Insights into Good Clinical Practice (GCP) Inspection Program activities 2023-2024, 9 May 2025

Speaker key:

• MV: Michelle Vo
• AM: Anastasia Makshakova
• NI: Nishi

NI: Okay. Now, without further ado, I will pass on this presentation to our speakers, Michelle Vo, who is the Assistant Director, and Anastasia Makshakova, who is a Senior GCP Inspector of the Pharmacovigilance Branch in the Pharmacovigilance Compliance and Clinical Trials section at the TGA. Over to you, Michelle.

MV: Thanks, Nishi. A warm welcome and thanks for joining us. I'll start with a roadmap for today's presentation. I'll set the scene with some background on the Inspection Program. We'll then walk you through some key insights into our second metrics report. I'll briefly cover the consultation process for the adoption of the third revision of ICH GCP E6. The second revision of the GCP guidelines was covered in our metrics report, and it's still valid today. I'll walk you through our focus for the future, and finally, we'll wrap up with a Q&A.

A shout-out to everyone who submitted pre-webinar questions. We moderate the questions to ensure they align with the scope of today's presentation. This means that questions outside of the scope of the program aren't addressed in this forum. We've incorporated some responses into our presentation, and others will be addressed at the start of the live Q&A. So we can cover as many questions as possible, we've combined questions on the same topic. Let's kick off.

The foundation for today's presentation is our second metrics report, covering the two-year period, 2023 to 2024. There are some valuable insights into the inspection findings on compliance expectations for clinical trial sites. These can be found in the report.

A common question we receive is, does the TGA provide checklists to help sites be inspection ready? The answer is no. While we don't provide specific checklists, the metrics report is an excellent resource. You can use its detailed findings and compliance expectations to create a customised checklist for your site. If you haven't read it yet, please, I encourage you to go and have a look.

Our report should be read alongside our GCP guidance, which is shown to the right of your screen. As part of a TGA-wide initiative, our guidance has moved into a web-based format, focusing on consistency, accessibility and improved navigation. Key new features include coloured call-out boxes announcing changes, a page history showing changes to guidance, and a sticky navigation that allows you to jump from headings once you've scrolled past the table of contents.

Our content has mostly moved from PDF to a web-based format, but there's a “Save As PDF” function for when you do need a PDF. We're aiming to make sure our website is clear, easy to use and current, so it has the trust and the confidence that you'd expect from a regulator.

Before discussing the GCP Inspection Program, let's touch on what is Good Clinical Practice, GCP is an international standard for designing, conducting, recording and reporting clinical trials. In Australia, compliance with GCP for clinical trials involving unapproved therapeutic goods has been required for over 20 years, with two guidelines recognised by us.

ICH GCP E6 R2 applies to medicines and biologicals. You'll see that we include E6 R2 when referring to ICH GCP. What do they mean? The ICH, the International Council for Harmonisation, publishes a suite of what are called efficacy guidelines. They have 22 on their website right now, and E6 reflects the piece of work on Good Clinical Practice. And R2 simply refers to Revision 2, the version that's currently in force in Australia. And I'll be addressing the third revision later in my presentation.

ISO 14155 applies to medical devices. For trials involving a medicine or biological, in combination with a medical device, both guidelines apply.

So, why do we inspect? The TGA's GCP Inspection Program strengthens the TGA's monitoring activities to help protect the rights, safety and well-being of Australian trial participants. It also ensures the quality and the credibility of trial data. We don't provide certifications, accreditations or product or trial approvals to institutions or organisations where trials are conducted. Our inspections are an opportunity to provide education and work with you to ensure you have effective systems in place, aligning with Australian legislation and the relevant GCP guidelines.

What this looks like in practice is, during inspections, sites can ask questions to understand best practice. Inspectors undertake interviews to help understand the processes. They will check their understanding, and you'll also have opportunities to correct any misunderstandings during or after the inspection. The goal is to be inspection ready. We may inspect at any stage of the clinical trial life cycle, from early recruitment to completed trials. A key takeaway from today's presentation is not to wait for an inspection announcement to be inspection ready.

Inspectors will check your compliance with your obligations under the Therapeutic Goods Act and the regulations. The Therapeutic Goods Act provides the basis for the CTN, or the Clinical Trial Notification, and the CTA, Clinical Trial Approval schemes. It regulates access to unapproved goods for use for experimental purposes in humans.

The regulations, these set out the conditions that therapeutic goods used in clinical trials must comply to be exempt from the Act. It's under the regulations that we have legal powers to inspect. The legal powers to authorise officers to inspect a site is found in the Therapeutic Goods Regulations section 12AC for medicines and biologicals. As for investigational devices, these powers are found in the Therapeutic Goods Medical Devices Regulations section 7.4.

Inspectors will check your compliance against the relevant GCP guidelines for your investigational product, the National Statement, and the trial-specific protocol and amendments approved by the Human Research Ethics Committee.

This is a good opportunity for me to address a pre-webinar question we received. Do all HREC-approved documents, including safety reports, need to be RGO authorised? The answer is we assess compliance against HREC and RGO, or Approving Authority, requirements. To be inspection ready, you should familiarise yourself with these requirements.

Let's talk a bit about who we can inspect. We inspect all Australian investigator sites involved in Clinical Trial Notification and Clinical Trial Approval schemes. These fall under the GCP Inspection Program. This includes commercially sponsored trials and investigator-led trials. We can inspect any party contracted by the site to carry out clinical trial-related activities at the site level. This might include pharmacies, pathology labs and imaging facilities. But don't worry, once an inspection is announced, we confirm the exact locations with the site.

This isn't on the slides, but a common question we get asked after an inspection is, why me? The answer is our inspections aim to cover a diverse range of clinical trials, including all phases, enrolment stages and therapeutic areas. We can inspect trials at any stage, from early recruitment to completed trials. Our goal is to achieve a broad representation of different trial types and a wide geographical spread across Australia.

We don't inspect Human Research Ethics Committees, trial sponsors, approving authorities or the Research Governance Office. We don't inspect clinical research not subject to the CTN or the CTA schemes. This usually means clinical research not involving an unapproved therapeutic product. This could be a study on the relationship between lifestyle factors, like diet, physical activity, sleep patterns and long-term health outcomes. This sort of research is not within the scope of our program.

I'll now touch on what we inspect. Our inspectors focus on five main inspection categories. These are protection of participants, protocol compliance, documentation, investigational product and trial management. In the table to the right of your screen, you'll see several subcategories. We don't inspect everything. Instead, what we use is a risk-based approach to the type and the number of documents requested during an inspection. But you should maintain inspection readiness across all five categories.

Before I hand over to our Senior GCP Inspector, I'll share an overview of the inspections conducted in the two-year period covered in our metrics report.

The types of inspections. A total of 13 GCP inspections were conducted, including trials that contained more than one unapproved therapeutic good, 12 routine, announced inspections, and one for-cause announced inspection, which was the result of a routine inspection.

Inspections were delivered in person and in hybrid formats. Inspected sites included private and public sites, various locations across Australia and commercial and investigator-initiated trials. Inspected trials included phases one to three, ongoing and completed trials, 11 therapeutic areas and various investigational products.

This takes me back to the question we're often asked, why me? You'll see that our inspections are consistent with our goal to achieve a broad representation of different trial types and a wide geographical spread across Australia.

Summarising the deficiencies in the two-year period, at least one deficiency was identified in all inspections. Critical deficiencies were identified in protocol compliance, trial management and therapeutic good or investigational product categories in both years. No deficiencies were identified in commercially sponsored trials. Full compliance in one or more categories was observed in several inspections, and the highest level of compliance was observed in therapeutic good or investigational product.

I will now hand over to Anastasia, our Senior GCP Inspector, and she'll walk you through some of the example scenarios on compliance expectations. Over to you, Anastasia.

AM: Thank you, Michelle. As Michelle mentioned, we identified deficiencies in all inspections included in the metrics report. I will start with a summary of example scenarios from the 2022 metrics report.

I will then present all example scenarios based on the current metrics report, a scenario based on common deficiencies identified in this reporting period, questions to support self-evaluation of compliance at your site, and I'd like to highlight that this is not an all-inclusive list of questions, applicable regulatory requirements for every scenario, and the key message.

Rather than going through the deficiencies one by one, we combined a few of the common things we saw and reported on in the metrics report in these more general and identified scenarios. I'll introduce each scenario. Scenarios apply to all types of clinical trials regulated under the Clinical Trial Notification and Clinical Trial Approval schemes, including medicines, biologicals and devices. As you may know, the protocol is referred to as a Clinical Investigation Plan, or CIP, in devices trials. CIP and protocol are used interchangeably in this presentation.

The applicable compliance requirements will be displayed on the slides for your reference. I will identify what these requirements relate to at a high level, but I will not read them. We will frame the questions that we think you need to be asking when you face a similar situation, and I will have some additional considerations not present on the slide. I will announce when I'm moving on to the next dot point to make it easier for you to follow the slides.

All learnings from four scenarios from our first metrics report that we presented in 2023 are still applicable. They include, a modified consent form signed by participants but not investigators, all trial ECGs done out of window, decentralised trial management, and managing investigational products in a decentralised trial. We encourage you to listen to that webinar recording, published on the TGA website.

The first example scenario relates to communication with the Ethics and Approving Authority. We identified several significant deficiencies associated with the investigator not ensuring that all required documents were submitted to the responsible Ethics. In this scenario, as an investigator, you need to review the initial document package for completeness and decide which documents to submit to the reviewing Ethics and the Approving Authority at your standalone clinical trial site.

The document package included the protocol of CIP, trial blinding plan, several manuals that you can see on the screen and initial contract. This document package did not include Investigator's Brochure or equivalent, Participant Informed Consent Form and recruitment materials. And applicable compliance requirements relate to communication with an Ethics and Approving Authority and also to the content of the consent form.

Questions to support your self-evaluation of compliance at your site include, first dot point, do you know which documents are required to be submitted to the reviewing Ethics and Approving Authority? Do you have all of these documents? Next dot point, who reviews the document package for completeness? What is the process? Is this process the same for all types of trials?

Next dot point, how do you assess if any additional documents may be required to be submitted? In this scenario, you received two documents that are always required to be submitted, protocol and contract, and you need to assess if any other documents require submission.

In case when no clear regulatory requirements exist for a particular type of document you received from the sponsor, read this document and assess if any information not included in the protocol or other submitted or approved documents is included in the document you received. Is there any contradicting information in those additional documents? If yes, does this information have potential to influence Ethics or Approving Authority approvals or favourable opinions?

In this scenario, you were a missing Investigator's Brochure and consent form that were definitely required to be submitted, and you also didn't receive any recruitment materials, which you may or may not need, depending on how you plan to recruit participants.

Next dot point, who is responsible for ensuring that the submitted documents comply with the National Statement, ICH GCP E6 and ISO 14155, as applicable? And the final dot point is, how are these documents reviewed for compliance at your site? For example, how do you check that the content of the consent form is compliant with ICH GCP or ISO requirements? Is it checked for compliance before it is submitted to the Ethics and Approving Authority?

The key message here is the investigator is responsible for ensuring that the HREC and Approving Authorities are provided with all information which may influence their approvals or favourable opinions. And the same logic applies for progress reports and ongoing approvals or favourable opinions.

We are now moving on to a different scenario. As an investigator, you received a protocol amendment with significant changes to trial procedures and increased data entry requirements for your trial site staff. Applicable compliance requirements relate to protocol compliance and having sufficient resources to conduct a trial.

Questions to report self-evaluation of compliance at your site include, first dot point, do you have a process to assess if you still have appropriate resources to comply with the updated protocol requirements?

Next dot point is, have you considered these changes before indicating your acceptance of the protocol or clinical investigational plan in writing? The intent behind requesting the principal investigator's signature on the protocol acceptance page is to get reassurance that the principal investigator can still comply with all proposed changes to the protocol.

And the final dot point is, do you have a process to communicate any anticipated issues that may hinder your ability to comply with protocol before amendment is submitted to the reviewing Ethics or Approving Authority?

In this scenario, let's suppose that you can comply with the proposed changes to the trial procedures, but you do not have enough staff to comply with the increased data entry requirements. There is no single solution that would work for all sites, but it is very important to consider all anticipated challenges before implementing the updated protocol at your site. And the key message here is, when changes occur, re-evaluate your staff and facilities requirements for the foreseen duration of the trial.

Moving on to a different protocol amendment scenario, here, as a pharmacist, you received a protocol amendment with significant changes to schedule and type of participant visits and also investigational product management. Your recruitment is now closed, and you have ten participants receiving oral investigational product. Participants will now come in less frequently and will require remote dispensing.

Applicable compliance requirements relate to protocol compliance, having sufficient resources to conduct a trial, and to investigational product management.

Questions to support self-evaluation of compliance at your site include, first dot point, do you have a process to assess if you still have appropriate resources to comply with updated investigational product management requirements before you accept this amendment?

Next dot point, what is the impact of the changes to investigational product management at your site? Next dot point, do you have sufficient space to keep more investigational product for the anticipated higher volume of investigational product deliveries? Next dot point, do you have a process to accommodate the change of dispensing from onsite to remote? And the final dot point is, where will participant returns be documented? Who will ensure that all returns are accounted for and compliance with the investigational product is calculated?

In this scenario, let's suppose that you do have enough space to keep more investigational product and have a process to accommodate remote dispensing, but you don't have a standard process on how to manage participants' returns from remote dispensing because you always assess it on a case-by-case basis.

In this case, the investigational product cannot be returned via post, and there is no budget for the returned courier. You need to assess what solution would allow for IP compliance to be calculated without significantly increasing the risk of participant safety. Is this process sufficiently described in the updated protocol? If yes, are you able to follow it?

If no, some of the solutions could be to seek principal investigator's input on whether it's feasible to only do accountability and assessment of compliance with investigational product at less frequent face-to-face visits. What should the process be if participants forget to bring their investigational product to those visits? Is a remote compliance review feasible?

Can initial compliance be done based on indirect source of data, such as participant diaries, for example, and then confirmed once accountability is done? Is it feasible to organise alternative methods for accountability, for example, for the participant returns to be collected by a home nurse, if one is available for the trial?

The key message here is consider impact of change on the investigational product accountability, including reconciliation of participant returns of the investigational product. Incomplete investigational product accountability can compromise the integrity of the trial and the safety of participants.

And the final scenario is related to sponsor-investigator. As Michelle mentioned, sponsor responsibilities are outside of the GCP inspection scope, except for investigator-initiated trials. Applicable compliance requirements relate to sponsor responsibilities, all of which apply to sponsor-investigator in a Clinical Trial Notification and Clinical Trial Approval trial.

This scenario is mainly for those taking on sponsor-investigator responsibilities. However, it is also an important scenario for the site staff to better understand what to expect, and for other types of sponsors to understand what we review in the TGA GCP Inspection Program.

I'd like to highlight that the scenario is focused on the TGA requirements. Any other commonwealth state and local site-level requirements are not included in this scenario. And we're also not focusing on resources. The reality is that if you don't have the right resources, then a CTN or a CTA trial cannot be conducted.

In this scenario, as a sponsor-investigator, you are considering conducting an investigator-initiated trial under a Clinical Trial Notification scheme. You plan to supply one type of unapproved medicine. And there are a lot of questions you could be asking yourself. I will only cover questions that relate to the points to consider that are on the slide.

Do you know if a CTN or a CTA are required for your trial? Is your CTN or CTA form complete and accurate? And to answer this question, you need to understand what type of therapeutic goods you plan to supply. In Australia, clinical trials require an exemption if unapproved therapeutic goods are supplied. Refer to the metrics report in the clinical trial handbook for definitions. Supply of unapproved therapeutic goods cannot commence prior to the notification to the TGA under a CTN scheme applicable to this scenario.

Next question to consider is, do you have a process to ensure compliance with all aspects of the trial, including requirements related to risk management, clinical trial monitoring and protocol or CIP design? Careful planning of trial conduct is important.

You need to know all applicable regulatory requirements before you initiate a trial to have a fast site initiation process and have a process to monitor these requirements during the trial. Success of planning relies on both the content of the plan and its execution, so make sure that your processes support compliance.

Next question is, do you have all required information on the investigational product? Can you ensure that investigational product is not supplied until all required approvals and favourable opinions are received? Do you have access to investigational product for the duration of the trial? If you don't have information, where can you obtain it? Do you have a process to ensure that this information remains current for the duration of the trial? Do you have the required training and resources to conduct an investigator-initiated trial?

This also relates to a question we received. There are no regulatory requirements for a specific type of training. There are a number of GCP training providers. The TGA doesn't provide specific advice or endorse any GCP training courses.

The training courses recognised by TransCelerate Mutual Recognition Program and official training course by International Council for Harmonisation of Technical Requirements for Pharmaceutical for Human Use, ICH, are commonly used. For example, ICH have a dedicated training program for sponsors that may be of interest to you.

Another commonly asked question is about electronic systems. GCP validation requirements are not always the same as traditional IT validation. You need to refer to ICH GCP E6 R2 section 5.5.3 or ISO 14155 20 section 7.8.3 to check whether the systems that you plan to use meet validation requirements, and you need to only use the systems that are fit for purpose.

And the final point is, can you ensure that the trial is registered on a publicly accessible database before recruitment of the first participant? World Health Organisation has a list of registries that can be used. One of the examples commonly used for local trials is Australian New Zealand Clinical Trial Registry, ANZCTR. And the key message from this scenario is, know your obligations as a sponsor-investigator.

And I will now hand over back to Michelle to summarise the key messages from our presentation. Thank you.

MV: Thanks, Anastasia. The key takeaway messages from this presentation is don't wait until an inspection to be inspection ready. Take the time to proactively understand the TGA requirements and guidance on clinical trial conduct, this means knowing the requirements that apply to your trial and carefully plan the trial. Compliance with GCP should be integrated into the site's processes. It's not a standalone function. Inspectors are looking for evidence of compliance and complete documentation.

Inspectors aim to work with clinical trial sites and provide education to improve compliance and protect clinical trial participants. If you're selected for an inspection, our advice is to maximise the education opportunity and ask questions. Finally, our inspections aim to cover a range of different clinical trials. This includes different phases, stages, enrolment stages, therapeutic areas of trials within our scope.

I've talked quite a bit about the GCP Inspection Program. Now I'd like to touch on when we will consult on the third revision of ICH GCP guidelines. Public consultation will commence this year. And this is consistent with the statement published on our website in January. The second revision, so R2, is still valid.

So why do we consult? We undertake an extensive process of internal and external consultations to ensure that the guidelines are consistent with the prevailing uses and the requirements in Australia. We aim to align our regulatory approaches to therapeutic products with those of comparable international regulatory counterparts, wherever possible. Follow us on LinkedIn to receive timely alerts when the consultation is announced.

What's in store for the GCP Inspection Program for the future? Our GCP Inspection Program has a very important role in Australia in strengthening TGA’s oversight of clinical trials, both CTNs and CTAs.

Our focus will be on the consultation on R3, enhancing education and collaboration, awareness building by supporting compliance and engaging with clinical trial sector through face-to-face events, targeted communication and guidance updates, as well as self-paced online modules to come.

Our inspections team is growing, and we're planning to conduct more inspections and shorter ones across a diverse range of trial sites from low to high-risk trials. And we're committed to continuous improvement. We're proactively seeking feedback from inspected sites to refine the program.

I'll close by saying that we're optimistic about the opportunities to support the clinical trial sector to continue to make Australia an attractive destination for clinical trials. And finally, thanks for your ongoing engagement with us and for choosing to join us today.