Review of the Clinical Trial Approval (CTA) Scheme

Updates on the CTA review

We performed a targeted consultation with Human Research Ethics Committees (HRECs) about the CTA scheme in May 2024. The feedback summary has been published on the Consultation Hub. An overview of the current CTA scheme is provided below. 

Next steps:

• We will be undertaking further rounds of discussion with wider groups of stakeholders.
• We will soon be seeking stakeholder feedback on the CTA review through the Consultation Hub.

Background and resources for the current CTA scheme

The CTA scheme involves an application to the TGA for approval to supply an ‘unapproved’ therapeutic good(s) in a clinical trial. This involves the evaluation of scientific data about the therapeutic good(s) (quality, preclinical and early clinical safety data) and a decision to approve supply of the ‘unapproved’ good(s) by the TGA prior to the start of a trial. The approving Human Research Ethics Committee (HREC) is responsible for the review and approval of the trial protocol along with the ongoing monitoring of the trial. 

The CTA scheme is mandatory for Class 4 biologicals, except where evidence from previous clinical use supports the use of the biological, or a national regulatory body with comparable regulatory requirements has approved a clinical trial for an equivalent indication outside Australia. For trials involving all other therapeutic goods, the choice of which scheme to use (Clinical Trial Notification (CTN) or CTA) lies firstly with the trial sponsor and then with the HREC that approves the protocol. The determining factor for an HREC is whether the committee has access to appropriate scientific and technical expertise in order to assess the safety of the product.

Resources

More information can be found at:

• The Australian clinical trial handbook
• The TGA website - Clinical Trials
• CTA scheme forms

Overview of the usual CTA process

The process for a typical CTA application is summarised below. This process has not been formalised, but we have provided it to help with general understanding of the possible steps.

1. Pre-submission meeting

We encourage all sponsors to request a pre-submission meeting. The pre-submission meeting form should be sent to clinical.trials@health.gov.au with your questions. 
In the pre-submission meeting, we can:

• clarify any questions the applicant has about existing studies or the proposed data package for a CTA application
• give specialised advice on the CTA application process, including the best ways to submit the application and dossier

2. Submission of the CTA application

The sponsor submits the application form and supporting data to clinical.trials@health.gov.au. Generally, we do a preliminary assessment to ensure that the data is sufficient to begin evaluation. If there is critical data missing, we will request further information. Once we are satisfied that there is sufficient data/information to commence evaluation, we will send an invoice. Once the fee has been paid by the sponsor, the evaluation begins.

3. TGA evaluation

Evaluations are performed by multiple specialist evaluation areas across the TGA to assess the quality and safety of the therapeutic good(s) proposed to be used in the trial. During the CTA evaluation process, the TGA generally evaluates the following: 

Medicines and biologicals

1. Quality of the therapeutic good(s), including:
   1. Manufacturing process, including process validation
   2. Proposed specifications, including release and stability
   3. Transportation
2. Safety of the therapeutic good(s)
   1. Non-clinical safety studies
   2. Clinical assessment of publications and data supplied as part of the CTA dossier
   3. Adventitious agent safety (if materials are of human or animal origin)
   4. Microbiological safety/sterility
   5. Container integrity
   6. Endotoxin risks
3. Compliance with applicable Therapeutic Goods Orders, international guidelines and TGA adopted international guidelines such as EMEA/CHMP/SWP/28367/07
4. Labelling (including traceability)

Medical Devices 
To date, the TGA has not received an application for a medical device CTA. We would apply similar principles to the evaluation of a medical device CTA as those applying to medicines and biologicals.

Process
The evaluation process usually consists of two rounds of evaluation and one round of request for information from the sponsor. Additional rounds may be required if there is outstanding information required to support the evaluation process or decision.

4. TGA decision

Once evaluation is complete, evaluation reports with recommendations are submitted to the decision maker for consideration. A senior medical officer of the TGA decides on whether to approve the supply of ‘unapproved’ therapeutic goods under the CTA scheme.

The decision maker considers the overall risk-benefit profile of the trial, which may include:

• TGA evaluation reports
• The trial’s usage guidelines (which may include the trial protocol, investigator’s brochure, literature references and pharmacy guidelines)
• Plans for shipment and storage at trial sites

The decision maker may seek expert advice from TGA statutory advisory committees.  

The TGA informs the sponsor of the decision whether to approve or not in a decision letter.

5. HREC review and approval

Following TGA approval or in parallel with TGA evaluation, the sponsor contacts their chosen HREC. The HREC will then complete reviews of the scientific and ethical details of the trial proposal. Trials can only commence once both TGA and HREC approval has been received.

6. Commencement of the trial and addition of trial sites

The sponsor must notify the TGA the commencement of each new trial conducted under the CTA scheme, and any additional sites in ongoing CTA trials.

The form should be sent to clinical.trials@health.gov.au within 28 days of commencing supply of the goods at each site. There is no fee for this notification.

7. Completion of the trial

The sponsor should notify the TGA of the completion of trials conducted under the CTA scheme after the trial has been completed at all sites. The form should be sent to clinical.trials@health.gov.au. There is no fee for this notification.

Variations

We have not published variation forms or guidance on what constitutes a variation to a previously approved CTA application – please contact us at clinical.trials@health.gov.au for specific advice.

If a sponsor wishes to change the therapeutic good(s) or any aspect of the clinical trial that was evaluated in the original CTA submission, a variation requiring additional evaluation by the TGA may be required. These changes are assessed to ensure that the quality and safety of the good(s), or the overall risk-benefit profile of the trial, will not be inadvertently altered by the variation. Examples may include significant changes to the manufacturing process, intended patient group, route of administration and/or container.

CTA variations incur a fee.

Any changes that were not evaluated in the original submission or are predicted to have no effect on the therapeutic good or safety of the trial will not be assessed by the TGA. However, all changes should be communicated to and approved by the HREC before commencement.