Navigating the regulatory
terrain down under:
trends in Australia for 2024

Regulatory Rapporteur

March 2024  |  Volume 21  |  No.3

Introduction

Australia is the most populous country in Oceania, and ranks 55^th globally with its population around 26 million. It also ranks consistently high in other indicators that demonstrate the country’s above-average wealth. Factors such as a skilled workforce, high-quality research infrastructure, government incentives and well developed regulatory and health technology assessment (HTA) frameworks encourage research and development (R&D) activities and continue to make Australia an attractive destination for therapeutic goods sponsors and manufacturers. Australia’s Therapeutic Goods Administration (TGA) sits at the centre of it all.

The TGA is an Australian government federal agency that regulates the supply, import, export, manufacturing and advertising of therapeutic goods across all six states and ten territories of the Commonwealth of Australia. The TGA is a large and well-respected regulator in the Asia-Pacific region, and worldwide. Ten years ago, the Australian government initiated an expert review of medicine and medical device regulations.

Its aim was to achieve a reform that would strike a balance between timely access to therapeutic products for Australian patients, flexible regulatory pathways for industry, and an overall regulatory framework that is appropriately aligned to risk. These reforms are now coming to fruition, highlighting how Australia is well-placed to tackle current and emerging challenges, globally, being faced by stakeholders working across the sector. In this article, we present some key developments in hot topics across the Australian regulatory landscape and consider what they mean for the broader industry.

Expedited application pathways in Australia

Before 2018, any medicine registered in Australia had to go through the standard registration pathway. To enable faster patient access, reduce duplication and increase flexibility, the TGA has been progressively implementing efficiencies in the application process. Today, applicants can choose from several approval pathways meaning that the inclusion of Australia in a global registration strategy has never been more important.

Like other major regulators, the TGA has recognised the importance of early access to medicinal products and established provisional and priority review pathways. These pathways still require full TGA assessment of data, however, applicants can apply for registration based on early clinical data indicators (provisional pathway) or request a faster review for important new therapies (priority pathway).

There has been a noticeable focus on international reliance and work-sharing programmes in Australia, especially since the pandemic. There are now pathways that offer greater reliance on overseas assessment reports while enabling the TGA to maintain sovereignty over decision-making. The comparable overseas regulator (COR) pathways are used for medicines that have been registered in at least one major world market, with the same dossier then rolled out to Australia.

Under these pathways, the TGA focuses its evaluation on the assessment reports generated by the recognised overseas regulator. This allows for faster evaluation timeframes (120 or 175 working days) and a high level of harmonisation across registered dossiers in different regions. A good indication of the success of these pathways is that all 25 applications using the COR pathways in Australia in 2023 were approved even faster than the mandated evaluation timeframes.

International work-sharing procedures available in Australia include the Access Consortium and Project Orbis. Under these pathways, participating agencies will harmonise their evaluation timelines, coordinate their reviews and share evaluation reports between themselves. In a recent development, the Access agencies also agreed to harmonise their determination evaluations for priority review requests.

Where there is a public health interest, the TGA can approve the temporary import or supply of an overseas medicine as a substitute for a registered medicine in short supply…

When planned and executed well, working-sharing procedures can result in parallel registrations in several major countries, offering benefits in terms of resource use, harmonisation of dossiers and greater predictability during the evaluation process. The TGA expects to see continued growth in international collaborations. It also looks to further integration of frameworks across Access agencies with the scope being frequently extended, the latest being the use of Access for biosimilars.

A good regulatory strategy helps navigate the requirements of such pathways in a timely and cost-efficient manner without compromising safety, quality or efficacy. Importantly, the inclusion of Australia in early global strategy planning can secure a key registration in the Asia-Pacific region in unison with major markets like the US and EU, which could enable further registrations in the region.

Securing supply and mitigating medicine shortages

Despite best efforts to establish strategies which mitigate the risk of supply disruptions globally, medicine shortages can happen for a multitude of reasons. To further their efforts, the TGA is currently looking at various avenues to strengthen the medicine supply system in Australia.

National shortages of all prescription medicines and some over-the-counter medicines must be reported to the TGA within mandated timelines. The TGA uses this information to investigate alternatives for continued supply in the interests of public health. The list of current shortage notifications is published online and provides consumers and healthcare professionals with an estimate of how long the shortage is expected to last and whether an alternative medicine is available.

In the short term, where there is a public health interest, the TGA can approve the temporary import or supply of an overseas medicine as a substitute for a registered medicine in short supply. In the longer term, industry is encouraged to register new generics, potentially using one of the previously discussed expedited regulatory pathways.

The TGA is also working to design a new programme for repurposing registered medicines for new indications. The programme would target medicines for which there is a significant public health benefit, but little or no commercial incentive for a sponsor, to pursue regulatory and reimbursement application. Clinicians, academics and patient groups would be encouraged to actively participate bay identifying new usages, or off-label uses for existing medicines.

Applicants would then be encouraged to submit applications to extend the indication of the medicine. Features of the programme may include provisions for non-commercial applicants or sponsors and incentives such as fee reductions, expedited timeframes or exclusivity.

The programme is currently in the public consultation phase, with the outcome expected later in 2024.

Cell and gene therapy: the role of the Office of Gene Technology Regulation in Australia

The continued rapid advances in cell and gene therapy (CGT) are transforming how the treatment of disease is managed, with a shift toward medicines that provide a durable, preventive or even curative effect. The rapid development of these advanced therapies brings new challenges for regulators globally as they gain insight into, and seek to regulate, technologies involving new methods of manufacture, non-standard clinical endpoints and the need for extended duration of efficacy and safety data required prior to regulatory approval and funding.

As more of these therapies approach late-stage development, it is important to understand the unique aspects of the regulatory landscape that need to be considered when looking to register CGT products in Australia. Some CGTs are regulated as therapeutic genetically modified organisms (GMOs), meaning they fall under the remit of both the TGA and a second regulatory body, the Office of Gene Technology Regulation (OGTR). While the TGA is responsible for assessing a product’s efficacy and safety, the focus of the OGTR is on wider public health and the potential impact on the environment should the product be either intentionally or unintentionally released.

The OGTR assesses the potential risks associated with the proposed use of the gene technology and acts to manage those risks by regulating specific activities with GMOs. For example, a GMO manufacturing site in Australia may require accreditation by OGTR, an in vivo gene therapy using adeno-associated virus vectors would require an OGTR licence, whereas ex vivo gene and cell therapies are more likely to be exempt from this additional monitoring.

CGTs that fall under the remit of the OGTR must have appropriate accreditation and/or licence(s) in place before they can be manufactured, imported or supplied in Australia (including their use in clinical trials). The process can be complex and time-consuming and can cause significant delays to product launch timelines if not appropriately factored into project planning.

OGTR licence applications, which can be pursued in parallel to registration applications, require the submission of substantial information on product development, manufacture, transport, administration and disposal. The type of licence required is dependent on the perceived potential for release of the product into the environment, such as via shedding from the patient. To avoid any unwanted surprises, sponsors are encouraged to engage with the OGTR early to plan activities in parallel with TGA engagement.

The OGTR can impose licence conditions in the form of post-marketing obligations and commitments, and may conduct site inspections of sponsors, manufacturers, trial sites and clinics. Changes to procedures related to handling of the product need to be notified to the OGTR and a report that captures supply and compliance details must be submitted annually. These obligations are in addition to any imposed by the TGA, so it is important for the sponsors to plan their regulatory resourcing accordingly.

To date, the OGTR has approved 88 licences for the use of GMOs in clinical trials and 10 licenses for the commercial release of therapeutic GMOs. Licences issued for commercial release include Novartis’ Luxturna® and Zolgensma®, Amgen’s Imlygic® (T-VEC) and CSL Behring’s Hemgenix®. As the number of advanced therapies proposed for the Australian market increases, there is a need to further streamline the TGA and OGTR application process.

Cell and gene therapy: broader considerations

There have been a number of parliamentary inquiries and reports which have identified shortfalls in Australia’s HTA system, particularly in regard to advanced (or innovative) therapies. CGTs were not envisaged when programmes such as the Pharmaceutical Benefits Scheme and the Medicare Benefits Schedule were established in the 1980s. The average time it takes for an innovative medicine to go from registration to funding in Australia is 391 days, which stands is in stark contrast to only three months in the top five OECD nations.^[1]

To facilitate reform, the Australian government has announced the first major review of the Australian HTA system in 30 years. The independent Health Technology Assessment Review, overseen by an independently chaired Reference Committee, involves representatives from all stakeholder groups and aims to ensure that Australia’s HTA process keeps pace with advancements in medical technologies. Indeed, one of the central aims of the review is an investigation into new evaluation and funding pathways for innovative medicines to ensure efficient ways of assessing therapies that do not fit neatly into the current system (such as CGTs and precision medicines).

With such improvements, Australians will continue to have access to the latest technological advances and Australia may increasingly be looked to as a first-launch country for new and innovative therapies.

Updates to Software as a Medical Device regulation in Australia

Software is becoming increasingly important in healthcare as the capabilities and functionality of medical devices become more digitised and interconnected. It can be found across a wide range of uses, from informative and lifestyle apps to software that informs, drives or replaces clinical decisions, or that directly provides therapy to an individual. Software can be a standalone device (app), part of a device or may control a device.

Australians will continue to have access to the latest technological advances and Australia may increasingly be looked to as a first-launch country for new and innovative therapies…

Software that meets the definition of a medical device as per the Therapeutic Goods Act 1989 is regulated by the TGA, unless excluded or exempt (e.g. clinical decision support software, etc). The term Software as a Medical Device (or SaMD) refers to software that can function on devices such as a laptop, computer, smartphone or tablet and that has an intended purpose consistent with the definition of a medical device. Rapid innovation has led to a large increase in the number of SaMD products and this prompted the TGA to implement reforms in 2021 with the aim of clarifying the requirements for these products. Under these reforms, the agency introduced new (higher) device risk classification rules and added several exclusions and exemptions for specific types of software.

Spotlight on cyber security and artificial intelligence

There is an increased focus on cybersecurity among manufacturers to demonstrate the compliance of their medical devices with the TGA’s essential principles. As the complexity of software increases, so too does the level of cyber security risk, with the potential for patient harm, such as:

• Blocking the intended service or therapy.
• Altering the device function to directly cause patient harm.
• Loss of privacy or altering personal health data.

Developers should consider any associated risks in the pre- and post-market environments (i.e. in the device design) and have in place a cybersecurity risk management strategy. Sponsors should consider international cybersecurity guidance for medical devices, in addition to best practice from the broader technology sector.

The Australian government regularly provides updates and advice on cybersecurity which are useful sources of information, as is the Office of the Australian Information Commissioner’s Notifiable Data Breach Scheme. There is an increased awareness globally of the potential for product recalls due to the discovery of cybersecurity vulnerabilities, threats and risks.

The number of SaMD products with an artificial intelligence (AI) component is also rapidly growing. The requirements for the supporting evidence for these devices must be at least the same standard as those devices without AI. However, they become more stringent for higher risk products. Developers will need to demonstrate the sources and quality of text inputs used to train and test the model, in addition to showing how the data is relevant and appropriate for use in the Australian population. Given the TGA’s involvement in the International Medical Device Regulators Forum, updates in this area in Australia are likely to be aligned with other leading medical device regulators.

Reference

^[1] Medicines Australia (2020) Medicines Matter: Australia’s Access to Medicines 2014-2019. Available at: http://www.medicinesaustralia.com.au/wp-content/uploads/sites/65/2020/11/Medicines-Matter-Access-Report.pdf