August 13, 2024 • 28 mins
In this episode, host Harriet Edwards is joined by Dr Katherine Bowen and Shalini Gupta to explore the transformative changes in the European Union's clinical trial landscape. The focus is on the transition from the Clinical Trials Directive (CTD) to the Clinical Trials Regulation (CTR) and its significant impact on the regulatory environment.
Join us for an insightful discussion on how the CTR is shaping the future of clinical research in Europe and the positive impact it aims to have on patients.
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:00):
Music.
(00:24):
Music.
Instalment of conversations in drug development. I am your host for today's episode,
Harriet Edwards, part of the regulatory team here at Boyds, and I'm delighted
to be joined by not one but two guests today, two of our regulatory affairs
(00:45):
team, one who is a familiar member of the podcast team, Dr. Catherine Bowen.
Hello, nice to meet you. Hello and welcome.
And also Shalini Gupta, pleased to welcome you for the first time,
our Senior Manager of Regulatory Affairs here at Boyds.
Hello, nice to be here. Yeah, it's excellent to have you both here.
And I'm really pleased with the topic that we're going to be discussing today.
It's a regulatory affairs topic, unsurprisingly, and we're going to be focusing
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very much on the EU and some legislation changes.
But don't worry, it's all very interesting.
There's a lot going on in the EU at the moment with regards to clinical trials.
So we're going to be talking about the Clinical Trials Regulation, also known as the CTR.
So I'm very excited to have you both here to talk about that with me today.
Before we jump into the CTR though, I think Catherine, it's probably worth starting
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with some background and some history on the environment of clinical trials in the EU,
because for those people maybe listening that haven't worked in the EU in clinical
trials to date, or maybe those that are new to regulatory affairs,
there is some significant changes to where we are today, isn't there?
Yeah, that's a great place to start, I think. I always seem to get the history
lesson, which is ironic considering I hated history in school but anyway yeah
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so in order to put everything we discussed today into context it's probably
important to understand where we came from so.
If we go back to, say, the back end of last millennium, last century,
which seems like a very long time ago now, clinical trials in Europe were completely
regulated at local national competent authority level.
It's really important to say that Europe is not one country.
(02:17):
No, absolutely. It is lots of countries. Contrary to popular belief.
We're at 27 member states at the moment. I actually don't know how many we were
at at the end of last century.
So there was a huge heterogeneity in the requirements across countries and regions.
And that was recognised to some extent.
So in 2001, the Clinical Trials Directive, which many of our listeners are probably
(02:37):
familiar with, was passed.
Now, Harriet's geeky regulatory question for you. What is the problem with the directive?
Well, the directive is transposed into national law, isn't it?
So given that we have many member states all interpreting things slightly differently,
it means that we have somewhat of a discordance between our member states and
how they interpret clinical trials regulation or directive, I should say.
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And that was the problem.
So the clinical trial directive was implemented into local law by 2004.
And although it was a great start in terms of starting to put some guardrails
around how clinical trials should be regulated in Europe, we did end up with
some peculiar local level foibles, some variation in timelines,
whether or not there were clock stops, document requirements.
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What was a substantial amendment, what was an IMP, all kinds of things.
And of course we were still doing submissions country by
country so if you think about a large scale phase three study
where you're going to most of the eu you feel like you spend literally years
yeah submitting applications to competent authorities and also to ethics committees
and then responding piecemeal to all of their questions so i think there was
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a recognition that doing clinical trials in europe was was expensive and complicated
particularly for people from the US, for example.
So, some efforts were made to try and harmonize everything.
So, in 2009, we got the voluntary harmonization procedure, which,
as you probably guessed from the name, was voluntary, which tried to coordinate
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multinational clinical trials and to at least coordinate the questions that
came from competent authorities. Okay.
And I think it's fair to say people have variable experiences of that process.
And I think you didn't find it as useful as maybe I did, Harriet.
Yeah, I think that's probably fair to say. Certainly in the early phase clinical
trials where you had maybe one or two or just a couple of countries.
(04:24):
Getting involved in a voluntary harmonization procedure was quite cumbersome,
actually, and not that beneficial.
But I can see for the later phases, as with your experience,
Catherine, it would have been useful at that point. Yeah, and I was quite a proponent of it.
If you're doing a massive phase three programme and spend your life responding
to questions, it did feel like a step forwards.
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But there was a recognition that there needed to be something more formal put in place.
And that brings us to the clinical trial regulation itself. Very nicely brings
us to the clinical trial regulation, Catherine.
Thank you for that overview, a whistle-stop tour through clinical trials regulations
and legislation over recent years.
But we're arriving at the clinical trials regulation, and that is significantly
(05:08):
different, as we will discuss over the course of the podcast today. day.
Let's start then with the main objectives of the regulation and moving from
the voluntary harmonisation procedure into something a little bit more concrete.
What are the main objectives of this regulation?
Yes, there were three main objectives to the CTR and they were really based
around trying to create an environment that was conducive for conducting clinical trials in the EU.
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So the first one was to get to a greater level of harmonisation across the EU
to increase provisions around clinical trial transparency, and also to ensure
the highest standards of patient safety.
And in order to achieve all of those, we are talking about a regulation here.
So without that necessity to transpose it into local law that kind of tripped
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us up a bit with the directive.
And all of those are incredibly laudable aims, but actually surprisingly difficult to achieve.
And I think you have to put into the context of the environment that we were in.
So there was an initial public consultation on the clinical trial regulation back in 2011.
It took a year or so to get a draft together off the basis of that.
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And actually, the text wasn't approved until 2014.
And if you think about this, you've got all of those stakeholders,
all of those competent authorities, ethics committees, all with their own ideas
around how trials should be regulated, countries with different standard of
care, different healthcare care systems.
You've got academia who just want to be able to run trials simply.
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This is on a backdrop of huge concerns about potential issues with data transparency
in the pharmaceutical industry, the era of Ben Goldaik in the Bad Pharma book,
if anyone remembers that.
The industry being genuinely concerned about the ability to protect their confidential data. So.
There was a huge amount of work went into actually pulling together everything
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that is in the regulation that's published today.
Yeah, and as you said, I think it's understandable when you think about how
many different stakeholders and
how many different opposing opinions and considerations each of them have.
It is really unsurprising that it's taken us the time that it has to get to the point we are today.
But in terms of the aims of the regulation, all, as you she said,
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sound very promising, putting patient safety first, etc, etc, and great if it works.
But what does it actually mean practically for the people that need to take
on board this regulation and start using it in the conduct of clinical trials across the EU?
Yeah, great question. So I'm going to give you the high level what's in it view.
And then I think Shalini can tell you what the actual practical experience is
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of it. But let's start with that high level view.
So probably the biggest and most significant change is that there is now a single
submission mission made for a multinational clinical trial.
And that goes through the clinical trial information system,
which is this one-stop shop for all things clinical trials.
It's where your submissions are made, your notifications, your amendments.
It's where your feedback from regulators and competent authorities is uploaded.
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It is a bare method of system. And that's one of the reasons that this CTR took
so long to implement because although the legislation was passed in 2014.
Actually, CETA's voluntary use didn't come in until 2022, and mandatory use
didn't happen until January 2023.
And actually, we still have trials operating under the CTD. They do all have
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to be transitioned by the end of January next year.
So the clock is ticking for that, which I think we'll probably come back to.
The other key thing was really, it did put some really strict timelines in place
around assessment, which to some extent is a bit of a double-edged sword because
it works on both sides, right?
I mean, it's that the regulators and the ethics committees have to review in
(08:47):
certain timelines, but also sponsors do have to respond.
And I think we'll come back to that a bit later as well.
Yeah, it's a really good point. I mean, as if those two massive things weren't,
you know, significantly different enough, there are some other key differences
as well, aren't there, Yeah,
and we formalised the idea of part one and part two documents with part one
being, I guess, what we would have
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traditionally thought of as our core regulatory package, the protocol.
IMPD, investigator brochure, etc.
And part two documents being those local level patient facing documents and
the idea that there would be a coordinated review across part one and a single
opinion provided per country that's applicable for competent authorities and ethics committees.
There's also increased transparency provisions which
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Shalini will talk through because that's been a bit of a movable feast
over time and additional safety requirements but it
also brought in this concept of a reporting member state because everything's
now coordinated of course someone has to take responsibility for that so we
now have that the reporting member state at the center of that who coordinates
everything with these member states concerned would be the the other member
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states who are participating in the clinical trial.
Now, that is really quite different, isn't it, from where we were?
I think that's probably an understatement for me to even say it's quite different.
It's significantly different.
And I wonder whether that means we're moving towards more of an IND-like system
that we see in the US, where there is this cradle-to-grave approach.
You have consistency with your project managers in the FDA review divisions
(10:18):
throughout development. developments.
Is that going to be the same thing here? Is that the idea or are we just having
an RMS per CTA application and we'll see how we go?
You know how I feel about this because I'd love more consistency through Review in Europe.
So sponsors can request their RMS and we are seeing evidence that there are
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particular agencies who are doing the majority of those RMS roles at the moment.
So I can see a situation whereby companies may use a particular RMS for their
phase two and ask for them again through phase three to try and build that relationship.
There is no evidence at the moment that that would feed through into the MAA
process, for for example, and your rapporteurship.
(11:02):
Now, whether it will develop in that direction over time, I guess that's possible.
But at the moment, there's no evidence that that is indeed the case.
And as you said, at the moment, there's no evidence, but we are still very much
in an interim implementation period. It's still quite new.
So maybe watch this space and see what happens.
But I think given the significant challenges, the differences that we've discussed
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us so far from what we had under CTD and where we are now with CTR,
some of those significant differences.
It's unfair of me to ask you, Shalini, whether or not this regulation has impacted
clinical research, because it would be really surprising if it hasn't.
So my question to you is, how has the regulation impacted clinical research in the EU so far?
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And maybe you could give us some highlights on that. Yeah, definitely.
So the regulation has truly transformed the way the clinical trials are being conducted in the EU.
So I'll talk about the numbers here. Because of the streamlined process,
the trial authorization has been drastically improved over time.
As per the report from the EU, from the EMA, as of May 2024,
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there are over 5,000 trials submitted.
And out of that, over 3,000 trials have been authorized.
So you can see the number. And if you talk about month by month breakup,
right when it was mandated, in January last year, it was just 76 submissions.
And now as of May, can you guess how many?
Oh, I don't know, maybe double? Well, it is 500 submissions on average.
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That's amazing. Yeah, so that's one. And it's not just about numbers.
So one of the main aim was for the CTR is access for the information that is
all real time, in real time.
And also the transparency has been a real game changer, which enables stakeholders
right from the researchers to patient
to stay informed what is happening in the latest development and
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findings in the clinical research and from the sponsor's
perspective it's not obviously transparency has been a big change but what has
helped sponsor for any multinational trial it has really facilitated that because
for example if you have rare disease there you cannot find enough patient in
one single country so you can go for multinational and with this efficient process
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it has really helped the sponsors.
So, overall, my experience is that it has been really a positive step forward,
which has made research in the EU a bit more transparent, efficient and safe,
as well as promoting innovation.
Well, that's really positive. With any kind of major changes to legislation,
it's always a worry as to how they're going to be implemented.
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But that certainly sounds very positive.
And I really like the sound of the real time access to information,
because I think that's incredibly important, not just for the sponsors,
but for regulators that need to be able to make informed decisions.
And of course, for patients who ultimately were doing the clinical research
to support. So I guess my next follow on question for that would be,
how has the regulation, if at all, impacted patients?
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Because even just the sound of the access to information in better time sounds
positive. But are there any other benefits?
Absolutely. For the patient, this regulation has really kept them in mind, really.
So what they did is they have enhanced the safety standards,
which means that patients in clinical trials are much more safer than ever before.
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A lot more transparent, we talked about that, which means that it promotes trust
and accountability. Yeah.
Right. And then with the change in CTR process, there has been really improvement
in the informed consent process.
That means a patient can really understand and make their informed decision
whether to participate in particular trial or not.
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And what's most important in my view was with CTR, there is a provision that
patient can now actually be involved in the trial designing,
which makes trials much more relevant for the patient.
So it's a big step forward for everyone involved. Absolutely.
And I think we can't not underscore how important this regulation is when implemented
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properly and to its full extent, how important it will be to patients,
which is ultimately the goal, isn't it?
But I think it's fair to say that there have been some challenges with implementation.
Something this massive, such a big an overhaul of legislation across a continent.
We said at the beginning, people often think of the EU as one country. Of course, it is not.
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So to implement something so massive and for it to take so long,
there, of course, has been challenges, hasn't there, Shalini?
So maybe give us the sort of top level challenges that we've seen to date and we've experienced.
Experienced yeah there were several challenges with the
implementation itself for sponsors and member
states so they really needed to prepare with
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this new system incorporate some processes and
system and obviously trainings not to think about
right with this big change and what stands out for me is a shorter response
time for the RFIs request for information just 10 calendar days for validation
phase and 12 calendar days for the assessment phase and on top of that the notification
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needs to be checked in CTIS. So that's a big change here.
Yeah, I think that's definitely worth noting. I know, Catherine,
you mentioned it earlier as well about the response times.
It is a double-edged sword, isn't it? And it's something significantly different
to what we were used to before.
Yeah, it is. I mean, companies weren't very happy spending months and months
and months responding to questions.
They're equally unhappy about getting them all in a very, very tight turnaround
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period, particularly if there's a requirement to update documents,
your protocol, for example.
During that time. And it is tight and it is difficult. I think we're all just going to have to.
Get used to doing it and do a really good job on our documents first time.
Yeah. So that we're not having to scurry around doing all of this in a really,
really short turnaround time.
Absolutely. I think it's worth noting that plan for success at the beginning
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and hopefully mitigate against questions that are received because the ones
that are received, we have a really short time to respond to.
So, I mean, there are challenges enough, Shalini, but there's a few others that
are probably worth noting as well, isn't there?
Yeah, some of them, for example, there's a lack of standardization.
For some of the still there are bits that still need
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standardization for example regarding fees patient facing
materials and part two application content there are
differences among member state what they need really and the
major one i would say we have talked about transparency so it
has been really a big challenge for the
sponsors to really understand how to balance the
transparency standard at the same time as protecting their
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confidential information as well as the patient data
yeah absolutely this this transparency and
CTR just they seem to be always in the same
sentence don't they and I think it's fair to say
that you know it's a huge consideration one of the biggest ones
and one of the biggest challenges as well so maybe let's just elaborate on that
a little bit further what are the problems or what were the problems I guess
(18:02):
I should say with the initial transparency requirements that came under CTR
yeah well when this CTR was launched there There was transparency requirements.
Which were quite complex in practice.
There was also issue with deferral mechanism because it was really difficult
to understand whether the deferral can be applied at the same time as redaction.
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So there are a lot of confusion around that.
And literally anything, everything in CTIS was supposed to be published as per the old rules.
And what that means is there could be some delay in publication of crucial documents
and which beats the purpose of transparency for the patient,
as well as there were some technical hurdles such as document size,
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some limitation on that, notification not received on time.
But the good news is that we have now got the revised transparency rules following
the consultation from public to address some of these challenges.
Yeah, and I think it's really worth noting that there have been some updates to transparency.
I certainly remember the days where the deferral was just a tick box exercise
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to particularly early phase clinical trials where we were like,
well, we don't want anyone to know what we're doing for the next seven years.
So let's just not tell them and we can tick that deferral mechanism.
So there were a lot of changes that needed to be made, rightly so,
to balance the need for protection of confidential information,
but also being able to access that critical information that people need around
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clinical trials, both patients and regulators. later.
So what's happened since those revised rules?
What's the main benefits or enhancements that those revised transparency rules bring?
Yeah, with the revised transparency rules, we have only key documents of interest
for the public, which are supposed to be published now.
So very limited. What that means for a sponsor is less redaction work.
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So that means less resources needed.
And then major one is the removal of deferral functionality,
which means the patient can access the documents much earlier than before.
With this all changes, there's still a provision of redaction of documents.
So that's good news for a sponsor.
Definitely sounds like a much-needed update, I think, and maybe a little bit
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more pragmatic than where we were at before.
In terms of other challenges, I think it would be really remiss of me not to mention CTIS.
I mean, Catherine, you talked about it right at the beginning as this one-stop
shop, this massive thing, it's not just an IT system.
It underpins how we actually enforce the regulation, doesn't it? It's huge.
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So, of course, it's unsurprising that there's going to be technical challenges
encountered with the use of CTIS. And one of the reasons why we've seen the
implementation of CTR take so long, actually, isn't it, Shalini?
Yeah, so numerous technical problems reported, such as issue with answering
RFIs, no access to uploaded documents, to name a few here.
But I would commend at first from service tests from EMA, that has been really positively received.
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Yeah, and I think we should just stop for a second to give some kudos to the
EMA for the quality of their training materials on using CETUS as well.
And I do think they've done an exceptional job on making sure that people have
got the best information available on how to use the system.
I think that's a really, really fair point, Catherine. And as we said,
this is not a small undertaking to implement something so massive.
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And for the regulators as well to get on board with it.
You know, it's been really tricky, but I think the collaboration has definitely
been there. So thanks for mentioning that.
We're talking about CTIS here in terms of challenges with initial uploads and
the initial CTA applications.
But of course, things do not stay the same as we move through clinical trials.
People change their mind, things change as responding to emerging safety data,
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et cetera, et cetera. There's often changes to clinical trial documentation.
So are there any challenges? with changing documentation throughout the course
of the clinical trial, Shalini?
Or is this challenge that we see with CETIS just at the beginning?
So there are challenges with the managing modifications.
Overlapping submissions are not allowed, with some exceptions.
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For example, there are part two documents for two different members that can be possible.
But other than that, yeah, it's a system rigidity.
But that's for a reason, because we don't want to have several versions going on in the system.
So definitely some careful planning needed i
think for managing clinical trials and of course
we're not turning off the ctd the directive one
day and asking everybody the following day to comply with the clinical trials
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regulation there is this transition period we've mentioned it earlier it's very
timely actually we're talking about it today i think with it looming but what's
happening for sponsors that maybe started their clinical trials under ctd and now they're going
to be expected to transition to CTR and the regulations that follow with that.
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It has been tricky for sponsors, particularly for multinational trial,
because they needed to have some suitable submission window when they can actually
submit the transition application, as well as formalizing key documents across
the different member states.
And post-transition, you need to align entire dossiers as per the CTR.
So again, quite a lot of planning and and coordination I think we need.
(23:11):
Is there a suggested timeline for this transition, Shalini?
Recommended submission no later than October the 16th of this year.
And I would say that there have been some scary numbers bandied around about
how many trials have still yet to be transitioned.
So just a little word to any of you listening to this who have not yet transitioned
your trials from CTD to CTR, you may wish to crack on.
(23:34):
And I think there is lots of information going around around the transition.
What actually happens if, like you say, Catherine, there's a scary number of
transitions that haven't been done yet.
And not that much time left, what is going to happen if we don't transition in time, Shalini?
So practically, there will be no
status of that trial if that doesn't transition by 30th of January 2025.
(23:58):
So there are some penalties and liabilities for the sponsors to be aware of,
as per different articles in CTR.
So yeah, watch out for that. Okay. So I think that the key message here is we
don't want anybody to be liable in any way for their trials to be non-compliant.
So certainly the transition is important, should be planned for.
(24:19):
Let's not end there. That's a bit of a scary point to end.
So let's look ahead a little bit further and talk about what the future might
look like for clinical trials in the EU. Catherine, is there anything else we need to be aware of?
Yeah, and I think the first thing to say is this has been a massive change in
the way in which we conduct trials in Europe.
So there's still quite a long way to go, I think, and it's all embracing it
(24:41):
and just getting the hang of how it all works. But But again, kudos to the EU.
I do think they are trying really hard to continue to build on what we've seen with the CTR.
So there is an initiative called the Accelerating Clinical Trials in the EU
or the ACT-EU, which is really looking at ways to foster innovation and collaboration
across all of the various stakeholders.
(25:02):
On a very practical level, we've seen some great things coming out of them.
They've got a pilot at the moment for combined scientific advice from the Scientific
Advice Working Party and the Clinical Trials Facilitation Group to try and bridge
that CTA-MAA gap that I whinge on about all the time.
And also the potential for scientific advice specifically on CTAs going through
CTR, including resubmissions if you've had a rejection.
(25:25):
So really practical ways that they're going to be helping people.
But I just think there's so much still to do and just get in the hang of doing
this well and getting our transitions in. Yeah, I mean, we keep coming back to that point.
But certainly in terms of future prospects, I think we've started something
relatively positive within the EU.
(25:45):
Let's hope that if it's all implemented well and people do get on board with
it, there is this effort from industry as well as from the regulators to really
make this work and make the EU an attractive place for clinical trials.
So I think overall, a positive note to end on.
We've covered an awful lot today, as we always do in these podcasts.
(26:06):
It's always a whistle-stop tour through what could be, I think,
a series, actually, of podcasts, particularly on this topic.
But if I was to ask you both what the main take-home messages are,
I think I can probably already guess yours, Catherine.
But maybe if I come to you, Shalini, for your take-home messages,
and then we'll go to Catherine to close out. Yeah, so CTR, despite the challenges,
(26:27):
we have talked a lot about its implementation, but it has been overall positively
received by everyone in this field.
For transition, I would recommend sponsor ActNow rather than waiting for the deadline.
Yeah yeah and I think I guess I would
second that from Shalini and I do also
agree and I think yes this is this has had its challenges but
I think this is such a great step forwards for trying to
(26:50):
bring some some real harmonization across EU
I do want to recognize that the quality of the
of the training I mentioned earlier but but also
the adaptability the fact that the issues with the transparency rules
were recognized and and acted upon there were
also changes in the the requirements for transitional trials to try and make
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it a bit simpler for companies to do all of this so I just I think this is all
such a positive step forward for continuing to make Europe an amazing place
in which to do clinical trials but for all the stakeholders including most importantly
patients living with diseases across the EU.
And that is ultimately what this whole industry is about that's why we all come
(27:30):
to work isn't it we want to make the the world a better place for patients who
need medicines that don't currently have access to them.
So a really nice way to end the podcast today. I think, Catherine,
thanks for that final note.
It's been wonderful to have you both on the podcast. It's been really fascinating.
And I think we'll probably revisit this topic again in the not too distant future
(27:50):
to see what's changed post-transition.
(28:13):
Music.
Music.
(00:24):
Music.
Instalment of conversations in drug development. I am your host for today's episode,
Harriet Edwards, part of the regulatory team here at Boyds, and I'm delighted
to be joined by not one but two guests today, two of our regulatory affairs
(00:45):
team, one who is a familiar member of the podcast team, Dr. Catherine Bowen.
Hello, nice to meet you. Hello and welcome.
And also Shalini Gupta, pleased to welcome you for the first time,
our Senior Manager of Regulatory Affairs here at Boyds.
Hello, nice to be here. Yeah, it's excellent to have you both here.
And I'm really pleased with the topic that we're going to be discussing today.
It's a regulatory affairs topic, unsurprisingly, and we're going to be focusing
(01:10):
very much on the EU and some legislation changes.
But don't worry, it's all very interesting.
There's a lot going on in the EU at the moment with regards to clinical trials.
So we're going to be talking about the Clinical Trials Regulation, also known as the CTR.
So I'm very excited to have you both here to talk about that with me today.
Before we jump into the CTR though, I think Catherine, it's probably worth starting
(01:32):
with some background and some history on the environment of clinical trials in the EU,
because for those people maybe listening that haven't worked in the EU in clinical
trials to date, or maybe those that are new to regulatory affairs,
there is some significant changes to where we are today, isn't there?
Yeah, that's a great place to start, I think. I always seem to get the history
lesson, which is ironic considering I hated history in school but anyway yeah
(01:57):
so in order to put everything we discussed today into context it's probably
important to understand where we came from so.
If we go back to, say, the back end of last millennium, last century,
which seems like a very long time ago now, clinical trials in Europe were completely
regulated at local national competent authority level.
It's really important to say that Europe is not one country.
(02:17):
No, absolutely. It is lots of countries. Contrary to popular belief.
We're at 27 member states at the moment. I actually don't know how many we were
at at the end of last century.
So there was a huge heterogeneity in the requirements across countries and regions.
And that was recognised to some extent.
So in 2001, the Clinical Trials Directive, which many of our listeners are probably
(02:37):
familiar with, was passed.
Now, Harriet's geeky regulatory question for you. What is the problem with the directive?
Well, the directive is transposed into national law, isn't it?
So given that we have many member states all interpreting things slightly differently,
it means that we have somewhat of a discordance between our member states and
how they interpret clinical trials regulation or directive, I should say.
(02:59):
And that was the problem.
So the clinical trial directive was implemented into local law by 2004.
And although it was a great start in terms of starting to put some guardrails
around how clinical trials should be regulated in Europe, we did end up with
some peculiar local level foibles, some variation in timelines,
whether or not there were clock stops, document requirements.
(03:20):
What was a substantial amendment, what was an IMP, all kinds of things.
And of course we were still doing submissions country by
country so if you think about a large scale phase three study
where you're going to most of the eu you feel like you spend literally years
yeah submitting applications to competent authorities and also to ethics committees
and then responding piecemeal to all of their questions so i think there was
(03:42):
a recognition that doing clinical trials in europe was was expensive and complicated
particularly for people from the US, for example.
So, some efforts were made to try and harmonize everything.
So, in 2009, we got the voluntary harmonization procedure, which,
as you probably guessed from the name, was voluntary, which tried to coordinate
(04:02):
multinational clinical trials and to at least coordinate the questions that
came from competent authorities. Okay.
And I think it's fair to say people have variable experiences of that process.
And I think you didn't find it as useful as maybe I did, Harriet.
Yeah, I think that's probably fair to say. Certainly in the early phase clinical
trials where you had maybe one or two or just a couple of countries.
(04:24):
Getting involved in a voluntary harmonization procedure was quite cumbersome,
actually, and not that beneficial.
But I can see for the later phases, as with your experience,
Catherine, it would have been useful at that point. Yeah, and I was quite a proponent of it.
If you're doing a massive phase three programme and spend your life responding
to questions, it did feel like a step forwards.
(04:45):
But there was a recognition that there needed to be something more formal put in place.
And that brings us to the clinical trial regulation itself. Very nicely brings
us to the clinical trial regulation, Catherine.
Thank you for that overview, a whistle-stop tour through clinical trials regulations
and legislation over recent years.
But we're arriving at the clinical trials regulation, and that is significantly
(05:08):
different, as we will discuss over the course of the podcast today. day.
Let's start then with the main objectives of the regulation and moving from
the voluntary harmonisation procedure into something a little bit more concrete.
What are the main objectives of this regulation?
Yes, there were three main objectives to the CTR and they were really based
around trying to create an environment that was conducive for conducting clinical trials in the EU.
(05:33):
So the first one was to get to a greater level of harmonisation across the EU
to increase provisions around clinical trial transparency, and also to ensure
the highest standards of patient safety.
And in order to achieve all of those, we are talking about a regulation here.
So without that necessity to transpose it into local law that kind of tripped
(05:53):
us up a bit with the directive.
And all of those are incredibly laudable aims, but actually surprisingly difficult to achieve.
And I think you have to put into the context of the environment that we were in.
So there was an initial public consultation on the clinical trial regulation back in 2011.
It took a year or so to get a draft together off the basis of that.
(06:15):
And actually, the text wasn't approved until 2014.
And if you think about this, you've got all of those stakeholders,
all of those competent authorities, ethics committees, all with their own ideas
around how trials should be regulated, countries with different standard of
care, different healthcare care systems.
You've got academia who just want to be able to run trials simply.
(06:37):
This is on a backdrop of huge concerns about potential issues with data transparency
in the pharmaceutical industry, the era of Ben Goldaik in the Bad Pharma book,
if anyone remembers that.
The industry being genuinely concerned about the ability to protect their confidential data. So.
There was a huge amount of work went into actually pulling together everything
(06:58):
that is in the regulation that's published today.
Yeah, and as you said, I think it's understandable when you think about how
many different stakeholders and
how many different opposing opinions and considerations each of them have.
It is really unsurprising that it's taken us the time that it has to get to the point we are today.
But in terms of the aims of the regulation, all, as you she said,
(07:19):
sound very promising, putting patient safety first, etc, etc, and great if it works.
But what does it actually mean practically for the people that need to take
on board this regulation and start using it in the conduct of clinical trials across the EU?
Yeah, great question. So I'm going to give you the high level what's in it view.
And then I think Shalini can tell you what the actual practical experience is
(07:41):
of it. But let's start with that high level view.
So probably the biggest and most significant change is that there is now a single
submission mission made for a multinational clinical trial.
And that goes through the clinical trial information system,
which is this one-stop shop for all things clinical trials.
It's where your submissions are made, your notifications, your amendments.
It's where your feedback from regulators and competent authorities is uploaded.
(08:05):
It is a bare method of system. And that's one of the reasons that this CTR took
so long to implement because although the legislation was passed in 2014.
Actually, CETA's voluntary use didn't come in until 2022, and mandatory use
didn't happen until January 2023.
And actually, we still have trials operating under the CTD. They do all have
(08:26):
to be transitioned by the end of January next year.
So the clock is ticking for that, which I think we'll probably come back to.
The other key thing was really, it did put some really strict timelines in place
around assessment, which to some extent is a bit of a double-edged sword because
it works on both sides, right?
I mean, it's that the regulators and the ethics committees have to review in
(08:47):
certain timelines, but also sponsors do have to respond.
And I think we'll come back to that a bit later as well.
Yeah, it's a really good point. I mean, as if those two massive things weren't,
you know, significantly different enough, there are some other key differences
as well, aren't there, Yeah,
and we formalised the idea of part one and part two documents with part one
being, I guess, what we would have
(09:09):
traditionally thought of as our core regulatory package, the protocol.
IMPD, investigator brochure, etc.
And part two documents being those local level patient facing documents and
the idea that there would be a coordinated review across part one and a single
opinion provided per country that's applicable for competent authorities and ethics committees.
There's also increased transparency provisions which
(09:32):
Shalini will talk through because that's been a bit of a movable feast
over time and additional safety requirements but it
also brought in this concept of a reporting member state because everything's
now coordinated of course someone has to take responsibility for that so we
now have that the reporting member state at the center of that who coordinates
everything with these member states concerned would be the the other member
(09:54):
states who are participating in the clinical trial.
Now, that is really quite different, isn't it, from where we were?
I think that's probably an understatement for me to even say it's quite different.
It's significantly different.
And I wonder whether that means we're moving towards more of an IND-like system
that we see in the US, where there is this cradle-to-grave approach.
You have consistency with your project managers in the FDA review divisions
(10:18):
throughout development. developments.
Is that going to be the same thing here? Is that the idea or are we just having
an RMS per CTA application and we'll see how we go?
You know how I feel about this because I'd love more consistency through Review in Europe.
So sponsors can request their RMS and we are seeing evidence that there are
(10:40):
particular agencies who are doing the majority of those RMS roles at the moment.
So I can see a situation whereby companies may use a particular RMS for their
phase two and ask for them again through phase three to try and build that relationship.
There is no evidence at the moment that that would feed through into the MAA
process, for for example, and your rapporteurship.
(11:02):
Now, whether it will develop in that direction over time, I guess that's possible.
But at the moment, there's no evidence that that is indeed the case.
And as you said, at the moment, there's no evidence, but we are still very much
in an interim implementation period. It's still quite new.
So maybe watch this space and see what happens.
But I think given the significant challenges, the differences that we've discussed
(11:26):
us so far from what we had under CTD and where we are now with CTR,
some of those significant differences.
It's unfair of me to ask you, Shalini, whether or not this regulation has impacted
clinical research, because it would be really surprising if it hasn't.
So my question to you is, how has the regulation impacted clinical research in the EU so far?
(11:47):
And maybe you could give us some highlights on that. Yeah, definitely.
So the regulation has truly transformed the way the clinical trials are being conducted in the EU.
So I'll talk about the numbers here. Because of the streamlined process,
the trial authorization has been drastically improved over time.
As per the report from the EU, from the EMA, as of May 2024,
(12:10):
there are over 5,000 trials submitted.
And out of that, over 3,000 trials have been authorized.
So you can see the number. And if you talk about month by month breakup,
right when it was mandated, in January last year, it was just 76 submissions.
And now as of May, can you guess how many?
Oh, I don't know, maybe double? Well, it is 500 submissions on average.
(12:38):
That's amazing. Yeah, so that's one. And it's not just about numbers.
So one of the main aim was for the CTR is access for the information that is
all real time, in real time.
And also the transparency has been a real game changer, which enables stakeholders
right from the researchers to patient
to stay informed what is happening in the latest development and
(12:59):
findings in the clinical research and from the sponsor's
perspective it's not obviously transparency has been a big change but what has
helped sponsor for any multinational trial it has really facilitated that because
for example if you have rare disease there you cannot find enough patient in
one single country so you can go for multinational and with this efficient process
(13:19):
it has really helped the sponsors.
So, overall, my experience is that it has been really a positive step forward,
which has made research in the EU a bit more transparent, efficient and safe,
as well as promoting innovation.
Well, that's really positive. With any kind of major changes to legislation,
it's always a worry as to how they're going to be implemented.
(13:41):
But that certainly sounds very positive.
And I really like the sound of the real time access to information,
because I think that's incredibly important, not just for the sponsors,
but for regulators that need to be able to make informed decisions.
And of course, for patients who ultimately were doing the clinical research
to support. So I guess my next follow on question for that would be,
how has the regulation, if at all, impacted patients?
(14:05):
Because even just the sound of the access to information in better time sounds
positive. But are there any other benefits?
Absolutely. For the patient, this regulation has really kept them in mind, really.
So what they did is they have enhanced the safety standards,
which means that patients in clinical trials are much more safer than ever before.
(14:26):
A lot more transparent, we talked about that, which means that it promotes trust
and accountability. Yeah.
Right. And then with the change in CTR process, there has been really improvement
in the informed consent process.
That means a patient can really understand and make their informed decision
whether to participate in particular trial or not.
(14:46):
And what's most important in my view was with CTR, there is a provision that
patient can now actually be involved in the trial designing,
which makes trials much more relevant for the patient.
So it's a big step forward for everyone involved. Absolutely.
And I think we can't not underscore how important this regulation is when implemented
(15:08):
properly and to its full extent, how important it will be to patients,
which is ultimately the goal, isn't it?
But I think it's fair to say that there have been some challenges with implementation.
Something this massive, such a big an overhaul of legislation across a continent.
We said at the beginning, people often think of the EU as one country. Of course, it is not.
(15:31):
So to implement something so massive and for it to take so long,
there, of course, has been challenges, hasn't there, Shalini?
So maybe give us the sort of top level challenges that we've seen to date and we've experienced.
Experienced yeah there were several challenges with the
implementation itself for sponsors and member
states so they really needed to prepare with
(15:51):
this new system incorporate some processes and
system and obviously trainings not to think about
right with this big change and what stands out for me is a shorter response
time for the RFIs request for information just 10 calendar days for validation
phase and 12 calendar days for the assessment phase and on top of that the notification
(16:12):
needs to be checked in CTIS. So that's a big change here.
Yeah, I think that's definitely worth noting. I know, Catherine,
you mentioned it earlier as well about the response times.
It is a double-edged sword, isn't it? And it's something significantly different
to what we were used to before.
Yeah, it is. I mean, companies weren't very happy spending months and months
and months responding to questions.
They're equally unhappy about getting them all in a very, very tight turnaround
(16:35):
period, particularly if there's a requirement to update documents,
your protocol, for example.
During that time. And it is tight and it is difficult. I think we're all just going to have to.
Get used to doing it and do a really good job on our documents first time.
Yeah. So that we're not having to scurry around doing all of this in a really,
really short turnaround time.
Absolutely. I think it's worth noting that plan for success at the beginning
(16:58):
and hopefully mitigate against questions that are received because the ones
that are received, we have a really short time to respond to.
So, I mean, there are challenges enough, Shalini, but there's a few others that
are probably worth noting as well, isn't there?
Yeah, some of them, for example, there's a lack of standardization.
For some of the still there are bits that still need
(17:19):
standardization for example regarding fees patient facing
materials and part two application content there are
differences among member state what they need really and the
major one i would say we have talked about transparency so it
has been really a big challenge for the
sponsors to really understand how to balance the
transparency standard at the same time as protecting their
(17:39):
confidential information as well as the patient data
yeah absolutely this this transparency and
CTR just they seem to be always in the same
sentence don't they and I think it's fair to say
that you know it's a huge consideration one of the biggest ones
and one of the biggest challenges as well so maybe let's just elaborate on that
a little bit further what are the problems or what were the problems I guess
(18:02):
I should say with the initial transparency requirements that came under CTR
yeah well when this CTR was launched there There was transparency requirements.
Which were quite complex in practice.
There was also issue with deferral mechanism because it was really difficult
to understand whether the deferral can be applied at the same time as redaction.
(18:23):
So there are a lot of confusion around that.
And literally anything, everything in CTIS was supposed to be published as per the old rules.
And what that means is there could be some delay in publication of crucial documents
and which beats the purpose of transparency for the patient,
as well as there were some technical hurdles such as document size,
(18:45):
some limitation on that, notification not received on time.
But the good news is that we have now got the revised transparency rules following
the consultation from public to address some of these challenges.
Yeah, and I think it's really worth noting that there have been some updates to transparency.
I certainly remember the days where the deferral was just a tick box exercise
(19:06):
to particularly early phase clinical trials where we were like,
well, we don't want anyone to know what we're doing for the next seven years.
So let's just not tell them and we can tick that deferral mechanism.
So there were a lot of changes that needed to be made, rightly so,
to balance the need for protection of confidential information,
but also being able to access that critical information that people need around
(19:27):
clinical trials, both patients and regulators. later.
So what's happened since those revised rules?
What's the main benefits or enhancements that those revised transparency rules bring?
Yeah, with the revised transparency rules, we have only key documents of interest
for the public, which are supposed to be published now.
So very limited. What that means for a sponsor is less redaction work.
(19:50):
So that means less resources needed.
And then major one is the removal of deferral functionality,
which means the patient can access the documents much earlier than before.
With this all changes, there's still a provision of redaction of documents.
So that's good news for a sponsor.
Definitely sounds like a much-needed update, I think, and maybe a little bit
(20:12):
more pragmatic than where we were at before.
In terms of other challenges, I think it would be really remiss of me not to mention CTIS.
I mean, Catherine, you talked about it right at the beginning as this one-stop
shop, this massive thing, it's not just an IT system.
It underpins how we actually enforce the regulation, doesn't it? It's huge.
(20:32):
So, of course, it's unsurprising that there's going to be technical challenges
encountered with the use of CTIS. And one of the reasons why we've seen the
implementation of CTR take so long, actually, isn't it, Shalini?
Yeah, so numerous technical problems reported, such as issue with answering
RFIs, no access to uploaded documents, to name a few here.
But I would commend at first from service tests from EMA, that has been really positively received.
(20:57):
Yeah, and I think we should just stop for a second to give some kudos to the
EMA for the quality of their training materials on using CETUS as well.
And I do think they've done an exceptional job on making sure that people have
got the best information available on how to use the system.
I think that's a really, really fair point, Catherine. And as we said,
this is not a small undertaking to implement something so massive.
(21:20):
And for the regulators as well to get on board with it.
You know, it's been really tricky, but I think the collaboration has definitely
been there. So thanks for mentioning that.
We're talking about CTIS here in terms of challenges with initial uploads and
the initial CTA applications.
But of course, things do not stay the same as we move through clinical trials.
People change their mind, things change as responding to emerging safety data,
(21:44):
et cetera, et cetera. There's often changes to clinical trial documentation.
So are there any challenges? with changing documentation throughout the course
of the clinical trial, Shalini?
Or is this challenge that we see with CETIS just at the beginning?
So there are challenges with the managing modifications.
Overlapping submissions are not allowed, with some exceptions.
(22:05):
For example, there are part two documents for two different members that can be possible.
But other than that, yeah, it's a system rigidity.
But that's for a reason, because we don't want to have several versions going on in the system.
So definitely some careful planning needed i
think for managing clinical trials and of course
we're not turning off the ctd the directive one
day and asking everybody the following day to comply with the clinical trials
(22:29):
regulation there is this transition period we've mentioned it earlier it's very
timely actually we're talking about it today i think with it looming but what's
happening for sponsors that maybe started their clinical trials under ctd and now they're going
to be expected to transition to CTR and the regulations that follow with that.
(22:50):
It has been tricky for sponsors, particularly for multinational trial,
because they needed to have some suitable submission window when they can actually
submit the transition application, as well as formalizing key documents across
the different member states.
And post-transition, you need to align entire dossiers as per the CTR.
So again, quite a lot of planning and and coordination I think we need.
(23:11):
Is there a suggested timeline for this transition, Shalini?
Recommended submission no later than October the 16th of this year.
And I would say that there have been some scary numbers bandied around about
how many trials have still yet to be transitioned.
So just a little word to any of you listening to this who have not yet transitioned
your trials from CTD to CTR, you may wish to crack on.
(23:34):
And I think there is lots of information going around around the transition.
What actually happens if, like you say, Catherine, there's a scary number of
transitions that haven't been done yet.
And not that much time left, what is going to happen if we don't transition in time, Shalini?
So practically, there will be no
status of that trial if that doesn't transition by 30th of January 2025.
(23:58):
So there are some penalties and liabilities for the sponsors to be aware of,
as per different articles in CTR.
So yeah, watch out for that. Okay. So I think that the key message here is we
don't want anybody to be liable in any way for their trials to be non-compliant.
So certainly the transition is important, should be planned for.
(24:19):
Let's not end there. That's a bit of a scary point to end.
So let's look ahead a little bit further and talk about what the future might
look like for clinical trials in the EU. Catherine, is there anything else we need to be aware of?
Yeah, and I think the first thing to say is this has been a massive change in
the way in which we conduct trials in Europe.
So there's still quite a long way to go, I think, and it's all embracing it
(24:41):
and just getting the hang of how it all works. But But again, kudos to the EU.
I do think they are trying really hard to continue to build on what we've seen with the CTR.
So there is an initiative called the Accelerating Clinical Trials in the EU
or the ACT-EU, which is really looking at ways to foster innovation and collaboration
across all of the various stakeholders.
(25:02):
On a very practical level, we've seen some great things coming out of them.
They've got a pilot at the moment for combined scientific advice from the Scientific
Advice Working Party and the Clinical Trials Facilitation Group to try and bridge
that CTA-MAA gap that I whinge on about all the time.
And also the potential for scientific advice specifically on CTAs going through
CTR, including resubmissions if you've had a rejection.
(25:25):
So really practical ways that they're going to be helping people.
But I just think there's so much still to do and just get in the hang of doing
this well and getting our transitions in. Yeah, I mean, we keep coming back to that point.
But certainly in terms of future prospects, I think we've started something
relatively positive within the EU.
(25:45):
Let's hope that if it's all implemented well and people do get on board with
it, there is this effort from industry as well as from the regulators to really
make this work and make the EU an attractive place for clinical trials.
So I think overall, a positive note to end on.
We've covered an awful lot today, as we always do in these podcasts.
(26:06):
It's always a whistle-stop tour through what could be, I think,
a series, actually, of podcasts, particularly on this topic.
But if I was to ask you both what the main take-home messages are,
I think I can probably already guess yours, Catherine.
But maybe if I come to you, Shalini, for your take-home messages,
and then we'll go to Catherine to close out. Yeah, so CTR, despite the challenges,
(26:27):
we have talked a lot about its implementation, but it has been overall positively
received by everyone in this field.
For transition, I would recommend sponsor ActNow rather than waiting for the deadline.
Yeah yeah and I think I guess I would
second that from Shalini and I do also
agree and I think yes this is this has had its challenges but
I think this is such a great step forwards for trying to
(26:50):
bring some some real harmonization across EU
I do want to recognize that the quality of the
of the training I mentioned earlier but but also
the adaptability the fact that the issues with the transparency rules
were recognized and and acted upon there were
also changes in the the requirements for transitional trials to try and make
(27:10):
it a bit simpler for companies to do all of this so I just I think this is all
such a positive step forward for continuing to make Europe an amazing place
in which to do clinical trials but for all the stakeholders including most importantly
patients living with diseases across the EU.
And that is ultimately what this whole industry is about that's why we all come
(27:30):
to work isn't it we want to make the the world a better place for patients who
need medicines that don't currently have access to them.
So a really nice way to end the podcast today. I think, Catherine,
thanks for that final note.
It's been wonderful to have you both on the podcast. It's been really fascinating.
And I think we'll probably revisit this topic again in the not too distant future
(27:50):
to see what's changed post-transition.
(28:13):
Music.
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