Presentation: updates to the CTN form and first-in-human high-risk implantable or cardiac invasive medical device clinical trials

Speaker Key:

EC              Edwina Chan 

EA              Erin Andrew 

00:00:07

EC: Good afternoon, everyone. I’m Edwina Chan, and as Nishi kindly introduced, I am a Medical Adviser in the Devices Clinical Evaluation Section at the TGA [Therapeutic Goods Administration], which is responsible for providing clinical advice regarding pre-market applications for inclusion in the ARTG [Australian Register of Therapeutic Goods] as well as medical device clinical trials. Joining me today is Erin Andrew, who is an Assistant Director in the Risk Management Section at the TGA. Thank you for listening in today in what we hope will be an informative session. 

In terms of what we will cover today, I will give a brief summary of the background that prompted the changes that are the focus of the webinar today. Erin will talk about the CTN [Clinical Trial Notification] form updates. I will describe the high-risk medical device review process. And we’ll have time at the end for questions. 

00:01:06

So starting with the background, the TGA made a commitment in the 2019 Action Plan for Medical Devices to review the arrangements for medical devices that are used in clinical trials to ensure their use meets community expectations. 

In 2022, we consulted publicly on two proposals. The first was to mandate the clinical trials approval pathway for certain high-risk medical devices, and the second was to include medical device trials conducted under a clinical trials notification in the GCP [Good Clinical Practice] Inspection Program.

The first proposal was met with mixed feedback. So supporters responded that this would raise public confidence, align better internationally, and they also noted variability across Human Research Ethics Committees with regards to medical device expertise. 

However, concerns were raised that the proposal could act as a deterrent to clinical trials in Australia beyond just those that would be regulated, and that there were no concerns with the safety of trials in the current system, with the TGA review potentially replicating the work of HRECs. The second proposal was met with broad support. 

00:02:35

After the feedback, we conducted some further targeted consultation and developed a revised proposal, which was approved by the Minister for Health and Aged Care in June of 2023. The key elements were, first, there would be no changes to the CTN/CTA pathways, so sponsors could continue to choose either the CTN or CTA pathway upon discussion with the Human Research Ethics Committee. 

Second, we would make updates to the CTN form to enable more accurate data collection about the devices studied in clinical trials. Third, using the information collected in the updated CTN form, we would commence a proactive monitoring process of the highest-risk device trials. And fourth, we would include medical device trials conducted under a CTN in the GCP Inspection Program. 

In November 2023, there we some legislative changes to facilitate the implementation of this proposal. Specifically, changes were made to enable the TGA to require information about the safety of devices used in trials, so for example, information relating to engineering, materials and sterility, and to enable medical device trials conducted under a CTN, and the documentation supporting them, to be inspected for compliance with good clinical practice. 

The GCP Inspection Program for medical device trials will be covered in a subsequent webinar, and we’ll provide you with further details in due course. 

00:04:23

Now we come to the present, with the CTN form updates, including new mandatory fields for accurate data collection and a new attachment upload function, to be implemented this month, and our proactive monitoring process, to commence shortly thereafter. I’ll now hand over to Erin Andrew to talk more about the CTN form updates.

EA: Thank you, Edwina. Okay, good afternoon, everyone. As stated earlier, my name is Erin Andrew, and I have recently taken on the opportunity to head up the clinical trials support team at the Therapeutic Goods Administration. The clinical trials support team is responsible for administering the Clinical Trial Notification, CTN, and Clinical Trial Approval, CTA, schemes that provide for the access and supply of unapproved therapeutic goods through clinical trials in Australia. 

To support the review of the highest-risk device CTNs, which Edwina Chan will talk about shortly, we’ve introduced some changes to the CTN form. We have also taken the opportunity to make some improvements to the form to address some of the pain points that users of the form have told us about. 

The updates CTN form will be available on 21 March, and the old form will be offline from late afternoon on 20 March. We would like to thank all the stakeholders who have communicated with us the pain points of the old CTN form. While we may not have been able to address all of the issues raised, we have attempted to address the more problematic issues that you have brought to our attention. The changes will make it easier for you to complete the form correctly. I’m going to briefly outline these changes that you will see in the updated form. 

00:06:10

We have also updated the CTN form user guide, to be published alongside the CTN form update. This will ensure that you can easily navigate these changes. The user guide contains step-by-step instructions on how to obtain access to the CTN form and how to submit a CTN. 

As foreshadowed, one of the key changes to the CTN form is the addition of mandatory fields. These correspond to key information that will be used by the medical devices evaluation team to identify the highest-risk medical device clinical trials. 

These include new requirements to indicate whether the clinical trial involves a biological, medical device, or IVD, as well as provide the classification; whether the clinical trial is first-in-human or is associated with a clinical trial that has been ceased overseas due to safety concerns; and lastly, to identify whether the clinical trial contains device software, either as an invasive device or implantable device. 

We are now making more use of drop-down menus within the CTN form to make completing the form easier for you. Not only have we included them for medical devices, but we have used them to replace many of the free fields within the CTN form, such as the container type, dosage form and route of administration, for all CTNs. 

Please be aware that any drafts currently within the system that use the old format will potentially lose the free text data when the form is updated on 20 March. This will occur for any field that is being changed from a free text field to a check box, circle select, or drop-down menu.

00:07:53 

What this means is that any unsubmitted draft that is ready to go at 6:00 PM Australia Eastern Standard Time on 20 March will require the sponsor to go back and fill in the data or information that has been lost after the form is updated. I emphasise that any CTN submitted prior to the 20th will not lose the information and will remain in the old CTN format. 

For example, the container field within the medicines and biological sub-form used to contain and open text field and the description of the container supplied within. This has been changed to a drop-down menu whereby the container can be selected. With the update to the CTN form, this data will not be transferred over. 

An agent or sponsor will need to review their draft in the CTN form and complete this field again, this time using the drop-down menu. However, as always, for any issues regarding your CTN draft and the update, please contact clinical.trials@health.gov.au. 

Another enhancement to the CTN form is that you will be able to select for the trial classifications and categories as before, but now the CTN form will also allow for selection of the trial type. The current CTN form does not allow for sponsors to select for trial phase for a medical device clinical trial. So as you can expect, trying to adequately identify which clinical trials were high risk is substantially more difficult using the current CTN form. 

00:09:30

This improvement will support the review of the highest-risk device trials and also the scheduling of Good Clinical Practice inspections. 

In order to ensure that the HREC information is entered correctly and consistently, we have included an auto-fill and searchability function to the CTN form for selection of HRECs. After typing a relevant HREC name or HREC code in the search field, a drop-down list will appear, with options to select. 

Another very simple but extremely beneficial enhancement to the CTN form is the function to upload documents, such as the Investigator’s Brochure for medical devices. If you choose to upload the IB for CTNs of the highest-risk medical devices, this will streamline the review by providing the necessary documents in one place within the portal. Edwina will explain more about this review shortly. 

I know that some of you will be very happy to know that another enhancement to the CTN form and associated processes is the generation of an automated email notification to update the sponsor primary contact and alternate contact when the status of your CTN changes. 

As part of the CTN process, you will now receive an email when your CTN changes from Draft to Submitted, Submitted to Being Processed, and Being Processed to Acknowledged. I will note though that for pushbacks, multiple emails will not be sent out. 

00:10:59

An important point that I would like to make here is what each status means for the progress of your CTN. Submitted means that you have submitted your CTN but payment has not been received. If a fee is not applicable, which is the case for some CTN variations, the status will change from Submitted to Being Processed within 24 hours. If you are invoiced for a fee, you will have to pay this before the CTN moves to the next stage. 

The next stage is Being Processed, which is called Under Review within the portal. This means that the TGA is processing your submission. This occurs after payment, if applicable, and means that we are checking that the information in the form has been entered correctly and the correct fee has been paid. For some changes to CTNs, we will also manually raise an invoice during this stage. 

I would like to clarify that in the system, it will say Under Review, but it’ll actually just be Being Processed. This is not the review that medical devices is describing in this webinar but is a standard pre-existing status within the portal. 

Acknowledged means the TGA has confirmed that the data has been entered correctly and the correct fee has been paid. One question we are often asked is, when is the CTN officially notified, and when can you start supplying the goods to clinical trial patients? 

Well, as per the Therapeutic Goods Regulations and the Therapeutic Goods (Medical Devices) Regulations, a clinical trial is deemed notified once the CTN form has been submitted, with payment of the relevant fee, to the TGA. Once this occurs, the exemption under the Therapeutic Goods Act comes into effect. 

00:12:45

We check that the CTN form has been completed correctly and the relevant fee has been paid during the Being Processed phase. As such, most sponsors prefer to wait until they have received the Acknowledged status to be confident that the exemption under the Therapeutic Goods Act is in effect. 

It is important to be aware that for CTN variations, you may or may not be required to pay a fee, depending on the type of variation. Variations that will incur a fee include addition of new sites, addition of a new therapeutic good to a previously notified trial or a change to a previously notified therapeutic good that creates a separate and distinct good. 

It is important to note that a change to a CTN may not automatically incur a fee, and therefore, it must be manually raised during the Being Processed phase. As such, when submitting CTN variations of this nature, it is important to be sure that the correct fee has been paid before supplying the new distinct therapeutic good in the clinical trial. 

Another enhancement that you’ll be happy to hear about is that we have reformatted the settings for Print Preview. For your CTN and CTN variations, your print preview is now presented in table format, with grey and white rows to distinguish between different fields. The intention of these changes is to improve readability for the user. 

00:14:15

Now, I’ve intentionally left the best to last, and I hope you’ll appreciate these enhancements. Throughout the CTN form, we have included the addition of numerous instructional texts, guidance and info tools. For a number of fields, we have incorporated instructional text that comes up when you hover over the field, providing a description or an example of what information should be supplied in the field. This should make it much easier for you to complete the form correctly. 

In a similar way, we have incorporated into the CTN form guidance and links to relevant information in the CTN form user guide, the Clinical Trials Handbook and other guidance on the TGA website. You will now have all you need to fill in the CTN form at your fingertips, from tools to determine whether your investigational product is a biological or a medicine to guidance on how to fill in that pesky dosage and formulation field that many have struggled with. 

To conclude, these enhancements to the CTN form will support the medical devices review of the highest-risk medical devices and also the Good Clinical Practice, GCP, Inspection Program. We have heard the issues you have raised with the old CTN form and have addressed many of these pain points in this update. 

We hope that these enhancements will make the experience of completing the CTN form much more efficient and easy for clinical trial sponsors. We expect to see that, through these changes and additional guidance, the number of pushbacks and processing time for CTNs will be reduced. 

00:1:50

These enhancements will also support the Good Clinical Practice Inspection team by providing them more accurate and correct information. By having this information available to them, the GCP team will be better able to schedule inspections based on risk. 

So just to finish off, a reminder that the CTN form will be unavailable from 20 March, 6:00 PM Australia Eastern Standard Time, that’s 3:00 PM for Western Australia, and it will be offline until around 5:00 AM on 21 March. The CTN changes will affect any draft residing in the portal at that time. 

If you have any further questions regarding the CTN form enhancements, please do not hesitate to get in contact with myself or the rest of the clinical trials support team at clinical.trials@health.gov.au. Thank you for your time, and I’ll hand back over to Edwina, who will continue this webinar to communicate the changes to the TGA processes specifically relating to medical devices. 

EC: Thank you very much, Erin. So the overarching objective of our monitoring program is to ensure the safety and wellbeing of medical device trial participants, by assessing potential risks and ensuring appropriate mitigation strategies are in place, as per our commitment in the Action Plan for Medical Devices. 

00:17:22

What trials will be the focus of our monitoring program? So within scope are CTNs for first-in-human trials investigating these eight pre-specified categories of high-risk implantable and cardiac invasive medical devices. We selected this particular list of eight on the basis that they are at high risk of immediate catastrophic harm to patients, should they fail. 

What devices or what trials will be outside of the scope of review? So we will not be reviewing trials of devices that are incremental developments of established devices. That is to say, our focus will be on trials of devices whose safety profile in humans is essentially unknown. Sometimes, we will take a preliminary look at the information provided to confirm whether or not this is the case. We will also not be reviewing CTN variations, nor will we be reviewing trials where the investigational product is a medicine or a biological.

And this is what the review process will look like. So you, the sponsor, submit the CTN form. And once we’ve received payment, you can commence the trial, or to be more specific, you can commence supply of the unapproved device, provided all other relevant approvals are in place. And this is just as you have always done. 

We scan the CTN form to identify first-in-human trials of high-risk devices. And for these trials, we will review the Investigator’s Brochure or similar documentation. If we have any questions or safety concerns, then we’ll liaise with you to resolve them. In very limited circumstances, if we have significant safety concerns that remain unresolved, we may discuss further regulatory actions with you. 

I’ll go into more details in the next few slides. But first, I’d like to emphasise a few things about the process. 

00:19:40

First, the review will not affect trial timelines, although we do encourage you to submit the CTN form as early as possible and to use the attachment upload function to submit the IB to minimise requests for further information down the track. In the vast majority of situations where the documentation is uploaded upfront, this will be sufficient for our review, and we won’t need to contact you further. 

Second, there will be no additional fee if your trial is reviewed, beyond the usual notification fee. And third, you won’t hear from us unless we have questions or concerns. So we won’t routinely notify you if we have commenced or concluded our review of your CTN. 

The time taken for a review will be subject to complexity and the need to request further information. However, as we have resolved to minimise the impacts on trial timelines, we will communicate with you as soon as a point of clarification is identified to discuss the matter. And this will generally be within two weeks of your CTN being acknowledged. 

I’d also like to take this opportunity to mention that we will soon be seeking your feedback on some draft web guidance that will describe the review process and is intended to be a supplement to this webinar, so watch this space. 

As part of a review, we will look at the device description and operation. This may include aspects such as design, components, materials, mechanism of action, anatomic site of use and indications. 

00:21:38

We will also look at the pre-clinical and clinical data on the investigational device. And this may include bench and animal testing and any international standards that have been applied to the device. Existing clinical data will likely be limited in the context of a first-in-human study but may include clinical data for similar devices, for example. 

And finally, we will look at the risk management documentation to ensure that relevant risks, for example, as identified in similar devices, have been considered and mitigation strategies to minimise these risks have been implemented. 

The reviews will be performed by the TGA clinical assessors and other assessors in relevant disciplines, for example, engineering, biomaterials, sterility and toxicology. We will also soon be seeking your feedback on draft guidance on the information to be included in an Investigator’s Brochure, which will broadly align with ISO 14155. 

In terms of outcomes, we expect that for the vast majority of reviews, scenario one will apply, that is, we won’t have any questions or safety concerns, and we will essentially reaffirm the HREC’s conclusion. And in that case, no further action will be taken. 

For reviews where we have questions or safety concerns, we will contact sponsors in the first instance to request further information or clarification. And generally, this will happen within two weeks after the notification is acknowledged. If the questions or concerns are able to be resolved, again no further action will be taken. 

00:23:39

If there is a significant safety concern that we are unable to resolve, we may consider further actions on a case-by-case basis, using a risk-based approach, in discussion with you. This process could take longer, but we will communicate with you on an ongoing basis until there’s a resolution. 

Risk-based considerations may include whether the safety concern relates to an isolated occurrence or systematic failure, the nature of the adverse patient outcomes and the likelihood of adverse patient outcomes. Further actions may include requesting a voluntary pause in the trial while we investigate further, a targeted GCP inspection and proposing to stop the trial, if continuing the trial is contrary to the public interest. 

I’d like to note that requesting a pause in the trial and proposing to stop the trial are extreme examples, to be considered as a last resort, and are likely to be exceptions to the rule, as we expect that the vast majority of concerns can be resolved in a timely manner. Proposing to pause or stop a trial is a power that the TGA has always held, so it’s not a new power that’s specific to this monitoring process. 

00:25:10

So to summarise, I’d like to reiterate that there won’t be any changes to the CTN and CTA pathways. Instead, we will be updating the CTN form and related guidance to improve data quality. And we will use the data captured by the updated CTN form to proactively identify and review the highest-risk device trials, so that is, the first-in-human trials involving those eight categories of implantable and cardiac invasive devices. 

To facilitate this, we would like to encourage you to submit your CTN as early as possible, to use the attachment upload function to submit the Investigator’s Brochure and to familiarise yourself with the general expectations of the contents of an IB, which will be outlined in ISO 14155 and in upcoming TGA guidance. 

And this brings me nicely to my next slide on upcoming guidance and webinars. So to supplement today’s webinar, we will be publishing an updated CTN user guide, as Erin has mentioned, which incorporates all of the changes that have been implemented, and web guidance on the high-risk device trial review process and what should be included in an Investigator’s Brochure for a medical device clinical trial. For the latter two, you will have an opportunity to provide feedback on the drafts we have developed in due course. 

There will also be a second webinar on GCP inspections for medical device trials, scheduled for sometime in May or June. And we will be sure to notify you of any developments in these spaces. That concludes our presentation today. 

00:27:28