To bring a stem cell-based product to patients in Australia, it must first clear the Therapeutic Goods Administration’s (TGA) approval pathway to be included in the Australian Register of Therapeutic Goods, typically through the biologics stream. To be eligible for any TGA submission, an Australian-based sponsor is required to submit the application on behalf of the developer. A biologic ‘either comprises, contains or is derived from human cells or human tissues’ or is presented as being used to treat, prevent, diagnose, or monitor disease, influence physiological process or the anatomy. This includes cell, tissue or organ-based products, combinations of a cell therapy and medical device and faecal microbiota transplant [1]. In Australia, TGA classifies biologics into four classes, each representing a progressively higher level of risk. The regulatory process for class 1 biologics differs to that of class 2-4, where class 2 typically involves minimally manipulated cells with local effects, while classes 3 and 4 involve greater manipulation and systemic use, respectively.
The standard pathway for class 2-4 biologics takes up to 255 working days and includes 6 steps from submission to decision with 2-3 rounds of evaluation. However, this overall timeframe is likely to be extended as the clock stops whenever the TGA requests additional information [2]. Alternatively, if the biologic is i) separate and distinct from anything on the register, ii) intended for use with a life-threatening or seriously debilitating condition, iii) either no similar treatments are already registered or there is strong evidence the new biological offers a significant improvement over existing treatments, and iv) there is substantial evidence that it provides a major therapeutic advance, then the priority pathway may be considered.
As the inclusion criteria suggests, the priority pathway is designed to allow vital and life-saving biologics to get to patients faster with provisions such as, rolling questions during the evaluation phase, applied. The priority pathway has a timeframe of 150 working days and, if applicants can provide any additional information promptly, this timeline could encompass the entire evaluation process.
How does the Australian process compare to global counterparts? In the United States, biologics are regulated by the Food and Drug Administration (FDA) through the Center for Biologics Evaluation and Research (CBER) [3], [4]. Within CBER, the Office of Therapeutic Products is responsible for overseeing stem cell therapies, gene therapies, vaccines, blood components, tissues, and combination products [5]. Like the TGA system, the conclusion of the regulatory process is an approval of the Biologics License Application to introduce the therapy to market [6]. The process to this point includes the preclinical stage, clinical trials and marketing applications with various meetings held throughout [7]. There are multiple options to speed up the application process including the fast track, breakthrough therapy, accelerated approval, and priority review programs [8]. Each program has a slightly different inclusion criteria, but a commonality is that the therapy treats (or intends to treat) a serious condition [8]. These programs utilise rolling reviews, more frequent meetings and/or shorter review of the marketing application to speed up the overall application time by typically 1-2 years [8]. Another option to decrease the application timeframe is the biosimilars route which has the same name under both the TGA and FDA. Within the biosimilars route the biologic is compared to a reference product which is highly similar and has been on the market for a sufficient period of time to prove its safety and efficacy [9], [10].
A couple of key differences exist between the TGA and FDA processes. Typically, TGA applications will only commence after the main clinical trials have been completed where in most cases the local Human Research Ethics Committee is reasonable for approving the trial. The TGA typically accepts international clinical trial data, provided it meets Australian regulatory and ethical standards. Assuming all trials were completed with suitable results, this removes one reason for stoppages during the application. However, the FDA itself is responsible for approving clinical trial requests for a biological and therefore is part of the overall approval process from an earlier stage. This means the total time for approval under the FDA can be many years. It also means it is difficult to directly compare the time it takes to gain approval for a biologic under each system.
Does having approval with a comparable overseas regulator help with obtaining TGA approval? The TGA considers comparable regulators to be those of the United States (FDA), certain European countries (that follow the regulatory frameworks of the European Union), Canada (Health Canada), Japan (Ministry of Health, Labour and Welfare and Pharmaceutical and Medical Devices Agency), Singapore (Health Sciences Authority) and the Medical Device Single Audit Program Auditing Organisation, in which multiple countries participate [11]. If approval has already been granted by one of these comparable regulators, an abridged application can be used, which comes with a reduced timeframe of 120-175 working days [12]. Therefore, while having approval from an overseas regulator doesn’t change the underlying evaluation criteria or requirements it is likely to result in a faster time to inclusion on the Australian Register of Therapeutic Goods and availability to patients. While comparable regulatory approval allows for abridged applications, applicants must still meet TGA-specific Good Manufacturing Practice and manufacturing site requirements.
For stem cell-based translational biologics, regulatory bodies are an essential, and often complex, part of the journey. While securing approval in one region can ease applications elsewhere, there’s no clear advantage in targeting a specific regulator solely to fast track another. Therefore, choosing which market to enter first should depend on other strategic factors. Additionally, developers must consider post-market monitoring requirements, including adverse event reporting and long-term follow-up obligations.
References
[1] Therapeutic Goods Administration, “Biologicals,” https://www.tga.gov.au/products/biologicals-blood-and-tissues-and-advanced-therapies/biologicals.
[2] Therapeutic Goods Administration, “Classifying biologicals,” https://www.tga.gov.au/resources/guidance/classifying-biologicals.
[3] U.S. Food and Drug Administration, “Center for Biologics Evaluation and Research Organization Chart,” https://www.fda.gov/about-fda/fda-organization-charts/center-biologics-evaluation-and-research-organization-chart.
[4] U.S. Food and Drug Administration, “FDA Overview Organization Chart,” https://www.fda.gov/about-fda/fda-organization-charts/fda-overview-organization-chart.
[5] U.S. Food and Drug Administration, “What Are ‘Biologics’ Questions and Answers,” https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/what-are-biologics-questions-and-answers.
[6] U.S. Food and Drug Administration, “Biologics License Applications (BLA) Process (CBER),” https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/biologics-license-applications-bla-process-cber.
[7] U.S. Food and Drug Administration, “Interactions with Office of Therapeutic Products,” https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/interactions-office-therapeutic-products.
[8] U.S. Food and Drug Administration, “Expedited Programs for Serious Conditions | Drugs and Biologics,” https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-serious-conditions-drugs-and-biologics.
[9] U.S. Food and Drug Administration, “Review and Approval,” https://www.fda.gov/drugs/biosimilars/review-and-approval.
[10] Therapeutic Goods Administration, “Registering a biosimilar medicine in the Australian Register of Therapeutic Goods (ARTG),” https://www.tga.gov.au/resources/guidance/registering-biosimilar-medicine-australian-register-therapeutic-goods-artg.
[11] Therapeutic Goods Administration, “Using assessments from comparable overseas regulators for medical devices,” https://www.tga.gov.au/resources/guidance/using-assessments-comparable-overseas-regulators-medical-devices.
[12] Therapeutic Goods Administration, “Comparable overseas regulators (CORs): Timeframes and milestones,” https://www.tga.gov.au/how-we-regulate/supply-therapeutic-good/supply-prescription-medicine/application-process-prescription-medicines/comparable-overseas-regulators/comparable-overseas-regulators-cors-timeframes-and-milestones.