Navigating the ‘regulatory quagmire’ for extracellular vesicle therapies in Australia

Extracellular vesicles (EVs) are tiny membrane-bound nanovesicles released by cells. Unlike cells, they are non-viable — they cannot replicate and they do not contain a complete genome. Instead, EVs carry a heterogeneous cargo of proteins, lipids, and nucleic acid fragments, including mRNA, microRNA, and even fragments of genomic and mitochondrial DNA. To put this in perspective, most human cells contain a nuclear genome of approximately 3.1 billion base pairs, organised across 23 pairs of chromosomes and encoding around 20,000 protein-coding genes, plus hundreds to thousands of copies of the small, circular mitochondrial genome (16,569 base pairs, 37 genes). EVs carry none of this intact machinery. They are biological in origin but non-cellular in nature. They are more akin, at least in regulatory terms, to plasma derivatives and purified proteins than to living cells or gene therapies.

This distinction matters because of where EVs sit — or fail to sit — within existing regulatory frameworks. EVs may be useful in their own right as therapeutic agents (such as in lung disorders) or be leveraged as transporters of drugs or genetic material when directed to specific organs in the body. Unsurprisingly, then, EVs have generated considerable excitement as tools for regenerative medicine and drug delivery in recent years. They are capable of carrying therapeutic cargo (such as antisense oligonucleotides, which ‘silence’ disease-causing genes), they’re biocompatible (that is, they are well tolerated by the body and provoke minimal immune response), and they offer a cell-free alternative to stem cell therapies.

A 2024 systematic review catalogued over 90 registered therapeutic trials involving EVs, and by 2025, more than 200 EV-related clinical trials (including both diagnostic and therapeutic applications) had been registered on ClinicalTrials.gov. Yet no EV-based therapeutic has received full market approval from any major regulator — not the Food and Drug Administration (FDA), not the European Medicines Agency (EMA), and not the Therapeutic Goods Administration (TGA).

Why not? The standard explanation points to inherent biological variability that comes with any biological — as opposed to pharmacological — product, but variability is especially pronounced where the product is still being studied. In more precise terms, variability means batch-to-batch differences, donor diversity, and the absence of standardised potency assays. And these are real problems, because it means that any clinical trial will face challenges in relation to how these products are compared across recipients, as well as how to recreate them in any post-trial or post-approval translation of the treatment. But in a new Perspective article published in Extracellular Vesicles and Circulating Nucleic Acids, my co-authors and I argue that the barriers are not solely technical. They are also regulatory.

The new Perspective article — ‘The regulatory landscape for extracellular vesicle therapies: Australian context and future directions’ — arose out of a Kickstarter grant awarded by Sydney Nano. The Perspective was authored by me, Sydney Health Law associate Reeve McClelland (BSc/LLB (Hons)) (Sydney Law School), Ryan L Davis (Senior Research Fellow, School of Medical Sciences, University of Sydney; Neurogenetics Research Group Visiting Scientist, the Kolling Institute) and Wojciech Chrzanowski (Professor of Nanomedicine and Head of Pharmaceutical Sciences, Sydney Nano Institute and School of Pharmacy, University of Sydney). We acknowledge the support of Sydney Nano in the completion of this research output.

In this Perspective, we examine how Australia’s therapeutic goods framework handles (or fails to handle) EV medicines. We trace the conventional pathway through which therapeutic goods pass, which is to be subject to research and development, clinical trials, and then submission for registration by the manufacturer (‘sponsor’) on the Australian Register of Therapeutic Goods (ARTG). We also focus on the Regulatory Framework for Biologicals in the Therapeutic Goods Act 1989 (Cth) and its guidelines, which were originally introduced in 2011, and propose that EVs derived from non-pluripotent stem cells will likely be classified as Class 3 biologicals requiring comprehensive non-clinical and clinical evidence dossiers.¹

However, we then examine the alternative access pathways — the Special Access Scheme (SAS), the Authorised Prescribers Scheme (APS), and various exclusions and exemptions under the Therapeutic Goods Act 1989 (Cth) — that might facilitate patient access to EV therapies without full ARTG registration. Indeed, it was through these special access schemes and regulatory exceptions that many stem cell treatments have been administered in Australia in the recent past, leading to tragic outcomes and disciplinary findings against medical practitioners.

The Special Access Scheme bears a functional resemblance to the US FDA’s ‘expanded access‘ (or ‘compassionate use’) program, though the two differ in important ways. The FDA’s expanded access pathway requires the sponsor or physician to file an Investigational New Drug (IND) application and to obtain FDA authorisation before the product can be administered. Under Australia’s SAS Category A, by contrast, a registered practitioner may access an unapproved product for a seriously ill patient — one who is reasonably likely to die within a matter of months — with only informed consent and notification to the TGA within 28 days of supply.

Despite these apparent opportunities for the regulations to be used in the case of specific medical practices and for the most at-risk patients, the overall picture that emerges is one that my co-author Ryan Davis aptly describes as a ‘regulatory quagmire.’ For instance, see the video below.

In practice, each of these multiple routes to clinical translation comes with significant limitations. The SAS and APS are patient-access mechanisms, not commercialisation pathways. The exclusions and exemptions for autologous cell and tissue products raise difficult interpretive questions — does extracting EVs constitute ‘minimal manipulation’? And what counts as ‘homologous use’ for a vesicle?

And the policy question of whether EVs should be specified as ‘not biologicals’ under section 32A(3) of the Therapeutic Goods Act 1989 (Cth) — potentially shifting them into a medicines-based regulatory paradigm — remains unresolved.

We also look internationally. South Korea has published dedicated EV therapeutic guidelines. Taiwan’s Regenerative Medicine Act explicitly encompasses EVs. Japan’s dual-track system permits conditional, time-limited marketing authorisations. What distinguishes the TGA from these jurisdictions is not a lack of regulatory sophistication but the absence of EV-specific guidance to help sponsors navigate applications.

The article also draws on the 2021 New Frontier Report, which identified the need for more flexible pathways to keep pace with medical and technological advances, and the recent HTA Policy and Methods Review, which confirmed that current funding arrangements for high-cost, highly specialised technologies are ‘not effective.’ These systemic critiques reinforce our argument: the difficulties facing EVs are not simply about getting the science right. They reflect the limitations of regulatory frameworks designed for a different generation of therapeutics.

We conclude by calling for three concrete reforms. We call on the TGA to issue EV-specific guidance on classification, characterisation, and evidence requirements. We urge the Commonwealth government to implement the proposed Centre for Precision Medicine and Rare Diseases recommended in the 2022 New Frontier Report, with explicit EV inclusion. And, finally, we call on scientists and others to adopt improved standardisation practices within the research and manufacturing communities themselves. Regulatory reform alone cannot solve the translation problem if the evidence base remains compromised by methodological inconsistency — a point underscored by the finding that only 12.1% of EV clinical trials report their isolation methodology.

One further avenue that our Perspective does not address — but that warrants attention — is the potential for the TGA to facilitate the systematic collection of real-world data from EV treatments administered through existing exceptional access pathways such as the SAS and APS. At present, these pathways generate individual clinical experiences that are neither routinely aggregated nor analysed at a population level. Yet they represent a potentially valuable source of real-world evidence — observational data on safety, tolerability, and preliminary efficacy drawn from clinical use outside controlled trials. In the short video below, I suggest that the TGA could do more to engage directly with scientists on the ground — working collaboratively to gather evidence and reach faster, more empirically grounded regulatory conclusions.

The FDA has recently moved in this direction for cell and gene therapies, issuing draft guidance in 2025 on post-approval methods that explicitly endorses the use of registries, electronic health records, and decentralised data collection to capture long-term safety and efficacy outcomes.

A regulatory sandbox — a structured, time-limited framework in which novel therapies can be administered under controlled conditions with prospective data collection — could offer a vehicle for generating such evidence in the Australian context, informed by international precedent. The concept has gained traction in financial services regulation (for example, through ASIC’s fintech sandbox) and has been adopted in the therapeutic goods context by Health Canada, whose Advanced Therapeutic Products framework — explicitly described as a ‘regulatory sandbox‘ — enables tailored, flexible regulatory requirements for products that do not fit existing frameworks. No equivalent mechanism exists in Australian therapeutic goods law.

For EV medicines, it could serve as an intermediate step between the exceptional access pathways (which permit clinical use but do not generate generalisable evidence) and the conventional clinical trial (which demands a degree of product standardisation and reproducibility that the EV field has not yet achieved).

This is not to suggest that biological variability is irrelevant to efficacy — inconsistent manufacturing can and does compromise therapeutic outcomes. But where batch-to-batch differences reflect the inherent characteristics of a personalised biological product rather than a failure of quality control, insisting on the reproducibility standards of a conventional randomised controlled trial may be neither scientifically necessary nor practically achievable. A real-world evidence framework, carefully designed and transparently governed, could help build the evidence base needed to inform both regulatory and Health Technology Assessment decision-making while patients in need are treated through existing lawful pathways.

The full article is available via this citation: Christopher Rudge, Reeve McClelland, Wojciech Chrzanowski and Ryan L Davis, ‘The Regulatory Landscape for Extracellular Vesicle Therapies: Australian Context and Future Directions’ (2026) 7 Extracellular Vesicles and Circulating Nucleic Acids 292 https://doi.org/10.20517/evcna.2025.129.

Featured image: Transmission electron microscopy images of extracellular vesicles derived from mesenchymal stem cells, showing non-sonicated (a, c) and sonicated (b, d) samples at higher (top) and lower (bottom) magnification. From Zubair Ahmed Nizamudeen, Rachael Xerri, Christopher Parmenter, Kiran Suain, Robert Markus, Lisa Chakrabarti and Virginie Sottile, ‘Low-Power Sonication Can Alter Extracellular Vesicle Size and Properties’ (2021) 10(9) Cells 2413 https://doi.org/10.3390/cells10092413. CC BY 4.0. Image has been digitally colourised.

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1. Also see earlier work authored by Rudge and Chrzanowski and co-authors on the same general question: Thanh Huyen Phan, Sally Yunsun Kim, Christopher Rudge and Wojciech Chrzanowski, ‘Made by Cells for Cells – Extracellular Vesicles as Next-Generation Mainstream Medicines’ (2022) 135(1) Journal of Cell Science jcs259166 https://doi.org/10.1242/jcs.259166. ↩︎