Good Clinical Practice (GCP) inspection program for clinical trials of medicines, biologicals and devices

This presentation will be recorded, and most of the content I'll be covering is in our inspection guidance. We've recently revised the inspection guidance to reflect the inclusion of devices in the program. I'd really like to emphasise the value of going through and having a look at this guidance. It steps you through the inspection process and preparing for an inspection. We’ll be finding out soon, through the polls, how many people have read this guidance. And if you haven't, please take the time to have a look. 

The key message is that the inspection process, the type of inspection and the grading of the inspection findings, is the same for medicines, biologicals, and devices. The only regulatory change is that devices have been incorporated into the inspection program. In updating our GCP inspection guidance, we've taken the opportunity to improve the structure and also the readability, so that it's easier for you to use. 

Have you read the full inspection guidance? I've got some poll results here, and it's telling us that 46% of attendees have read the guidance. That's some good reading ahead for some of you. I'd suggest that you take a look, if you haven't had a chance to read it yet. 

Let's get into the details of the inspection program. I thought I'd start off with addressing a question that's come up in one of our pre-webinar questions, as to what isa medical device. I'll just touch briefly on this.
 

You may need to determine, firstly, if the product is considered a therapeutic good, which would require an exemption or an approval. The TGA website has a handy tool, called Is My Product a Therapeutic Good? And that may assist you in identifying whether the product is a therapeutic good. 

There's also Is My Product A Medical Device? And that provides a very comprehensive definition of a medical device. So we'll be broadcasting those links, and you should see them in the chat. 

What is GCP? GCP is an international, ethical and scientific standard for designing, conducting, recording, and reporting clinical trials. Before I get into discussing the program, I'd like to touch on some key legislation and standards that apply. 

As I'm sure you might be familiar with, clinical trials involving unapproved therapeutic goods must be conducted in accordance with the relevant GCP guidelines, as well as complying with other requirements, such as the Therapeutic Goods legislation, the National Statement on Ethical Conduct in Human Research, as well as state and territory legislation. 
 

I think it's important to note that the requirements to comply with GCP in Australia are longstanding with both ICH GCP E6 and ISO 14155, having been recognised for over 20 years. The. ICH GCP E6 R2 applies to clinical trials involving medicines and biologicals, and ISO 14155 applies to trials of investigational devices. 

Both GCP standards apply for combination products with a device or trials involving a device, as well as a medicine or a biological. ICH GCP E6 and ISO 14155 are generally aligned to the extent that there is a perceived inconsistency between ICH GCP E6 and ISO 14155. The safest course of action will be to follow the strictest requirements, but you can get in touch with us if you're unsure. 

I'd like to touch on some of the key legislation that apply to clinical trials with a bit of a legal refresher. At the Commonwealth level, the Therapeutic Goods Act provides the basis for the CTN and CTA schemes. It regulates access to unapproved goods for use for experimental purposes in humans. 

The Regulation sets out the conditions that the therapeutic goods used in clinical trials must comply with to be exempt from the Act.  It's under the regulations that we have legal powers to inspect. 

The investigational devices, the Therapeutic Goods Medical Devices Regulation 7.4 is a very important piece of regulation for our inspection program as it gives us the legal powers to authorise officers, our inspectors, to examine, inspect, take measurements of or conduct tests, including by taking samples, anything on the site that relates to the trial, and take photos, make video recordings, or make sketches of the site or anything on the site. For investigational medicines and biologicals, the legal powers to authorise officers to inspect is found in the Therapeutic Goods Regulation 12(AC).
 

The clinical trial specification enables us to share the inspection report with the approving authority or the Human Research Ethics Committee. Under the CTN and CTA schemes, the approving authority gives the final authorisation for the conduct of the trial at the site. 

For those of us tuning in from a public health organisation, your approving authority may be commonly be known as the Research Governance Officer, or the RGO. A link to our website should be appearing in the chat for those wanting more information on the legal basis for the inspections. 

Do you use ISO 14155? 92% of our audience have responded no. Do you use ICH GCP E6? 121 have responded yes.

Who do we inspect? A risk-based selection of a proportion of eligible clinical trials will be undertaken. All Australian investigator sites involved in CTN and CTA trials of medicines, biologicals and devices are within scope of the GCP inspection program. This includes commercially-sponsored trials, as well as investigator-led or academic trials. All phases and all stages of the trial are in scope.

How do we define an investigator site? Investigator sites are all locations carrying out clinical trial activity, except for the patients’ homes. The exact location of inspection activities is discussed and confirmed with the site following an inspection announcement. 

To reiterate, we inspect Australian investigator sites conducting clinical trials under the CTN and CTA scheme. This includes investigator-initiated trials. We expect any party or organisation contracted to carry out some or all clinical trial activity related to the trial at the site level.

Entities we don't inspect. We don't inspect the Human Research Ethics Committee, the HREC. We don't inspect the approving authority, we don't inspect trial sponsors. 

Why do we inspect? The GCP inspection program strengthens the TGA's monitoring activities to help protect the rights, safety, and well-being of Australian clinical trial participants. It assures the quality and the credibility of the trial data.
 
A GCP inspection allows us to verify you are compliant with the relevant GCP standards, and you've met your clinical trial responsibilities. It's also an opportunity for education. It provides us with an opportunity to work with you to ensure that there are effective systems in place that are in alignment with Australian legislation and the relevant GCP standard. 

During inspections, there are opportunities for sites to ask questions to better understand best practice. Throughout their inspection, the inspectors will check their understanding about how you are conducting the trial. You’ll have an opportunity to correct things.

If you’ve misunderstood something, there will be plenty of opportunities for you to clarify or correct misunderstandings. More on this when I explain the inspection process later.

How do we prioritise inspections? With the high volume of clinical trial activity in Australia, it's not feasible, nor is it reasonable, for us to inspect every study throughout the calendar year. International regulators perform GCP inspections on approximately 1% to 3% of clinical trials. And we're currently targeting that same proportion. 

The question, of course, then, is how do we choose which 1% to 3%? We use a number of tools, information, and risk factors to prioritise clinical study sites for inspections. These include a risk assessment that is based on the NHMRC’s principles for risk-based management and monitoring of clinical trials involving therapeutic goods. 

We'll also consider a combination of external and internal intelligence. The assessment categories risks as those associated with the investigational product and those associated with the trial conduct, design, and methods.

We also consider some other elements when we make the decision or the final selection on the clinical trial site for inspection. For example, we look at the type of site, is it located at a large institution or a small clinic, so that we're inspecting a range of different types of sites. 

We also look at the geographic location to select sites throughout Australia, to get a good spread. Other factors, like the number of participants in the trial at the site, will be considered, as well as the compliance history of the investigator sites and sponsor, including findings from previous GCP inspections of investigator sites.

Let's talk about the inspection process. Most of our inspections are routine, and preferably conducted onsite, rather than remotely. There may be occasions when we need to perform GCP inspections remotely, using video or teleconferencing, for example where access to the investigator site or other sites is difficult. If a remote inspection reveals issues that require an onsite inspection, or the inspection objectives could not be met remotely, we may visit the inspection site.

Routine GCP inspections are scheduled in advance as part of the inspection program, and are prioritised based on our risk assessment and the other factors I've described. These inspections are usually of a single investigator site of a specific clinical trial, but other sites may be selected to verify and provide practical evidence of compliance. 

A for-cause inspection may be undertaken in response to a specific trigger, where a GCP inspection is the appropriate way to examine the issues. For-cause inspections generally focus on specific aspects of the clinical trial at a particular investigator site, or examine identified compliance issues and their impact, but we may also inspect other sites as a result of a trigger.

Significant safety concerns, or identified non-compliance are expected to be the most common triggers. We anticipate the majority of inspections to be announced, meaning we will notify you of them in advance to ensure the relevant personnel will be available for the inspection. 

Sometimes it may be appropriate to conduct unannounced inspections or to perform an inspection at short notice, for example when an announcement could compromise the objectives of the inspection, or when prompt inspection is required due to an urgent safety concern. 

There is no reinspection routinely planned for clinical trials inspected as part of our program. If a previous inspection of a clinical trial identified non-compliance, this may increase the chance you will be inspected at some time in the future. For example, where we've identified significant non-compliance, or to evaluate your ongoing compliance with requirements and evaluate changes to your clinical trial management systems.

Follow-up inspections may be performed, particularly for for-cause inspections to verify you have taken the appropriate corrective and preventative action to address any non-compliance. 
 

What does a routine inspection look like? At the pre-inspection phase, we will get in touch with the site about a month beforehand to organise logistics and timing. This includes notification, planning and preparation, agenda and logistics with the trial site, drafting and finalisation of the inspection plan.

During the inspection. So far, inspections have run over three days, and we've held them with all inspectors on site, as well as hybrid, some inspectors onsite, some virtual. 

A typical inspection looks like this. There's an opening meeting where inspectors introduce themselves and the site gives a presentation. There’s a facility tour. The inspectors undertake interviews with key staff and review documentation, including source data. 

It's usual to have a daily debrief. There's an opportunity to ask questions and clarify matters. Throughout the inspection, the inspectors will check their understanding of how the clinical trial is being conducted, and you have an opportunity to correct things. 

 On the final day, there's a closing meeting where the inspectors present a summary of the key findings, and there's an opportunity to ask questions or clarify matters with the inspectors.
 

In the post-inspection phase, after the inspection, we usually issue a report within 30 days, but it can take longer if complex issues arise, or if there are many issues. At the same time, we typically issue a Corrective And Preventative Action (CAPA) template for you to complete. The site will often ask for a meeting to discuss the CAPA options to resolve and agree with the inspectors on actions. 

The inspection team will assess your proposed CAPA plan and provide any comments if the initial response isn’t acceptable. If needed, we can meet with you to discuss the deficiencies and your proposed action to reach an agreement on acceptable actions and timeframes. 

For critical and major deficiencies, evidence will need to be provided to demonstrate implementation of your described actions. In this case, we will review the evidence you've submitted and assess the appropriate implementation of the CAPA plan. An inspection will be closed when the CAPA has been completed and accepted by the inspector. 

We're committed to ensuring that visits are as collaborative as possible. The work we do is built on a foundation of education under the TGA's Regulatory Compliance Framework. We promote high levels of voluntary compliance by effectively engaging with and educating the clinical trial sector with clear guidance on how to comply.

While it can be challenging to go through an inspection, it's an incredibly valuable education opportunity, and we've had really positive feedback about the learnings. The inspection is of the greatest value when these learnings are applied to other trials at the site, not just the trial we've inspected. 
 

Let's talk about the inspection scope. Our inspectors look at five main categories. Protection of participants, protocol compliance, documentation, the investigational product, and trial management. 

We don't review every trial-related document. We use a risk-based approach to the type and number of documents we ask to be provided during an inspection, but you should maintain inspection-readiness across all five categories. 

In our 2022 metrics report, documentation was a key area of non-compliance that cut across all categories. A key message is to have documented evidence and processes and decision-making.

While we do undertake interviews to help understand the process, if there's no supporting documented evidence or standard operating procedures, then this will lead to deficiencies being recorded. In other words, if it's not written down, did it actually happen? 

Deficiencies are rated as minor, major, or critical. Deficiencies can be attributed to clinical trial systems, practices, or processes that affect the rights, safety, or well-being of clinical trial participants, or the quality or the integrity of the data. 

A critical deficiency is an issue in clinical trial systems, practices or processes that adversely affects the rights, safety, or well-being of clinical trial participants, or adversely affects the quality or integrity of the data, or represents a serious violation of applicable legislation or guidelines. 

A major deficiency is an issue in the clinical trial systems, practices or processes that could adversely affect the rights, safety, or well-being of clinical trial participants, could adversely affect the quality or integrity of the data, or represents a violation of applicable legislation and guidelines. 

And a minor deficiency is an issue in clinical trial systems, practices or processes that would not be expected to adversely affect the rights, safety, or well-being of clinical trial participants, or the quality of, or integrity of, the data.

In the next slides, I will explain the steps you can take to be inspection-ready. The goal is to always be inspection-ready. Inspection-readiness refers to the ability of a clinical trial site to operate at a level that supports compliance. Inspection-readiness isn't simply something that you do, it's a state of operation. 

Clinical trial sites that maintain inspection-readiness will be well-placed to have a successful inspection without significant findings. Inspection-readiness needs to be fit for purpose for a specific clinical trial site. 

Inspection-readiness may include considering if there are any unique compliance requirements of a particular clinical trial, training of staff that's fit for purpose, prompt filing of all relevant documentation, ongoing documentation of significant decisions related to the trial. 

On the other hand, preparing for an inspection typically refers to the steps you take to facilitate an announced or unannounced inspection, such as pulling files from storage or archives, and starting the process to get our inspectors access to electronic data, for example. If you are always inspection-ready, it will be much easier to prepare for an inspection if you receive an announcement letter from the TGA. 

We may carry out a GCP inspection at any stage of the clinical trial lifecycle, from the early phase of participant recruitment to completed trials. One take-home message from today's presentation is to not wait for an inspection announcement from the TGA to be inspection-ready. Aim to be inspection-ready throughout the entire lifecycle of the trial. 

A reminder that sites must comply with all applicable Australian legislation and guidelines. Our inspectors will check your compliance with the Therapeutic Goods Act and Regulations, the applicable GCP standards: ICH GCP for medicines and biologicals, ISO 14155 for devices. Both GCP standards apply for combination products or trials involving a device, as well as a medicine or biological. Inspectors will check your compliance with the National Statement and the trial-specific protocol and amendments approved by the HREC.

We've talked quite a bit about guidance and legislation that you know underpins the requirements, but there are some additional resources that are really helpful and will set you up for success. A starting point is the Australian Clinical Trial Handbook. It describes the Australian Therapeutic Goods legislation relevant to clinical trials. It's a tool to help trial sponsors, HRECs, investigators and approving authorities understand their roles and their responsibilities under the CTA and the CTN scheme. 

To help clinical trial sites prepare for an inspection, we publish annual GCP metrics reports on inspection findings and compliance expectations. The report provides observations on how to improve the quality of clinical trials and reduce the potential for deviations at your site.

You can use the metrics report to self-assess if similar compliance issues may need to be addressed at your site. We'll be publishing the 2023 metrics report soon, so keep an eye out for that. 

The National Standard Operating Procedures for clinical trials, including tele-trials in Australia, ‘National SOP’ for short, is endorsed by the TGA. You'll find procedures and templates for key clinical trial activities you can apply at your site. 

You should have a resource plan in place at your site to ensure that site staff can accommodate an inspection within any given timeframe. Sites will usually be provided with four weeks’ notice for announced inspections. However, inspections may be unannounced or be performed at short notice. 

Inspectors will need view-only access to your trial management systems, so please review your IT processes to allow view-only access for the inspectors in this timeline as well. 

Do you know the difference between an audit and an inspection? Technology is being kind to me, and I can see the results. And 38 people do know the difference out of 47 who responded, but the results are still coming in.  A clinical trial sponsor is responsible for undertaking an audit, and a regulatory authority, such as the TGA, undertakes an inspection.

While our inspection program doesn't typically inspect trial sponsors, the sponsor plays a vital role in supporting the site to maintain inspection-readiness throughout all stages of the trial. 

Audits can help a site confirm protocol compliance and adherence to GCP and regulatory requirements, and can help you prepare for a regulatory inspection by the TGA. Our GCP inspection programm has a very important role in Australia in strengthening TGA’s oversight of clinical trials, both CTNs and CTAs. 

 What's in store for the GCP inspection program for the future? We're pleased that the scope of the program now includes devices. We’ll continue to publish metrics reports on the TGA website as a valuable education tool to guide compliance in the sector. 

We also look forward to working closely with the clinical trial sector to build greater awareness of the program by providing targeted communication and education to support compliance with GCP. This means more webinars to come, as well as self-paced online learning modules.

We're optimistic for the opportunities ahead of us in strengthening TGA's GCP inspection program and supporting the clinical trial and research sector to comply with the regulatory requirements.

We look forward to continuing our strong partnership with the clinical trials and the research sector. We also want to recognise the importance of your engagement to help support us in building real connections and capabilities within the sector, events like this webinar, and your time in responding to our public consultations and surveys.