The Therapeutic Goods Administration (TGA) has recently announced changes to the biologicals regulatory framework to introduce regulatory requirements around autologous human cell and tissue therapies, including stem cells. The proposed changes, expected to take effect from 1 July 2018, will bring the Australian regulatory framework into better conformity with corresponding US and European law, offering greater certainty to pharmaceutical companies developing autologous cell therapies. The proposed changes also aim to protect consumers from off-clinical trial use of experimental therapies. From a commercial perspective, the inclusion of autologous human cell and tissue therapies on the Australian Register of Therapeutic Goods (ARTG) should also provide for patent term extensions.
Human autologous cell and tissue therapy
Autologous cell and tissue therapy requires cells and/or tissue to be removed from, and then reinfused or applied to, the patent. Examples of autologous cell and tissue products include blood and blood components (i.e., erythrocytes, plasma, serum, platelets and platelet-rich plasma), skin grafts, bone grafts, genetically modified lymphocytes (e.g. CAR-T cells) and stem cells.
Under current law (Therapeutic Goods (Excluded Goods) Order No. 1 of 2011), certain categories of autologous human cell and tissue products are not considered therapeutic goods and can therefore be supplied without approval by the TGA. They include human autologous cells and tissue that are:
- Collected from a patient who is under the clinical care and treatment of a medical practitioner registered under a law of a State or an internal Territory; and
- Manufactured by a medical practitioner, or by a person or persons under the professional supervision of that medical practitioner; and
- For therapeutic application in the treatment of a single indication and in a single course of treatment of a patient by the same medical practitioner, or by a person or persons under the professional supervision of the same medical practitioner.
These exclusions were largely motivated by the limited application of human autologous cell and tissue therapies at the time the Order was made. The use of human autologous cells and tissues had also been restricted to either unmodified or minimally modified cells in well established procedures with proven safety and efficacy.
More recently, the industry has seen a growth of autologous cell and tissue therapies for a broad range of indications. In the context of stem cell therapies, the limited regulation in Australia has allowed for the emergence of direct-to-consumer therapeutic services based on little-to-no peer-reviewed evidence or clinical trial data to establish efficacy. Currently, there are a number of clinics throughout Australia that are offering stem cell therapies outside of clinical trials for the treatment of osteoarthritis and muscular pain, infertility, sports injuries, cancers, muscular dystrophy, multiple sclerosis, stroke and cosmetic application, such as facial rejuvenation and other anti-aging therapies. In addition, development in ex vivo cell culture and expansion technology has facilitated greater manipulation of cells, which increases the risks associated with patient response and safety, in addition to cell handling and manufacturing risks that may impact on product potency, purity, identity, traceability, safety and stability.
The increased risks associated with human autologous cell and tissue products prompted the TGA to conduct a comprehensive review of the biologicals regulatory framework to ensure that human autologous cell and tissue products are properly regulated in Australia. Similar reviews have previously been conducted by the FDA and the European Medicines Agency, which resulted in the regulation of human autologous cells and tissues, such as human cells, tissue, and cellular and tissue-based products (HCT/Ps) in the US and advanced therapy medicinal products (ATMPs) in Europe. As a result of these changes, a number of human autologous cell and tissue therapies are now registered in the US and Europe. The introduction of similar requirements for the regulation of human autologous cell and tissue products in Australia should provide more certainty and consistency for pharmaceutical companies looking to enter the Australian market.
Proposed regulation of human autologous cell and tissue products by the TGA
The proposed regulatory changes to the TGA’s biologicals regulatory framework were recently reported by Penny Field of Bioregulatory Consulting (article available here). As noted in Penny’s article, the proposed changes seek to clarify the type of human autologous cell and tissue products that are to be (i) excluded from regulation by the TGA, (ii) exempt from some regulatory requirements or (iii) fully regulated by the TGA.
Given the strict definitions associated under the revised guidelines, it is likely that a vast majority of human autologous cell and tissue products currently in use will be fully regulated by the TGA as biologicals. The Therapeutic Goods Regulations 1990 classifies biologicals based upon the level of modification or manipulation that the products are subject to and how closely their intended use matches their original biological function. For instance, Class 1 and 2 biologicals are minimally manipulated (e.g., centrifugation, washing, refrigeration, freezing, etc.) for homologous use. Class 3 biologicals are prepared using more complex methods, such as enzymatic dissociation, without altering the inherent biological properties of the product (e.g., demineralised bone, cultured fibroblasts for skin repair and mesenchymal stem cells for the treatment of graft-versus-host disease). Class 4 biologicals are high-risk, typically prepared using complex biological manipulation, such as genetic modification, that alter the properties of the product (e.g., genetically modified dermal fibroblasts for the treatment of muscular dystrophy, CAR-T cells, iPSCs).
Each of the products falling within these classes must comply with all applicable standards, reporting requirements for adverse events, conditions relating to records and reporting, advertising restriction, registration on the ARTG and manufacturing licencing or certification requirements. When the proposed changes come into effect, human autologous cell and tissue products that were not previously subject to these regulations will be required to conform to the new requirements.
Patent term extension for autologous cell and tissue products
Under Australian law, a patent term extension of up to 5 years is available for a granted patent where one or more pharmaceutical substances per se (or pharmaceutical substances produced by recombinant DNA technology) are disclosed in the specification and in substance fall within the scope of the claim or claims of that patent. In addition, goods containing, or consisting of, the pharmaceutical substance must be included in the ARTG and the period beginning on the date of the patent and ending on the first regulatory approval date for the substance must be at least five years.
For the purposes of patent term extension, a pharmaceutical substance includes “a substance (including a mixture or compound of substances) for therapeutic use whose application (or one of whose applications) involves a chemical interaction, or physicochemical interaction, with a human physiological system.” It is expected that human autologous cell and tissue products would to satisfy this requirement, insofar as they are “for therapeutic use whose application (or one of whose applications) involves a chemical interaction, or physicochemical interaction, with a human physiological system”.
For these reasons, the proposed regulatory changes to the TGA’s biologicals regulatory framework, as outlined above, should pave the way for patent term extensions for eligible claims that are directed to human autologous cell and tissue products and where such products are included on the ARTG.
The TGA expects the proposed regulatory changes to its biologicals regulatory framework to come into effect on 1 July 2018.
The proposed regulation of human autologous cell and tissue products represents an important step in ensuring that Australian consumers are protected from the increased risks associated with the use of such products, in particular those that have not been subjected to rigorous clinical testing for efficacy and safety. The proposed regulatory changes will also bring Australia into better conformity with the US and Europe. Harmonisation of regulatory requirements for pharmaceutical products allows for greater consistency in the approach taken to obtaining regulatory approval in key jurisdictions. The registration of pharmaceutical products on the ARTG is also likely to provide an opportunity for patent holders to secure patent term extensions for up to five years.