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Australian clinical trial handbook

Guidance on conducting clinical trials in Australia using 'unapproved' therapeutic goods

12 October 2018

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The CTN and CTX schemes

The CTN and CTX schemes aim to provide considerable benefits by providing the momentum to research, developing new therapeutic goods locally and facilitating early patient access to new therapeutic developments.

An application or notification to conduct a clinical trial involving an 'unapproved' therapeutic good is independent of an application for product registration. We will accept a notification or application to conduct a clinical trial while an application for registration of the same product is under review. Similarly, we will accept an application for product registration while a clinical trial for the same product is under review or under way in Australia.

For the purposes of the CTN and CTX schemes, because of the potential for conflict of interest, the same person cannot be listed as the HREC contact and as the principal investigator, nor can the same person be listed as the clinical trial sponsor and the HREC contact. We acknowledge that from time to time members of a HREC may be involved with a trial under review of that HREC. In these cases it is expected that the HREC will have procedures for managing conflicts of interest in accordance with the National Statement.

Choosing between the CTN and CTX schemes

The main difference between the CTN and CTX schemes is our level of involvement in reviewing data about the therapeutic goods before the clinical trial commences.

The choice of which scheme to use (CTN or CTX) lies firstly with the trial sponsor and then with the HREC that approves the protocol (except for certain Class 4 biologicals, which must be approved under the CTX scheme).

One of the determining factors for a HREC is whether the committee has access to appropriate scientific and technical expertise in order to assess the safety of the product. The approving authority takes the ultimate responsibility for determining whether the trial is allowed to proceed at the site.

If a HREC feels that it requires additional expertise to review a CTN, it may seek advice from external authorities or it may seek to collaborate with another HREC that has the required expertise.

A HREC may determine that it does not have access to the appropriate scientific and technical expertise to review the proposed trial under the CTN scheme and recommend review under the CTX scheme.

Medicines and biologicals

The CTN scheme may be used for earlier phase studies if there is adequate preclinical information available, especially regarding safety. The CTX route is generally for high risk or novel treatments, such as gene therapy, where there is no or limited knowledge of safety. Under the biologicals framework, the CTX scheme is mandatory for a clinical trial of any Class 4 biological unless:

  • evidence from previous clinical use supports the use of the biological. For example, the safety of the product has been evaluated in an earlier phase clinical trial. The effect on safety of changes in the manufacture of the product, or of use of the product for a new clinical indication, must be carefully considered; or
  • a national regulatory body with comparable regulatory requirements has approved a clinical trial for an equivalent indication. Seek advice from us if you intend to use this provision. You will need to provide evidence that the safety review by the overseas regulator is equivalent to that which would be performed by us. In addition, the product used in the trial approved by the overseas regulator must be the same as that in the proposed trial. The effect on safety of changes in the manufacture of the product, or of use of the product for a new clinical indication, must be carefully considered.

See the Australian regulatory guidelines for biologicals (ARGB) for further information and examples of Class 4 biologicals.

Medical devices

For medical device trials, the CTX scheme may be more appropriate where the experimental device introduces new technology, new material or a new treatment concept which has not been evaluated previously in clinical trials in any country. The CTX scheme should also be considered for medical devices that pose a risk of serious patient harm when the HREC does not have, or have access to, adequate expertise in the preclinical technical areas. This is especially relevant for implantable devices where areas of expertise include biological safety evaluation of medical devices, materials quality evaluation, engineering analysis of strength and fatigue of materials, finite element analysis for stress and fatigue prediction, and other computational simulations for device performance.

The CTN scheme

The CTN scheme is a notification scheme and as such we do not review or evaluate any data relating to clinical trials at the time of submission. All material relating to the proposed trial, including the trial protocol is submitted directly to the HREC. The HREC is responsible for assessing the scientific validity of the trial design, the balance of risk versus harm of the therapeutic good(s) and the overall ethical acceptability of the trial.

We may request further information from the trial sponsor regarding a clinical trial submitted to us under the CTN scheme (see Requests for information).

We may ask for information such as the investigator's brochure and protocol for first-in-human trials or because we have a degree of concern. The specific reasons will be different for each trial. The request will be made under the appropriate section of the Therapeutic Goods Act 1989.

Once we have reviewed this information, we may ask you specific questions to address any deficiencies or concerns that we identify.

A clinical trial must be notified to us using the online CTN form before the trial sponsor can supply the 'unapproved' therapeutic goods in the trial. A clinical trial is deemed to be notified as soon as the CTN form has been submitted and the relevant fee has been paid (as set out in item 3 of Schedule 5A to the Therapeutic Goods Regulations 1990 or item 2.3 of Schedule 4 to the Therapeutic Goods (Medical Devices) Regulations 2002. Once this occurs the exemption comes into effect and the trial sponsor can supply the goods subject to the necessary HREC approval and institutional authorisations.

The CTN exemption allows for the lawful supply of 'unapproved' therapeutic goods in a clinical trial. However, it is the responsibility of the trial sponsor to ensure that all relevant approvals (for example, ethics approval and site authorisation) are in place before commencement of the trial and supplying the 'unapproved' therapeutic goods.

If a therapeutic good is included in the ARTG during the course of the clinical trial then the trial sponsor must consult the HREC to determine the ethical acceptability of continuing to supply an 'unapproved' version.

Guidance on the online process for CTNs is available on our website.

Variations to a CTN

If there are any changes to the trial details notified to us (such as a change in the details of the principal investigator, change in address of the site or a change in the therapeutic good) it is necessary for the trial sponsor to update the relevant fields on the online CTN form. Certain changes to a previously notified CTN will incur a fee (see our Clinical trials FAQ tab for further information).

Notification of completion of a clinical trial under a CTN

The purpose of the CTN scheme is to provide an exemption for the supply of 'unapproved' therapeutic good in a clinical trial. Therefore, the completion advice should be submitted to us once the clinical trial related activity afforded by this exemption is complete and the exemption would no longer be required.

Trial sponsors should only notify us of the completion of a clinical trial after the trial has been completed at all sites. It is not necessary to notify completion dates for individual trial sites. This would usually correspond with the last patient last visit; however, it the responsibility of the trial sponsor to determine when the exemption is no longer required. Trial sponsors should notify us when a trial is completed using the online CTN form.

To ensure we maintain an accurate record for each clinical trial, we must be notified of:

  • the date the clinical trial was completed. This is the last date of completion for all sites. It is not necessary to notify completion dates for individual sites)
  • the reason the clinical trial ceased (for example, concluded normally, insufficient recruits etc.)

We do not require trial sponsors to submit end of trial study reports. However, this information should be made available if we request it.

The CTX scheme

The CTX scheme is an evaluation process and involves the review by us of relevant, but limited, scientific data (which may be preclinical and early clinical data) prior to the start of a trial. This can be particularly useful for therapeutic goods that are in the early stages of development. Our primary responsibility is to review the safety of the product and the HREC is responsible for considering the scientific and ethical issues of the proposed trial protocol. Conduct of a clinical trial under the CTX scheme must also be approved by the responsible HREC(s).

The trial sponsor's interaction with us for trials conducted under a CTX involves the submission of a formal CTX application.

If a trial sponsor is considering submitting a CTX application, we strongly encourage them to contact us for pre-submission advice regarding the application process.

Notification of a trial completion under a CTX

Trial sponsors should notify us of trial completion using the CTX clinical trial completion advice form. Trial sponsors should only notify us of the completion of a clinical trial after the trial has been completed at all sites. It is not necessary to notify completion dates for individual trial sites. This would usually correspond with the last patient last visit.

Extensions of clinical trials

The trial sponsor may seek approval from a HREC to conduct further trials with the same product. In each case, the trial sponsor is required to submit a CTN or CTX to us for trials involving the use of 'unapproved' therapeutic goods.

Building in a trial extension provision into the original protocol design not only fulfils GCP requirements but also can allow treatment to continue without having to prepare another trial proposal after the initial trial ceases. Of course, this is not the only way to provide ongoing treatment post-trial

Post-trial provisions

The National Statement requires a HREC to be satisfied that it is clearly explained to participants whether they will have continued access to treatments received during the trial when the trial is completed.

All parties involved in the planning, approval and conduct of clinical trials that involve the use of 'unapproved' therapeutic goods should consider mechanisms for allowing participants continued access to those goods following completion of the trial. This is especially important for participants where treatment has been found to be effective and where long term therapy would be appropriate. Consideration should be given to including a post study supply component in the trial protocol.

If supply of clinical trials goods is to continue after completion of the clinical trial, then it must be supplied within the provisions of the Therapeutic Goods Act 1989 for access to 'unapproved' therapeutic goods. If additional safety data is to be collected, the continuation of supply is usually undertaken using an open-label extension study. An open-label extension study is usually notified as a separate trial under the CTN and CTX schemes.

Alternatively, one of the other mechanisms for accessing 'unapproved' goods may be appropriate, such as the Special Access Scheme, Authorised Prescriber, or Personal Import Scheme.

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