0:17
So yes, thank you very much for the introduction and I'm going to speak to you all about how to monitor in vitro and companion in vitro diagnostic studies effectively.
0:29
Just a short introduction to myself.
0:35
I'm Amanda Ball and I am the Global Head of Clinical Operations at ARC Regulatory and I have been in this position with ARC for the last six months.
0:46
And prior to that, I had been working for 12 years within the companion diagnostic and clinical development at QIAGEN.
0:55
And then prior to that, I used to work in academia and I was working at the School of Tropical Medicine across a variety of different groups there.
1:04
Infectious diseases, parasitic nematodes, insecticide resistance, a variety of things that I worked on there.
1:13
So it kind of gives me quite a broad experience to bring to the field.
1:20
So I work for ARC and we are at stand 19, so please come and have a chat with us.
1:25
We provide lots of clinical trial solutions and in particular, we're just going to look at the clinical operations piece today and the monitoring.
1:38
In terms of the experience that we have we have a network that we could say is global here.
1:42
So we have representation across the USA, Europe, UAE, Singapore, Japan, China, and indeed we've got Australia there too.
1:55
And in terms of experience that we have there probably monitored more than 400 study sites over the last 7-8 years now.
2:07
And we work with 8 out of the top 20 pharma companies and biotechnology leaders too.
2:15
So I'm going to quickly go through this agenda starting off with why monitoring matters.
2:20
So study monitoring is essential element of medical device GCP.
2:28
Irrespective of your stage of clinical development of your therapy, I say where you reached your diagnostic and it ensures that you have the rights and safety and the welfare of your patients that are enrolled into those studies and making sure that you have the highest quality data for your programme decision making and then ultimately fewer regulatory submissions.
2:52
And during clinical studies, you will confirm that procedures are performed according to your approved protocols and you will identify any problems and recommend solutions as the study goes on.
3:06
So I've just pulled out some of our favourite regulations and definitions around monitoring here.
3:11
I won't go into a lot of detail.
3:12
You can, you know, find this for yourself.
3:15
They're available online, but basically what we're looking at is that same top line looking after the patient's safety here, making sure that the studies are run to your protocol, which obviously will be in line with approved ethics and requirements for whatever territories you're going for.
3:37
And at the end of it that you have that robust set of documentation in place for your submissions on your data next one.
3:46
And then this was just the IVDR here.
3:48
So I think it's really important to see here about appointing monitors.
3:53
So particularly with IVDR now we say that we they independent of the investigator site under the FDA regulations, it says it can be somebody that is employed within the same organisation.
4:06
But for me, I think it is really important that there is this element of independence when checking the paperwork and the conduct of the study because you wouldn't want to be held responsible for basically checking your own homework.
4:20
So the types of monitoring and we've sorted it into 3 here.
4:23
So you have on site.
4:25
So this is where the monitor would actually attend site.
4:27
They're going to review the source documents that are being produced, the investigator site file.
4:33
Look at all of the samples that are being stored, your devices, are they being stored appropriately and everything that's being logged.
4:42
Particularly for companion diagnostic studies, it's more favoured that there are central testing labs.
4:47
So this is where the drug sponsor would have a number of clinical sites where they're collecting the samples and then they're all sent to a centralised testing lab where your device would then be used to test those.
5:00
So the monitor would go in and then review all the documents that you've sent to testing lab.
5:05
And then certainly with COVID, I think we've all got used to working a bit more remotely now and using a lot more tools that are available to be able to look at information without being present.
5:18
So over COVID there was certainly a huge amount of remote monitoring that was conducted.
5:24
Fortunately, the world is hopefully going back to where we were before.
5:27
So certainly the doors have been opened up for the clinical sites that we help monitor and for the remote aspect, it's fine over a period.
5:39
But I certainly would recommend that at the end of the study, there has to be some eyes physically on site to make sure that the documentation that would be reviewed under BIMO inspection, etcetera is in place and everything does match up.
5:55
So first things first, you need to consider drafting your monitoring plan.
5:59
So some of the questions you may ask yourself, site selection, the duration of the study, the number of study sites.
6:06
So you go into centralised, remote, the number of samples that you need to ensure that you have sufficient power for your data set.
6:15
The complexity of processing the samples and testing the samples, the number of data points that are going to be generated and of those data points, what needs to be reviewed, so what are the critical ones.
6:23
The data that is being generated?
6:28
Do you have a data management plan in place and restrictions on sharing?
6:32
So certainly within certain territories there are limitations around the amount of data that is able to be shared, geographical locations, training, will that be on site?
6:44
Would it be remote?
6:46
If you already have engagement with the site, perhaps it would just be refresher your trial master file, are you looking at hard copy or do you have an eTMF and then the risk to the patients. So that could be the sampling procedure and the intervention.
7:04
So under GCP regulations now they're very much in favour of taking a risk based approach to monitoring.
7:15
So it's much more lean approach where you evaluate all of these different aspects that I've just listed out and then look for the critical pieces of data that you need to ensure that this is a robust set and that you're not basically wasting your monitor’s time looking at things that are a little superfluous to the study.
7:38
So this way you get more value out of their time and experience when they're actually monitoring on site and it's a good way to control the risk there.
7:50
The next thing, would be looking at your selection of your clinical research associates.
7:54
So they are the officially trained by experience training, etcetera to be able to go out and do these visits for you.
8:03
And I think a couple of things to consider here.
8:05
When you're reviewing the CV, have the appropriate experience, training and education to fit perhaps your sample type or the studying instrumentation, whatever it is that is fitting for your study.
8:19
Have the experience within the field of research and then the investigational product being used.
8:24
Have they got good working knowledge of the relevant regulations?
8:27
So the ISOs, your GCP, HIPPA for the US, have they got experience of using an eTMF if that's what you're going to be using?
8:36
Have they got prior relationships with testing facilities that could really accelerate your study startup if you have somebody that's on site, knows the people to go to, how their internal SOPs and QMS, etcetera are set up.
8:51
And indeed, do you need to have local language to be able to facilitate that good working relationship and ensure that your documentation is up to scratch?
9:03
So the first study that we would recommend that you do is a site qualification visit if you've not already used these sites before.
9:11
So usually you'd send out a questionnaire to a number of sites to narrow down ones that you feel would be appropriate for your study.
9:18
And then the monitor can go out and they can review the site.
9:21
Then I think it's really important to understand that this isn't an audit, this is a review of the sites experience around what they're able to support in terms of your study in particular.
9:32
So their experience of working with tissue types instruments, do they actually have the people available to resource it and turn the samples around in the time that you want them to?
9:47
All of these kind of fine questions.
9:50
And then at the end of that they produce a report for you that would obviously get filed as part of your trial master file.
9:58
And then really it's up to the sponsor then as to whether they want to proceed with the contractor, with the site or whether they would move to another.
10:09
So if we've picked our site, then the next thing we need to do is move to the site initiation visit.
10:14
And that will happen after your SQV and that the site has then been truly selected and contracted to participate in the study.
10:23
And the SIV is required to prepare and set up the testing site to conduct the study and would occur prior to the sample testing.
10:32
The principal investigator must be in attendance with all the members of the team or as many as you possibly can to attend this as part of really what is documented in the training.
10:43
So the protocol would be reviewed together with this group.
10:46
They'd review the instructions on specialist procedures, receive direction from case report form, filling out ECRFs, any of those kind of forms that would be particular to your study.
10:58
Define the source documents that need to be reviewed and be prepared to provide the sponsor with updates to any of the study related issues in a timely manner.
11:07
Document all study related training, CVs, GCPs, delegation logs, all of that lovely stuff.
11:13
And review the investigator site file together so they understand which documents they need to file.
11:20
Clarity on the overall scope, accountability and responsibility of the site.
11:24
I think this is really important so everybody knows exactly what they should be doing and things don't get missed.
11:33
Ensuring that your IRB ethics approval is in place and the approved informed consent form.
11:38
And then finally, I have here that the principal investigator has signed the financial disclosure and investigator agreement.
11:47
Then the next round of monitoring visits that they would support then is a cadence of intermediate monitoring visits.
11:53
So these would be in accordance with your monitoring plan.
11:56
And the frequency would be risk based upon the number of samples that are coming in the regulatory requirements around that.
12:04
And that would obviously be a part of the monitoring plan.
12:08
And these studies would maybe occur once every three months or two weeks and it might be one day or it might be over 4 days.
12:15
The source documents would then be reviewed by the monitor.
12:19
They would try and close out any of your outstanding actions to ensure that you don't have anything missing as part of your filing and documentation.
12:29
They would review the investigational product, your sample storage conditions, making sure that the training logs, etcetera are all still up to date in terms of your personnel that are supporting your study, making sure you have allocation accountability of your investigational products.
12:45
Those logs are current, they're up to date and everything is in order there in account in line with the protocol performing the STV and ensure that the study data produced is accurate and valid.
12:58
And then identification of any protocol deviations, adverse events, serious adverse events and all study approvals remain current.
13:10
And then as you get to the end of the study, which will be your closeout visit, this will be the final visit that your monitor would conduct for you.
13:17
And at this point really it's where you start to wrap all of those loose ends up.
13:22
All of the documentation is fully signed off and completed.
13:26
So during these visits, it would be discussing timelines and strategies for the completion of outstanding case report forms, any queries, return or destruction of your investigational products or samples, collecting outstanding essential documents and your monitoring logs, performing that final review of the study file documents and then discussing with the principal investigator plans for record retention.
13:53
And that might be 15 years or 25 years depending on where they're located on the regulator requirements and also the possibility of them being audited.
14:02
So a BIMO inspection, for example, and ensuring that all of the final payments are in order and then notification to ethics that the study has been closed.
14:16
So just a few common errors that I've pulled together.
14:18
These are probably the top six in my experience over the last 12 years of monitoring.
14:24
So a lot of them are fairly basic typographical errors, names misspelt, bunts misspelt, stuff like that, missing documentation.
14:36
So somebody's training log isn't there, they hadn't filled it out, or somebody's CV hasn't been filed.
14:44
So all of these would be picked up by the monitor and adjusted accordingly.
14:49
Incomplete documentation.
14:51
Very often it will be signatures and dates that are missing.
14:53
I think is probably the most common error that I've seen there.
14:59
Incorrect storage of investigational products.
15:02
So, you know, under your protocol, it may say that your investigational product has to be stored at 4°c and some tubes within it have to be at -20.
15:13
So you know, it's going to check the graphs that you have, the readout from the fridges and freezers.
15:20
And if there's been a temperature excursion, what has been the impact on your investigational product.
15:30
Deviation from the protocol I've seen this really quite often.
15:32
So it might be that if you have an FFP that is being used as part of your starting tissue, it states that the thickness of that slide has to be, you know, 2 to 5 microns.
15:43
But actually what's being sent from the collection sites is 20.
15:48
Is that appropriate?
15:49
That has to be recorded as a deviation to the protocol and then obviously an impact to whatever the result would be based on that and then a QMS non-compliance.
15:59
So that might be the internal SOPs that are used to run your studies under the QMS and there may be a deviation.
16:07
So for example, it could be the turnaround time for a draught report if the SOP says 5 days, but it's taken 10 days to turn it round.
16:16
So again, there's a non compliance there.
16:18
Obviously, these are the kind of my top six.
16:20
There are lots of others.
16:23
So ways that you can sort of help facilitate the reduction of these.
16:27
So this isn't a sell on any of these particular ones, but, you know, it's the use of electronic tools and certainly over COVID that I think there's been a much bigger uptick in the use of eTMF,EDC systems.
16:42
People are able to access information remotely at any time.
16:47
And, you know, they help with the cheques and balances to make sure.
16:50
Have documents been filed, who filed them, who signed them off?
16:54
Have they been signed off?
16:55
And you know, they'll keep sending reminders if things are missing or there are QC issues.
17:03
And then just moving on really to companion diagnostics because this is my favourite area.
17:09
I’ve worked in it a long time.
17:10
So these are a few little bullet points or nuggets of my wisdom to consider.
17:16
So I think, as in most cases, communication is key and having a great plan, escalation routes clearly defined across all parties and points of contact is essential.
17:29
If there's a problem, who needs to know?
17:31
Who can help solve it?
17:32
When do people need to know?
17:34
Helps move things along much quicker.
17:37
Agreement on the roles and responsibilities of each of the parties are defined as well.
17:41
The two things go hand in hand.
17:43
Has the site had an SQV conducted?
17:46
Like I say, it's not a site audit.
17:48
Sometimes it can be difficult for some partnerships to understand why this is essential.
17:54
So sometimes it's an educational point.
17:57
But obviously having that SQV means that you're set up for success right from the get go.
18:04
Or equally you find out that the site is possibly not suitable for your studies, so you've not wasted time progressing any further.
18:13
Scheduling an SIV at the right time.
18:15
So this is making sure that most of the activities have been completed prior to the you know the study start up.
18:23
If you start it too early on, you have a list of outstanding actions as long as your arm.
18:28
If you leave it too close to when you want your first patient first visit in, you might not have enough time then to close out any of the remedial actions that you want.
18:38
Clarity on your data management and transfer absolutely key to have this in place, particularly in territories like China where there are big restrictions around data sharing to the point where you might not get any. Access to your source data and documents to ensure your monitor can conduct the STV in accordance with the monitoring plan.
18:56
You don't want them turning off and they can't actually review the documents they're supposed to. Agreement in the frequency and duration of your monitoring visit.
19:04
So that ensuring that there is budget there, it's in your monitoring plan, it will be risk assessed and making sure that you have good oversight.
19:14
And then I think another key thing here is making sure that if required your CRA is in country and has local language if that's needed.
19:25
And then I think the other big thing here is understanding your regulatory requirements.
19:30
There's a couple of examples here.
19:31
So under IVDR the regulation is now a requirement for EU and EMA countries where samples are being collected that separate applications must be submitted to each of the national competent authorities.
19:46
Where a member state is concerned.
19:47
This is something new and it's a responsibility that would sit with the device sponsor.
19:54
And then another example is the investigational product doesn't need to be CE marked.
19:58
However, the requirements for interventional high risk or CDx studies described in Article 58 that it must be followed regardless of where the EU patients sample is being tested.
20:11
So you might be collecting samples within Europe, but they're all being shipped to a central testing lab in the US.
20:17
So therefore this is a requirement.
20:21
So to help navigate these country specifics, I'd just like to point you in the direction of stand 19 because we have a very nice platform where you can go put in all of the countries that you might have be collecting samples or where you have a central testing lab.
20:35
And our navigator tool pulls out all of these requirements, links to the appropriate documents, etcetera, to help figure out what you need to do for each of these specific countries.
20:49
So that's our ARC360.
20:50
Please come and have a chat with us.
20:52
And then finally, just to wrap up, so how to successfully monitor.
20:57
So in summary, understand your relevant regulatory requirements under IVDR there's a lot of nuances there now across different countries.
21:08
The selection of appropriate CRA support.
21:10
If you've got a good CRA, honestly, they're there.
21:13
They build up a good relationship with your site.
21:15
They can really help smooth over waters as if there's a difficult situation.
21:20
And equally, you know, building up that rapport that if there is a problem, people are more open to discuss that and resolve it.
21:27
Selection of appropriate testing sites, good testing sites, you get good data, you get your study done on time and within budget.
21:35
Having a robust monitoring plan, so making sure that you are monitoring the things that are key to your study, the use of E tools, think there.
21:43
There's great value in these in terms of making sure your documentation is up to date and always audit ready.
21:51
Establishing good relationships with your test labs and support staff.
21:55
Honestly, if you've got a good lab there, you stick with them.
21:59
I think everybody's always, you know, had a relationship within our industry where you understand the value in this. Consistent review of essential documents and source document verification to make sure that you don't end up with 500 documents that need to be reviewed on the final day of your closeout visit.
22:18
It's not great.
22:19
You need to be doing that consistently because if you find a problem, that's a lot of stuff that you need to unwind. Timely close out of outstanding actions.
22:27
Otherwise again, they all end up at the end of the study.
22:29
It can be difficult to close them out because people have left, people can't remember, stuff's been lost, you know, all of these examples.
22:38
And then completion of all tasks at the closeout visit to ensure that you are audit inspection ready.
22:44
And everybody feels confident that if somebody comes in and starts to look through all of the documentation that everything is there.
22:52
And we'd be confident to explain what's going on in the study.
22:56
So we're up to Q&A, but I don't know whether are we a little overtime?
22:59
Do we want to do you want to come and see me at stand 19 instead you can go and get your lunch.
23:06
But thank you very much everybody.
