Regulation Policy for Cell and Tissue Therapies in Australia

Introduction

Therapeutic goods in Australia are regulated by the Therapeutic Goods Administration (TGA), a division of the Department of Health of the Australian Government. The TGA regulates the safety, quality, and efficacy of therapeutic goods for Australia. It does this by setting standards, maintaining the Australian Register of Therapeutic Goods (ARTG), evaluating safety, quality, and efficacy before registration, monitoring products on the market, licensing manufacturers, performing ongoing audits, and by controlling access to unregistered products. The TGA is empowered under the Australian Government Therapeutic Goods Act 1989 and associated legislation. ¹

Therapeutic goods are considered to be any products used to treat, prevent, or diagnose diseases, ailments, defects, or injuries and include medicines for treating and preventing health conditions, as well as medical devices and diagnostic tests. In 2011, following an extensive review and consultation with the sector, a new regulatory framework in Australia was introduced to accommodate the emerging biotherapies. The main driver for this change was that the original Therapeutic Goods Act had been written in terms of medicines and devices, and the requirements for cell- and tissue-based products were ambiguous. There were exemptions in the Act for medicines and devices that were not appropriate for tissues, and stronger regulation for the minimization of infectious disease transmission was indicated. In addition, since the worldwide movement of cell- and tissue-based products was evolving, international harmonization of regulatory standards would assist in exchange and availability of products within the different jurisdictions. Given the rapid development and diversity of the emerging biotherapies, regulation needed to be flexible to respond to technology changes, with the adoption of a risk-based approach preferred. In 2011, the Biologicals Regulatory Framework was introduced, with full implementation occurring in June 2013 and compliance by manufacturers required by July 2014. ² The framework provides the legislation for the regulation of human cell- and tissue-based therapies that are for supply in or export from Australia.

In the new regulatory framework, therapeutic goods are now classified into three groups as medicines, medical devices, or biologicals (Fig. 1). Before the introduction of the Biologicals Regulatory Framework, products were regulated as Medicines, Devices, and Blood and Tissue. For blood and tissue, the code of good manufacturing practice (cGMP)—Human Blood and Tissues 2000 ⁴ was the standard to which compliance for biologicals was required, but this code had been primarily designed for the blood sector and did not adequately accommodate human tissues and the emerging biological therapies. Subsequently, following consultation with the sector, the Biologics Regulatory Framework was developed and implemented with a new code of GMP and some specific regulatory orders. The scope of this review is limited to the regulation of biologicals.

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FIG. 1.

Classification of Australian therapeutic goods. Adapted from TGA Australian Regulatory Guidelines for Biologicals Part 1 V1.0 June 2011. ³ TGA, therapeutic goods administration.

Biologicals

As part of the update of regulations to meet the emerging human cell and tissue therapies, the Australian Therapeutic Goods Act was amended to define biologic as “an item made from, or containing, human cells or human tissues that is used to treat or prevent disease or injury, diagnose a condition of a person, alter the physiological processes of a person, test for susceptibility of a person to disease or to replace or modify a person's body part(s).” ⁵ Although this definition is sufficiently broad to capture most applications of human cell- and tissue-based products, an item may also be specified as a biological by the authorities.

To be captured under the new regulations for biologics, a product must fall under the definition of a therapeutic good. In addition, some products may be excluded or exempted as being a biologic by declaration and are discussed later. The new regulations do not apply to products of nonhuman biological sources (animal or bacteria) or to medicines made from biological or biotechnology sources. Human tissue therapy products that are regulated as a biologic include skin, musculoskeletal tissue such as bone and tendon, cardiovascular tissue such as heart valves, and ocular tissue such as the cornea. Human cellular therapy products that are regulated as a biological include stem cells such as mesenchymal stem cells, neural and epithelial stem cells, and progenitor cells, such as hemopoietic cells, for use other than hemopoietic restoration. Other human cell-based products, such as fibroblasts, epithelial cells, and chondrocytes, are subject to regulation, as are immunotherapy products such as cell-based tumour vaccines and human cellular vaccines. Genetically modified cells are also captured.

For those products consisting of more than a single component, the classification under which therapeutic goods class the product falls is more complicated. ⁶ In the case of combination products, where a biological is combined with a medical device, the product is regulated and listed as a biologic. For kits, systems, or procedure packs containing individually packaged therapeutic goods and which may include combinations of medicines, medical devices, and biologicals, regulation is dependent on the combination. For a combination of a biological and a medicine, the kit is regulated as a listable medicine. For a biological and medical device or biological, medicine, and medical device, the system or procedure pack is regulated as a medical device. For a biological combined with a biological, the Biological Kit is regulated as a biologic. However, any biologic included in a kit, system, or pack must be individually included on the ARTG before the regulatory application for the combination can be made.

Biologic Framework Exclusions

Various exclusions and exemptions exist within the new framework for human cellular and tissue products. There are some biologics that have been declared as not a therapeutic good and are, therefore, excluded from regulation. Excluded goods are listed in the Therapeutic Goods (Excluded Goods) Order No. 1 of 2011. ⁷ They include fresh viable human organs or parts of human organs for direct donor to host transplantation, fresh allogeneic hemopoietic progenitor cells (HPCs) for hemopoietic restoration, and reproductive tissues that are unmanipulated. Products can also be excluded if the collection and manufacture of the fresh viable tissues or cell human tissue and cells are for a single course of treatment under the professional supervision of a single medical practitioner for a single patient.

Biologic Framework Exemptions

Some human cellular and tissue products that fall under the definition of biologics are regulated as therapeutic goods, but not as a biologic. They are declared as to not be a biological and are currently regulated as either a medicine or a medical device. ⁸ Human tissues for diagnostic use and animal tissue products are regulated as therapeutics goods, but not as a biological. Products that are declared not to be biologicals include HPCs used for hemopoietic reconstitution (other than those previously excluded), cells and tissues used for diagnostic purposes in an individual, blood and blood components, and in vitro diagnostic devices. In addition, biological medicines such as vaccines that do not contain viable human cells, recombinant products, and plasma-derived products or products containing plasma-derived products are declared as not to be a biologic. It may be that at a later time the status of these products will change and that they may eventually be regulated as a biological.

Classification of Biologicals

The new regulations have taken a risk-based approach to the classification of products, with the degree of regulatory oversight related to the perceived degree of risk. There are four classes (1–4), with the classification level based on both the extent of manipulation during processing and whether the intended use for the product is its usual biological function. ⁹ Alternatively, a product may be declared by order to a specific class. The classification system is summarized in Table 1. Minimal manipulation is understood to mean a process involving any of the following actions: centrifugation; trimming; cutting or milling; flushing or washing; refrigeration; freezing; freeze drying (of structural tissues only); the use of additives such as cryopreservatives, anticoagulants, antimicrobial agents; irradiation for the purpose of bioburden reduction; and any other action that is similar to an action mentioned in this list.

The regulatory compliance for each of these classes increases with the classification and is summarized in Table 2. Products from all the classes are required to be listed on the ARTG. Since class 1 products are considered very low risk, only a declaration of compliance with relevant standards is required. A manufacturing licence is not required. Currently, there are no class 1 products specified. For the other three classes, compliance to standards is assessed through a dossier submission, which is evaluated to ensure compliance with relevant Therapeutic Goods Orders (TGOs), such as product-specific standards and labeling standards, as well as with default standards, such as pharmacopoeia monographs. Dossier requirements for clinical data increase with the classification of a product.

Class 2 products are considered as low risk and manufacturers must comply with cGMP and provide a product manufacturing dossier demonstrating compliance with the relevant standards according to the guidelines for class 2 biologicals. ¹⁰ Examples of class 2 products are bone allografts, heart valves, and corneal tissue.

Class 3 products are medium risk and manufacturers, as well as demonstrating conformance to cGMP and compliance to relevant standards, must demonstrate safety, quality, and efficacy, based on clinical trial data. A dossier according to class 3 dossier guidelines must be submitted. ¹¹ Examples of class 3 products include culture-expanded cells such as keratinocytes and mesenchymal stromal cells.

The class 4 products are associated with the highest risk. In addition to demonstration of cGMP conformance and compliance to the relevant standards, clinical data analysis must demonstrate safety, quality, and efficacy. The class 4 dossier submission is, therefore, more complex and must meet the class 4 requirements. ¹² Examples of a class 4 product are genetically modified cells.

Therapeutic Goods Regulations

Apart from defining what is captured by the regulation, the regulatory framework defines manufacturing principles and sets standards for compliance. The new Australian cGMP was introduced in 2013 to replace the previous code of 2000, which was specifically developed for the blood and tissues sector. ¹³ The new code aimed to harmonize with standards, product with compliance required by July 2014. In addition, a number of TGOs have been developed, some of which apply generally while others are tissue-type specific. TGO 88 relates specifically to donor selection and addresses the minimization for the transmission of infectious diseases. ¹⁴ TGO 87 sets out the standards for labeling of biologicals. ¹⁵ TGO 84, 83, 85, and 86 are the product-specific standards for cardiovascular, musculoskeletal, ocular, and skin, respectively.^16–19 These are minimal standards, detailing the minimum technical requirements for the specified tissue. As the framework matures, other TGOs may be developed for other product types and processes. Where no standard currently exists, reference to general default standards, which are statements and monographs in the latest editions of the British Pharmacopoeia, European Pharmacopoeia, or the US Pharmacopoeia, is made. ³

Australian Register of Therapeutic Goods

Therapeutic Goods in Australia must be listed on the ARTG before they are supplied, imported, or exported in Australia. ²⁰ The only times this does not apply is if the products are excluded or exempted or otherwise authorized or approved. Before a biological can be included on the ARTG, it must meet the regulatory requirements, as previously described for the product class, and the manufacturer must hold an appropriate manufacturing licence or, in the case of overseas manufacturers, must have been given clearance by the TGA. Once listed, the TGA continues to review and monitor the products to ensure all requirements are met and collects reports on possible risks and adverse events. Manufacturers are expected to perform postmarketing surveillance and notify TGA of any serious adverse events or risks relating to listed products. Any listed product on the register can be modified, suspended, or removed as appropriate by the TGA.

In some cases, products regulated as a biological may be supplied on the market before listing on the ARTG. This may apply to the use of a biologic for emergency use or for compassionate use. The Special Access Scheme (SAS) permits the importation or supply of an unapproved biological for a single medical procedure or for personal importation, while the Authorized Prescriber Scheme allows access to particular unapproved biologicals for certain patients and classes of patients. ²¹ In addition, unapproved biologicals may be permitted when an approved equivalent is unavailable or in limited supply.

Biologics provided for clinical trial evaluation, although subject to regulation, are exempt from listing on the ARTG. However, the TGA requires notification of the products and clinical trial through the Clinical Trial Notification (CTN) Scheme or by application through the Clinical Trial Exemption (CTX) Scheme. ²¹ Under the CTN scheme, Human Research Ethics Committees, of the relevant institutions conducting the clinical trial, are responsible for reviewing and approving the provision of the trial product. Under the CTX scheme, the TGA evaluates the investigational product and clinical trial protocol and may raise concerns over the product or to the proposed usage. The CTX scheme is usually accessed for products considered of higher risk. Authorization must be received before a trial can proceed under either CTN or CTX.

Discussion

The new regulatory framework for Therapeutic Goods in Australia has generally been endorsed and accepted by biologic manufacturers as providing greater clarity to regulatory requirements. The risk-based approach to product classification and escalating requirements for the different classes of products are in line with other regulatory jurisdictions. However, the retention of exemptions and exclusions to regulatory oversight has allowed manufacturing and importation of therapies under medical practice to circumvent regulations in Australia. This has resulted in commercial clinics being able to manufacture, supply, and market unproven autologous cell therapies without any formal regulatory oversight. It also has permitted the import and supply of unregistered allogeneic products under SAS. This is not in line with other jurisdictions and may need to be addressed to ensure that safety, quality, and efficacy standards are maintained for products supplied in Australia.

With the roll out of the framework, there have been difficulties encountered by both the regulators and manufacturers as they grapple to determine the depth of dossier requirements for the different classes of products. The simplification of the code of GMP with the development of TGOs and product-specific standards has resulted in a more defined regulation that is less subject to interpretation. However, the ability to perform and meet requirements of TGO88, the order for donor selection, testing, and the minimization of infectious disease transmission, has provided challenges in both availing the testing and also in meeting requirements, including for epidemiological monitoring, particularly for cadaveric donors. Biovigilance responsibilities for products have also impacted on manufacturers. Hopefully, as manufacturers progress with the new regulatory process, compliance will be more easily demonstrated and the regulatory process becomes more streamlined.

Summary

In summary, there has been a significant change to the regulation of therapeutic goods in Australia to accommodate the emergence of biotherapies. Cell and tissue therapies are classified as biologicals and regulated through compliance to a newly developed cGMP and to more general and specific TGOs. Compliance must be demonstrated through a dossier submission. As with many other jurisdictions, a risk-based approach has been taken so that those products of perceived highest risk are subject to greater regulatory oversight and more rigorous dossier requirements to demonstrate safety, quality, and efficacy. Approved products are then listed on the ARTG before being generally available for supply. There are some exclusions and exemptions to the regulations that have been retained in the new regulatory framework, some of which relate to the declaration of a product as not to be a therapeutic good or not to be a biological and others as falling under the medical practice exclusion. The exclusion under medical practice is currently allowing unproven therapeutic products to be supplied without regulatory oversight. However, overall, the new regulatory framework has provided greater clarity for manufacturers of cell and tissue therapies and has attempted to harmonize with international standards as far as possible.