Overview of requirements for running pre-market clinical trials for medical devices in Australia – February 2023

Pre-market clinical trials for medical devices in Australia – CTN and CTA schemes

By Val Theisz

Regulatory requirements defined in the essential principles

Essential principle EP 14 of the Australian Medical Device Regulations requires that the safety and performance of medical devices be supported by clinical evidence. EP 14 states that every medical device requires clinical evidence, appropriate for the use and classification of the device, demonstrating that the device complies with the applicable provisions of the EPs.

The clinical evaluation procedures in Part 8 of Schedule 3 of the Medical Device Regulations stipulate that the manufacturer must obtain and evaluate clinical data in relation to the device in the form of clinical investigation data or a literature review, or both (clause 8.3).

Clinical investigation data (clause 8.4) includes:

1. documentation in relation to the design, approval, conduct and results of each investigation carried out by the manufacturer in relation to the use of the device in or on a human body;
2. a record of qualitative or quantitative information obtained through observation, measurement, tests, or any other means used to assess the operation of the device; and
3. a written report by an expert in the relevant field, being a report that contains a critical evaluation of all the clinical investigation data held in relation to the device.

If clinical investigation data is collected in Australia, the investigation must have been conducted in accordance with the ethical standards set out in the ‘National Statement’ relating to ethical conduct in human research published by the National Health and Medical Research Council (NHMRC), as in force at the time (clause 8.4(4)).

If clinical investigation data is collected outside Australia, the investigation must have been conducted in accordance with the principles of the Declaration of Helsinki, as in force at the time and place where the investigation was conducted (clause 8.4(5)).

Before using an investigational device in human subjects, the device must be bench tested and found compliant with the applicable essential principles of safety and performance, except EP 14 which is addressed by providing clinical evidence.

Compliance with Australian or international standards (ISO, IEC) is preferable, but not mandatory, to demonstrate compliance with the relevant EPs, especially for devices based on technologies with well-established safety and performance characteristics.

Clinical data (meaning safety and performance information that is generated from the clinical use of a medical device) may be generated for either the subject device or a comparable device (including substantially equivalent devices). It includes:

• data from clinical investigations (synonymous with trials and/or studies)
• literature reviews
• post-market data
• other clinical experience data (also known as Real World Data).

High risk devices, those based on technologies where there is little or no experience, and those that extend the intended purpose of an existing technology (i.e., a new clinical use) are most likely to require clinical investigation data.

The TGA recognizes international standard ISO 14155 Clinical investigation of medical devices for human subjects — Good clinical practice as the guidance for conducting clinical trials for medical devices and the necessary documentation to be generated.

Other legislative requirements applicable to clinical trials are the Australian Privacy Act 1998 that covers all activities related to the collection, use or disclosure of personal and sensitive information.

CTN and CTA schemes

Clinical trials can be conducted within Australia under either the Clinical Trial Notification (CTN) or Clinical Trial Approval (CTA) schemes for devices not currently included in the Australian Register of Therapeutic Goods (ARTG), or to extend the intended purpose of a medical device beyond the current market approval.

The choice between CTN and CTA lies firstly with the trial sponsor and then with the Human Research Ethics Committee (HREC) that approves the protocol. CTN is a notification to the TGA, and as such the TGA does not review or evaluate any data relating to the clinical trial at the time of notification. The notification is done via the online CTN form. After the trial has been completed at all sites, the trial sponsors must notify the TGA that the trial has been completed. Most clinical trials in Australia are notified under the CTN scheme.

CTA is an evaluation process and involves the review by TGA of relevant, but limited, scientific data (which may be preclinical and early clinical data) prior to the start of a trial. For certain Class 4 biologicals, clinical trials must be approved by the TGA under the CTA scheme. CTA applications are submitted using paper-based forms. There are two forms (part 1 and part 2) that must be completed by the sponsor and submitted to us via clinical.trials@health.gov.au .

Approving authorities are public or private legal entities (institutions or organisations) where trials are conducted (i.e., trial sites). Under the CTN and CTA schemes, the approving authority gives the final authorisation for the conduct of the trial at the site following approval by the reviewing HREC.

Private clinics may be used as trial sites for clinical trial purposes and therefore take on the responsibilities of the approving authority. These sites must comply with good clinical practice and all other applicable clinical trial legislation and requirements.

Approving authorities conducting trials under the CTA and CTN schemes have specific responsibilities as outlined in the National Statement, Guideline for Good Clinical Practice and ISO 14155 and the Therapeutic Goods Act 1989.

Finding suitable sites and ethics committees for clinical trials

The Australian Commonwealth Department of Health manages the australianclinicaltrials.gov.au website which provide useful resources for running clinical trials in Australia, including a list with Australian clinical trial sites.

Ethics approval and oversight is provided by HRECs which are often (but not always) located at the site(s) where the clinical trial will take place. Where confirmed by the ethics office, sponsors can use the national human research ethics application (HREA) form prepared by the NHMRC.

The NHMRC maintains a list of registered HRECs that have declared that they are constituted and operate in accordance with the National Statement, as well as a list of certified institutions under its National Certification Scheme of Institutional Processes related to the Ethical Review of Multi-centre research (National Certification Scheme).

Many (but not all) certified institutions are also recognised under the National Mutual Acceptance (NMA) scheme, a system for single ethics review operating in New South Wales, Queensland, South Australia, the Australian Capital Territory and Victoria.

Each Australian state has an ethical review process and information is available from the State and Territory website links below:

• New South Wales
• Queensland
• South Australia
• Victoria
• Western Australia
• Australian Capital Territory
• Northern Territory
• Tasmania

Additional information related to clinical trials

Clinical trials should be registered in a public clinical trials registry at or before the time of first patient enrolment as a condition of consideration for publication. For more information refer to ICMJE clinical trial registration requirements. Registries include clinicaltrials.gov or any registry participating in the WHO International Clinical Trials Registry Platform, such as the Australian New Zealand Clinical Trials Registry (ANZCTR).

A Post-Market Clinical Follow-Up (PMCF) study is a study carried out following marketing authorisation intended to answer specific questions (uncertainties) relating to safety, clinical performance and/or effectiveness of a device when used in accordance with its labelling. Data obtained from PMCF studies are a subset of post-market data. PMCF studies can be used to collect additional clinical data to address the remaining uncertainties about the potential benefits and residual risks of the device.

Advertising of unapproved therapeutic goods is illegal in Australia [ref Therapeutic Goods Act 1989 section 42DL (1)]. Manufacturers and/or sponsors of clinical trials aimed at establishing safety and performance of unapproved therapeutic goods are not allowed to advertise those products. They are however allowed to promote the clinical trial itself to encourage patient enrolment, but without specifically mentioning the name of the therapeutic good being used in the trial.

Any advertisement for a clinical trial should be approved by the ethics committee reviewing the trial as specified under section 5.2.23 of the National Statement and section 4.4.1 of the ICH Guideline for Good Clinical Practice.

For therapeutic goods included in the ARTG, advertising must be consistent with the information included in the ARTG entry, and consistent with the indication or the intended purpose of the therapeutic good. When advertising an approved therapeutic good, manufacturers and sponsors must comply with all applicable requirements of the Advertising Code of 2021.