A novel immunotherapy is garnering much excitement for its ability to treat cancers. Called Chimeric Antigen Receptor T-cell therapy, known as CAR-T, involves using a patient’s own (autologous), or another individual’s (allogenic) human cells to treat cancer. The process involves obtaining a patient’s blood, isolating the white blood cells, engineering cancer fighting cells into those cells, then returning the cells to the patient’s body. The cells that are returned to a patient include the T-cells (original white blood cells) and a CAR. The intention is the CAR-T cells will then attack the cancerous cells.
This article was originally published in the Lexis Nexis Health Law Bulletin Volume 31 No 10.
This article discusses the regulation of CAR-T therapy in Australia, including considerations for commercialising the product across the Australian states and territories in light of existing state-based human tissue regulation, and future liability risks.
Key takeaways for manufacturers and suppliers: An overview
- Adequate protocols for the management of treatment must be put in place to ensure informed consent is obtained at the initial stage of collecting the patient’s blood cells, and each stage following.
- Manufacturers and suppliers should consider the concept of ownership in the cells at each stage of the process and cover any such transfer of ownership within patient authorities and/or consents.
- Due to the complicated process of extraction and manufacture, the classification of the tissue at each stage needs to be carefully considered within the confines of each of the relevant state/territory human tissue legislation.
- Advertising rules in respect of CAR-T may differ from state to state due to state-based legislation on human tissue.
- Similar to considerations for other products on the Australian Register of Therapeutic Goods (ARTG),1 manufacturers should ensure they provide adequate warnings at each stage of the treatment in respect of the risks of the therapy.
CAR-T therapy in Australia
In Australia, there are currently 3 CAR-T cell therapies approved for use by the Therapeutic Goods Administration (TGA): Kymriah® sponsored by Novartis, and Yescarta® and Tecartus®, both sponsored by Gilead. These approved treatments are regulated as biologicals used for autologous treatment.
Regulation under the Therapeutic Goods Act
Therapeutic goods are regulated by the TGA, a division of the Department of Health of the Commonwealth government through the Therapeutic Goods Act 1989 (Cth) (TG Act). The TGA is responsible for regulating the supply, import, export, manufacturing and advertising of therapeutic goods in Australia. The TG Act defines a 'therapeutic good' as one that is represented to be or is likely to be for therapeutic use, for use as an ingredient or component in the manufacture of a therapeutic good and includes biologicals and medical devices.2
A therapeutic good that is to be imported, exported or supplied must be included in the Australian Register of Therapeutic Goods (ARTG), unless it is excluded from the TG Act or specifically exempted from being included.3
Exemptions are allowed under certain circumstances including in the case of emergency, shortages or when a healthcare practitioner has been granted specific approval to import or supply medicines not on the ARTG (such as under the Special Access Scheme).4
Biologicals regulation
In 2011 following extensive review and consultation within the life sciences sector, a new framework was introduced to regulate emerging biotherapies, called the Regulatory Framework for Biologicals (RFB). Prior to this the TG Act was written in terms of medicines and devices, with the consideration of cellular and tissue-based products unclear. The additions meant that a new category of therapeutic goods had been created, dubbed Biologicals. This is contained within Pt 3-2A of the TG Act. In addition, the Therapeutic Goods Regulations (TG Regulations)5 were amended, and the Australian Regulator Guidelines for Biologicals were published to contain guidance for consumers, practitioners and manufacturers of biologicals.
The aim of the framework was to improve the regulation of human tissues and cell-based therapies.6
The TG Act defines biologicals as a thing that either comprises, contains or is derived from human cells or human tissues, and is represented in any way to be, or is, for use in the treatment or prevention of a disease, making a medical diagnosis, modifying a physiological process in a person, testing the susceptibility of persons to a disease or ailment or in the replacement or modification of parts of the anatomy in persons (s 32A).
Following the extraction of the blood cells, the cells are frozen and taken to the facility at which they will become CAR-T cells. At this point, under the TG Regulations, they are deemed 'blood components', and later at the transformation into CAR-T cells, they are deemed biologicals and regulated under the TG Act accordingly.
Other examples of biologicals include cells and cell therapies, skin grafts or bone grafts and products derived from human cells. A biological may also be specified by way of legislative instrument.7 In turn, a legislative instrument can also determine that a specified thing is not a biological for the purposes of the TG Act.
Manufacturing requirements
The TGA has developed Australian-specific standards for the manufacture of biologicals, human blood and blood components and haematopoietic progenitor cells. The Therapeutic Goods (Standards for Biologicals — General and Specific Requirements) (TGO 109) Order 20218 and Therapeutic Goods (Standard for Biologicals — Labelling Requirements) (TGO 107) Order 20219 (the Standards) set out the general manufacturing and quality requirements for therapeutic goods comprising those derived from or containing human cells or tissues, and it also regulates the consistency of product quality, including labelling quality.
As part of the registration evaluation process under the ARTG, the TGA must evaluate whether the manufacturing and quality control procedures used to manufacture the biological are acceptable.10 Once registered, the TGA must certify that manufacturing steps taken outside of Australia are acceptable.11
State-based human tissue legislation
CAR-T is the result of human tissue and is therefore arguably covered by the prohibition on the trade of human tissue products set out in the various state and territory human tissue legislation.12 The human tissue legislation broadly define 'tissue' as including organs, parts of the human body and substances extracted from the human body.13 However, each state/territory Act has exceptions to this prohibition.
- New South Wales, Queensland, South Australia and Tasmania — there is an express exemption where the tissue has been subjected to processing or treatment and is supplied for use in accordance with the directions of a medical practitioner for therapeutic, medical or scientific purposes.14
- Australian Capital Territory — an exemption to the supply of tissue for consideration applies to tissue which has been processed or treated for therapeutic or scientific purposes, but this exception does not apply to blood or any of its constituents.15 It is possible for Ministerial approval to override this specific prohibition.16
- Northern Territory — the supply of tissue for valuable consideration is prohibited, however similar to the Australian Capital Territory, the Minister can authorise a person to enter a contract if satisfied that there are special considerations to do so.17
- Victoria — the selling and buying of tissue is prohibited unless the sale is to a person holding a permit to buy the tissue.18 It is unclear whether CAR-T once manufactured would constitute 'tissue', noting it is not a substance 'extracted' from the human body, owing to having been modified since its extraction.
- Western Australia — the supply of tissue for valuable consideration is prohibited. However the Governor may make an Order exempting products derived from tissue that has been subject to processing or treatment. Similar to Victoria, it is unclear whether CAR-T would properly be considered 'tissue' given at its manufacturing completion, it is arguably a substance extracted from the human body.
Advertising
Generally, biologicals cannot be advertised to the public. In addition, under the TG Act, HCT products that are regulated as biologicals are prohibited from being advertised to the public.19 They can, however, can be advertised exclusively to health care professionals. However, under the Queensland, Western Australian and Victorian human tissue legislation, advertisements relating to the buying of tissue are prohibited, unless the proposed advertisement has been approved by the Minister and contains a statement to that effect.20 Arguably, in these states, CAR-T therapy would not be able to be advertised to healthcare professionals due to the comprehensive ban in their relevant human tissue legislation.
Common law considerations
Under the common law, there are additional considerations that apply. Property rights to human tissue has previously been considered by the Australian courts. The earliest cases in this area concern issues relating to who owns a human body after death. In Australia, the legal position is set out on the decision in the case of Re Cresswell21 where Brown J determined that there were property rights in the samples of sperm that had been released from a deceased man. Her Honour found that despite the application of work or skill, property rights could still be found.22
It is difficult to determine whether the same considerations in Re Cresswell would apply in circumstances where the tissue was taken from a live patient for medical purposes prior to being manufactured into therapy. However, noting the uncertainty, manufacturers should consider the concept of ownership in the cells at each stage of the process, and cover any such transfer of ownership within patient authorities and/or consents. This is likely to be a more significant issue in the case of allogenic as opposed to autologous CAR-T cells.
Liability risks
As a product on the ARTG (despite it potentially being the patient’s own tissue) appropriate warnings must be given by both clinicians involved and manufacturers. Adequate warnings relevant to each patient should be provided at each stage of the process in compliance with the requirements of the Australian Consumer Law such that they are of acceptable quality and fit for the purpose specified.23 Failing to do so could result in an action against the manufacturer or sponsor for a breach of the consumer guarantees or misleading and deceptive conduct claim under the Australian Consumer Law.
In addition to product liability risks, the CART-T cell treatment gives rise to medical liability issues. In particular, it is critical that informed consent must be obtained by the administering practitioners at each stage of the process in order to legally and ethically remove the blood from a patient’s body prior to any subsequent processing. The removal of blood cells without a patient’s consent gives rise to an action in battery under the common law and the failure of a doctor to disclose relevant information regarding the treatment, in particular, any side effects and risks can give rise to an action in negligence.24
Conclusion
The regulation of CAR-T therapy under the federal TGA Act is comprehensive and provided with relevant guidance from the TGA. In regulating CAR-T under the common law, there is little to be gleaned from case law concerning property rights of tissue from deceased corpses, however it is nonetheless an important consideration for manufacturers in terms of making clear the ownership of the tissue at each stage of the therapy and ensuring that proper consent is gained in line with the informed consent principles.
In relation to the state-based human tissue Acts, it is clear that there is some inconsistency across the states and territories. There should be some alignment of the different legislation to ensure consistency in manufacturers and sponsors being in a position to commercialise their products amongst the states. Further clarity in respect of commercialisation of new products using tissue also needs to be considered to enable manufacturers to understand the limits with respect to promoting and selling their products.
1 www.tga.gov.au/resources/artg.
2 Therapeutic Goods Act 1989 (Cth) s 3.
3 Therapeutic Goods (Excluded Goods) Determination 2018 (Cth).
4 Therapeutic Goods Act 1989 (Cth), ss 18A, 19, 19A, 32CB, 32CK, 32CM, 32CO.
5 Therapeutic Goods Regulations 1990 (Cth).
6 Therapeutic Goods Administration, 'Regulatory Framework for Biologicals', 17 August 2020, online at: www.tga.gov.au/regulatory-fram....
7 Therapeutic Goods Act 1989 (Cth) s 32A(2).
8 Therapeutic Goods (Standards for Biologicals — General and Specific Requirements) (TGO 109) Order 2021, online at: https://legislation.gov.au/Det....
9 Therapeutic Goods (Standard for Biologicals — Labelling Requirements) (TGO 107) Order 2021 at www.legislation.gov.au/Details....
10 Therapeutic Goods Act 1989 (Cth) s 32DE(1)(e).
11 Therapeutic Goods Act 1989 (Cth) ss 32EA and 32EB.
12 Transplantation and Anatomy Act 1979 (Qld); Human Tissue Act 1983 (NSW); Human Tissue Act 1982 (Vic); Transplantation and Anatomy Act 1983 (SA); Human Tissue Act 1985 (Tas); Human Tissue and Transplant Act 1982 (WA); Transplantation and Anatomy Act 1978 (ACT); Human Tissue Transplant Act 1979 (NT).
13 Transplantation and Anatomy Act 1979 (Qld), s 4; Human Tissue Act 1983 (NSW), s 4; Human Tissue Act 1982 (Vic), s 3; Transplantation and Anatomy Act 1983 (SA), s 5; Human Tissue Act 1985 (Tas), s 3; Human Tissue and Transplant Act 1982 (WA), s 3; Transplantation and Anatomy Act 1978 (ACT), s 4; Human Tissue Transplant Act 1979 (NT), s 4.
14 Transplantation and Anatomy Act 1979 (Qld), s 42AA(1); Human Tissue Act 1983 (NSW), s 32(2); Transplantation and Anatomy Act 1983 (SA), s 35(3); Human Tissue Act 1985 (Tas), s 27(2).
15 Transplantation and Anatomy Act 1978 (ACT), s 44(1), (2).
16 Transplantation and Anatomy Act 1978 (ACT), s 44(4).
17 Transplantation and Anatomy Act 1979 (NT) s 22E.
18 Human Tissue Act 1982 (Vic) ss 38 and 39.
19 Therapeutic Goods Act 1989 (Cth) s 42DL(11).
20 Transplantation and Anatomy Act 1979 (Qld) s 41; Human Tissue Act 1982 (Vic), s 40; Human Tissue and Transplant Act 1982 (WA) s 3.
21 [2019] 1 Qd R 403; [2018] QSC 142; BC201805255.
22 Above, at [163].
23 Competition and Consumer Act 2010 (Cth); Australian Consumer Law, Sch 2.
24 Rogers v Whitaker (1992) 175 CLR 479; 109 ALR 625; 67 ALJR 47; BC9202689.
