissue and cell extracts example. Adipose tissue may be collected and then re-injected with minimal manipulation, or may be subjected to processing to extract the cellular portion from the tissue. Generally the HCT extracted from adipose includes various cellular fractions (of varying purity), and are collectively referred to as Stromal Vascular Fraction (SVF). Where the adipose tissue is the HCT to be provided to the recipient the basic functions include:
    1. providing cushioning and support for other tissues, including the skin and internal organs
    2. storing energy in the form of lipids, and
    3. insulating the body.

In contrast, where the HCT provided to the recipient is a cell extract, the determination of homologous use would make reference to the basic functions of the cells located in the adipose, rather than those of the tissue collectively. This may be complicated by the need to understand the cells and mechanisms responsible for the desired mode of action. The following represents our current thinking on homologous use of adipose tissue and cell extracts from this tissue:

  1. Adipose tissue is used for transplantation into the subcutaneous areas of breast for reconstruction or augmentation procedures. This is homologous use because providing cushioning and support is a basic function of adipose tissue.
  2. Stromal Vascular Fraction (SVF) isolated from adipose tissue is used to treat musculoskeletal conditions, such as arthritis or tendonitis by regenerating or promoting the regeneration of articular cartilage or tendon. This application is not considered a homologous use because regenerating or promoting the regeneration of cartilage or tendon is not a basic function of the cells isolated from adipose tissue.
  1. Platelet-rich plasma example. The mechanism of platelet–rich plasma action in the treatment of musculoskeletal disorders remains to be determined and evaluation of platelet–rich plasma in clinical trials is in its infancy. The basic functions that would apply to platelet-rich plasma are based on the understanding of the normal healing process of musculoskeletal tissue. The repair response of musculoskeletal tissues starts with the formation of a blood clot and degranulation of platelets. This degranulation of platelets releases a range of growth factors and cytokines into the local environment that trigger a cascade of events that lead to healing of the wound. Where it can be demonstrated or justified that the intended use of PrP can augment or stimulate healing by turning on the same repair response it could be considered to be a homologous use.

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