>>Anabela Marcal: Hello everyone.
My name is Anabela Marcal.
And I'm the European Medicines Agency
liaison official to the U.S. Food and Drug Administration.
I have been at the European Medicines Agency for 24 years.
And I have different roles including in clinical trials,
pharmacovigilance, and inspections.
In this lecture, I'll give you a broad overview
of the European Union regulatory framework
for the authorization and supervision of clinical trials.
In this lecture, I will mainly focus on the legal framework
for the authorization of clinical trials in the E.U.,
and, in particular, the new E.U. Clinical Trials Regulation
and its business tool,
the Clinical Trials Information System.
I will also touch on publication provisions,
drive it from this new regulation,
which increased greatly transparency.
Finally, I'll give an overview
of the accelerating clinical trials
in the E.U. initiative, which is a business initiative
to transform the E.U. clinical research environment.
This slide shows how the legal framework
for the authorization of clinical trials
has progressed in the E.U.
Pre-2004, there was no harmonization.
All clinical trials or authorization of clinical trials
was following national rules and different process
in each Member State.
In May 2004, there was a Clinical Trials Directive
adopted that brought some harmonization,
but still a lot of national systems
and process varied amongst Member States.
Finally, as of 31st of January last year, 2022,
we had a new Clinical Trial Regulation
that enter into application with the goal
of harmonizing clinical trial submission,
authorization, and supervision across the 27 E.U. member
states as well as Norway, Iceland, and Liechtenstein.
There are three main pillars
of the Clinical Trial Regulation.
And these are, harmonization of clinical trial process,
transparency of clinical trials data,
and safety and protection of trial participants.
These regulations streamline regulatory process
throughout the lifecycle of a clinical trials
and makes it much easier for clinical trial sponsors
to run large multinational trials
in a number of E.U. member states.
Prior to the Clinical Trial Regulation,
and as I show it in my previous slide,
sponsors had to submit clinical trial applications
separately to each Member State of the E.U.
And within each Member State, they had to submit separate
to national competent authorities
and ethics committees. Now, sponsors can submit
a single clinical trial application,
which covers regulatory and ethics
approval for the clinical trial,
greatly reducing the administrative burden
to initiate clinical trial
in a number of E.U. member states.
This new harmonization approach makes it easier
for clinical trial sponsors to collaborate across borders.
Meaning that academic researchers,
for instance, in different countries,
can work together on the same clinical trial.
Or as we can see, more and more consortia
of academic researchers and pharmaceutical companies
can work together easily to combine innovations
in the research and commercial sectors.
Enabling large multinational clinical trials
is a key focus for the European regulators.
By helping sponsors, including academic sponsors,
to run bigger, better clinical trials,
the European medicines regulatory network
aims to support the delivery of high-quality clinical evidence.
The regulation also introduced clear and maximum timelines
for clinical trial assessment,
bringing pre-visibility on the process to the sponsors
and to the patients and healthcare professionals
that would like to enroll subjects in clinical trials.
Collaborative assessment by Member States,
it's also of benefit for all stakeholders involved.
Another pillar of the Clinical Trial Regulation,
as I mentioned before, is transparency.
Clinical trial data throughout the life-cycle of the trial
will be available in the public domain.
Publication of clinical trial applications,
assessment reports, clinical trial modifications,
supervision activities, summary of results
for laypersons will be made available.
These empowers patients and the healthcare professionals
to find recruiting trials and enabling research.
It also increased trust and public support scrutiny.
Finally, the other pillar,
it's safety and protection of trial participants.
With regards to safety, there is also a single process
of submission and safety cooperation
in assessment by Member States.
Finally, in terms of patient protection,
there are specific rules for informed consent
for incapacitated subjects, clinical trials in minors,
clinical trials in pregnancy and breastfeeding,
clinical trials in emerging situations,
and informed consent in cluster trials.
What is in scope of this Clinical Trials Regulation?
The Clinical Trial Regulation applies to interventional
clinical trials with human medicinal products.
And it also introduced a new category of clinical trials,
the so-called low-intervention clinical trials.
What is a low-intervention clinical trial?
A low-intervention clinical trial
means that the investigational medicinal products
are authorized.
The IMP is going to be used in accordance
with the terms of the marketing authorization,
or its use is supported by published scientific evidence
on safety and efficacy.
And there is only minimal additional risk or burden
to the safety of the subjects compared to normal practice.
These low-interventional clinical trials
also link to the risk-based approach introduced
in this Clinical Trial Regulation.
What does it mean?
It means that there will be less stringent rules
applying to those trials conducted
with authorizing medicines
and which pose minimal risk compared to clinical practice.
For example, these risk-based approach will apply
in terms of simplified means for informed consent.
With regards to monitoring of the clinical trial
by the sponsor, it --
the legislation clearly says that the monitoring will be --
the extent and nature of the monitoring
will be proportional to the type of trial.
And there are also specific provisions for --
in terms of damage compensation.
What is not in scope of this regulation?
Non-interventional trials.
So, observational studies are not within the scope
of the regulation,
as well as trials without medicinal products.
For instance, trials only for devices.
I'll give you now a brief overview of how does it work
and the procedure itself for authorization
of a clinical trial
according to the new Clinical Trial Regulation.
The sponsor will submit a clinical trial application
through the so-called Clinical Trials Information System.
This Clinical Trials Information System,
it's the IT tool that supports the whole process foreseen
by the Clinical Trial Regulation
throughout the full lifecycle of the clinical trial.
This system is accessible to national
competent authorities and ethics committees.
And the access from national competent authorities
and ethics committees, is regulated nationally.
There is a new Clinical Trial Application dossier content.
And it's structured on Part I and Part II.
And there is a harmonized dossier content,
meaning when the sponsor submits,
he submits only once through this portal --
through the IT portal.
And the submission -- the content of the submission
needs to fulfill the requirements
of Annex I of the Clinical Trial Regulation,
which clearly describes all the information
that needs to be submitted
as part of a clinical trial application dossier.
One of the big advantages of the Clinical Trial Regulation
is that it introduced clear timelines for the evaluation
process of a clinical trial application
and after authorization for any process
during the trial life-cycle.
The assessment of a clinical trial application
and supervision of a clinical trial
are responsibilities of the Member States concerned,
including national competent authorities
and ethics committees.
The role and composition of the ethics committees
in the assessment process of the so-called Part
I and Part II, remains a national decision.
However, the regulation is clear that at least one layperson
shall participate in the assessment
of a clinical trial application dossier.
There is a separate assessment for each part,
Part I and Part II, with a final conclusion
and corresponding assessment report.
The assessment report Part I, is issued by the so-called
reporting Member State, meaning the Member State
that takes the lead on the assessment.
And assessment report Part II is issued
by each of the Member States concerned by the trial.
There is a coordinated assessment between
the reporting Member State and the Member States
concerned for Part I of the dossier.
And this is also a big benefit
of the Clinical Trial Regulation.
The Member States collaborate in the assessment
making a much better use of available resources in the E.U.
The reporting Member State takes a leading role
in drafting an assessment report
with input from the Member States concerned.
Each Member State concerned, produce the assessment report
for the Part II of their concern.
And then based on the conclusions on Part I
and Part II,
each Member State concerned will individually issue
a single decision on the authorization
of the clinical trial application.
And what I meant by a single decision,
so each Member State concerned will need to issue a decision.
But conversely to what happened before, the Member State --
each Member State only issues one decision.
That is a common decision
between the national competent authority
and the ethics committee.
While before it used to be two decisions,
one coming from the national competent authority
and the other from the ethics committee.
Off note, a single decision per Member State concerned
can be tacit and based only on Part I conclusions.
What does it mean?
What does it mean is that where the Member State concerned
does not notify the sponsor within the legal timelines
of its decision in that Member State,
then the conclusion of the assessment of Part
I becomes the final conclusion for that Member State.
And this is what we call then the tacit approval.
This slide summarizes the overall procedure and timeline
for the assessment of clinical trial.
And it just illustrates what I have mentioned
in previous slides.
When a sponsor wants to get approval of
a clinical trial in E.U., it'll submit a single submission
through this IT system, the so-called E.U. portal.
And it can be just a submission for --
to run the trial in one Member State
or it can be a submission to run the trial
in all 27 Member States
plus Norway, Iceland, and Liechtenstein.
So, it can be any variation of those.
The process is always the same, submission through the portal.
When the sponsor submits through the portal,
needs to indicate which Member State the sponsor
is proposing for reporting Member State.
Meaning the Member State taking the lead
on the assessment of Part I of the dossier.
Within three days of the submission of the dossier, it --
the Member State concerned by the submission --
by the trial, needs to say if they are interested
to be reporting Member State or not.
And the proposed reporting Member State by the sponsor,
needs to say, if -- in case they are not interested.
If only one Member State
is willing to become the reporting Member State,
then this Member State will become reporting Member State.
However, if there is more than one Member State
with an interest to become reporting
Member State, there is need --
there is a process in place to agree on which
Member State will take the reporting Member State.
In case there is no agreement reached amongst the concerned
Member States by the trial,
then the proposal from the company
will become the one valid. Meaning the reporting
Member State proposed by the company will be the one
that will become effectively the reporting
Member State.
Once decided on the reporting
Member State, then there is a validation that takes place.
And this validation basically,
it's just to check if the clinical trial falls
within the scope of the regulation,
if the dossier is complete and in accordance with Annex
I of the regulation. Meaning if all documents
foreseen by the regulation are there.
And if this is not the case,
there will be an opportunity for 10 more days.
So, the reporting Member State will feed back to the sponsor
and the sponsor will have 10 more days
to comment or supplement with any information necessary.
And all of these happens through the portal.
So, it's -- everything is done through the IT system.
Once the dossier is validated, then the assessment part starts.
We have, in one side, the so-called Part
I of the dossier that you can see in the slide.
It includes; the protocol and study design;
it includes the justification from the sponsor in case
it's a low-interventional clinical trial;
all the manufacturing and importation documents
for the IMP;
the investigation medicinal product dossier;
the investigator's brochure.
And in case the sponsor has previously asked
for scientific advice or if the sponsor
has a pediatric investigation plan approved,
it needs also to include it here.
And this part will also look at the labelling of the IMP.
So, all these aspects will be looked through
a coordinated assessment
between all Member States concerned by the trial,
with reporting Member States
taking the lead on the assessment.
So, the reporting Member State will have initially 26 days
to produce a draft assessment report,
or an initial assessment report,
that then will be circulated to all Member States concerned,
which have 12 days to comment on this draft assessment report.
And further to that, the reporting Member State
has an additional seven days
to finalize and incorporate comments,
receive it from the Member States concerned.
In total, we have 45 days of evaluation timeline for a trial.
In case there are questions at the end of these 45 days,
and there are issues that need clarification,
a list of questions will be sent to the sponsor
and a maximum of 31 days
plus will be allowed to complete the assessment of the trial.
At the same time, we are having this coordinated assessment,
each Member State concerned
will have the national evaluation of Part II.
And what is in Part II?
Part II it's; informed consent; subject recruitment;
data protection; rewards, compensation;
suitability of investigators and of trial sites;
damage compensation;
and collection storage and use of biological samples.
So, these will be assessed by each Member State concerned.
After this assessment period
and once we have finalized assessment of Part I,
then each Member State concerned should notify the sponsor
through the E.U. portal whether the trial is authorized,
authorized subject to conditions, or refused.
If the reporting Member States considers
that Part I of the dossier is acceptable,
then the Member States concerned should consider it acceptable
with very few exceptions.
And these exceptions will be that the participation --
the Member State concern considers
that participation in the trial
will lead to a subject receiving an inferior treatment
than in normal clinical practice in that E.U. member state.
Or that the trial is infringing national laws
or there are specific considerations
regarding subject safety and data reliability.
Overall, a trial can be refused if a Member State
concerned disagrees with Part I, as I just explained.
Or if there are aspects of Part II
that are not complied with.
Each Member State concerned needs to put its decision
in the system through the E.U. portal
within five days of the reporting Member State
finalizing its assessment.
As I mentioned before,
a single decision coming from national competent authority
and ethics committee is issued by each Member State concerned.
Just of note, the authorization of the trial can expire.
And this is also a new feature introduced
by the Clinical Trial Regulation.
If no subject has been included in a trial in a Member State
concerned within two years of the authorization,
then the authorization of that trial
in that concerned Member State will be considered expired.
Linked to the Clinical Trial Regulation,
there have been also two delegated acts adopted.
And delegated acts are -- in fact, it's regulations
that are published and adopted to further clarify
certain aspects of the initial regulation,
more on a practical aspect of it.
So, from the Clinical Trial Regulation,
we have two delegated acts that have been adopted.
One is regarding aspects
of good clinical practice inspection procedures.
And it covers; GCP inspectors training;
qualification; impartiality;
Member States quality system for GCP inspections;
Member States procedures for
GCP inspections; inspections records and reports.
Just off note, inspection reports
prepared by the E.U. inspectors
need to be submitted through the Clinical
Trials Information System as foreseen in Article
78 of the Clinical Trial Regulation.
The other delegated act that has been adopted,
it's the one regarding the rules
and procedures for cooperation of the Member States
in safety assessment of clinical trials.
And this delegated act covers the cooperation
between Member States in the assessment of information
and reports submitted under Article
42 and Article 43 of the Clinical
Trial Regulation.
In this act, it's also defined as safety assessing
Member State for each active substance
used in investigational medicinal products.
There is a transition period for the Clinical
Trial Regulation.
So, this is a three-year transition period
to the Clinical Trials Information System.
As I mentioned before, the Clinical Trial Regulation
became applicable as of 31st of January, 2022.
Between this date and 31st of January this year,
sponsors could choose if they were submitting
the clinical trial application through the old legislation,
or if they would submit according to the new regulation
and using the new IT system.
So, it was optional. As of 31st of January this year,
any new clinical trial to be conducted in the European Union
needs to be in accordance to the new Clinical
Trial Regulation and submitted through the Clinical
Trials Information System.
Between January this year and 31st of January, 2025,
we have two years transition
for the trials that were already ongoing before the Clinical
Trial Regulation became applicable.
As of 31st of January, 2025, all ongoing clinical trials
must be transferred to the Clinical
Trials Information System.
To give you a little bit more information
about these Clinical Trials Information System.
This system is made of the so-called E.U.
portal and E.U. database.
As I mentioned before, everything that happens
during the life-cycle of a clinical trial
will be submitted through the E.U. portal.
And every document will then be stored in the E.U. database
as mentioned in Articles 80
and 81 of the Clinical Trial Regulation.
This system allows sponsors for --
to apply for a clinical trial in up to 30 E.U./EEA countries
with a single application as illustrated before.
Facilitate involvement of trial participants
by allowing easy expansion of trials
to other E.U./EEA countries.
Meaning if a sponsor submitted initially
a clinical trial application
to run the trial in five member states
and then decides they want to add two or three,
there is a specific procedure for that
and it's a much simpler procedure
that is done again through this system.
It also facilitates collaboration across borders.
And at the end, ensures that E.U. and EEA
remain an attractive location for clinical research investment
because the procedures have been greatly simplified
compared to the past legislation.
The Clinical Trials Information System
also allows the fulfillment
of all clinical trial publication requirements
with no additional effort.
Because all documents that are submitted through the portal,
will be stored in the E.U. database.
And the majority of the documents in the database
will then be --
become available in the public domain.
It's a question of time and type of document.
And we'll speak about that later on, on this presentation.
The Clinical Trials Information System is --
consists of a public website and two secure domains.
The public website, everyone can search for information
on clinical trials --
ongoing clinical trials, any other information.
And I'll show it later on in the presentation.
In addition to the public website,
there is what we call a sponsor workspace
where the clinical trial sponsors and organizations
that work with them, so the CROs,
can apply for and manage a clinical trial.
And then an authority workspace for E.U. member states,
EEA countries,
and the European Commission to assess, authorize,
and oversee clinical trials.
This is a busy slide.
But it just to give you an overview of all the process
that you can do -- all the actions that you can do
in the Clinical Trials Information System.
As you can see, sponsors, they submit initial dossier.
They can update the dossier.
All type of notifications like; withdrawal; start of the trial;
first visit, subject; end of recruitment;
end of trial; submission of clinical studies result summary;
submission of inspection reports in third countries.
All of these for the sponsors is done through the portal.
And then you have also all the actions
that are possible for Member States
and all the other stakeholders
concerned by the Clinical Trial Regulation.
According to Article 81(4) of the Clinical Trial Regulation,
the E.U. database shall be publicly accessible
unless confidentiality is justified.
And this is to protect personal data,
commercial confidential information,
draft assessment reports, supervision activities.
But by default, with these exceptions,
all data submitted will become available in the public domain
at a certain point in time.
The Clinical Trial Information System users like sponsors,
marketing authorization applicants, Member States,
EMA, Commission,
are the so-called joint controllers
for protection of personal data
when using the Clinical Trial Information System.
And this has been established in this
so-called Joint Controllership Arrangement.
Regarding CTIS in the public domain,
you can search for information on clinical trial applications,
information on ongoing and recruiting trials.
And there is also an obligation that has been introduced
by the Clinical Trial Regulation
that the sponsors need to prepare a summary of the results
in lay language for laypersons.
So, just to give you a little bit more information
regarding which data
is published for a specific clinical trial.
Only applications on which a decision has been reached
by the Member State concerned will be made public.
The sponsor will need to provide a summary of results
for laypersons once the trial is finalized.
The default is always to make public at the first opportunity.
However, sponsors have options to defer the timing
of publication of specific data documents.
There has been lots of discussion on what to publish
and not to publish still in compliance
with the Clinical Trial Regulation.
And what has been achieved, tends to be --
to strike the balance between access to information
and protecting the interest of sponsors.
You can find more information on this document,
the so-called functional specifications
for the E.U. portal and database
to be audited on an appendix on disclosure rules.
Just to give you some examples.
Once a decision on the trial is published -- post on the --
through the Clinical Trials Information System,
automatically, the date of decision of the --
on a trial will become publicly available.
The same when there is a notification
on the first visit of first subject,
this will also become immediately available
in the public domain.
The end date of subject recruitment
also becomes available once put in the system.
Dates of temporary out,
main characteristics out of the trial,
this is all information that as soon as it
is submitted through the system,
will become available in the public domain.
Other type of information, for instance,
the protocol of the study will become available by definition
at the time of the decision on the trial,
decision to authorize or refuse the trial.
But here, there are possibilities to defer
because we need to strike the balance
with the commercial confidential information.
For instance, for protocols, it's possible to defer.
If it's a Phase I study or a bio-[inaudible]
study, the sponsor can ask to defer up to seven years
after the authorization of the study.
Or up to the time of the marketing authorization
where the study is used.
For instance, if it's for a Phase II or Phase III study,
the sponsor can ask for the protocol publication
to be deferred up to five years after the end of the trial.
When it comes to the clinical trial results summary
and summary for laypersons,
the sponsor has an obligation to publish
it 12 months after the end of the trial in the E.U.
And in terms of clinical study reports, the sponsor --
the marketing authorization applicant
will have an obligation to make it available in the system
and to be published 30 days
after marketing authorization decision,
or 30 days after withdrawal of a marketing authorization
application where the study was used.
Which documents will never be published?
All the quality-related information that include;
IMPD quality; quality-related requests for information raised
during the assessment; quality assessment reports;
any draft assessment reports;
any documents versions not for publication
containing personal data
or commercial confidential information;
and financial agreements between the sponsor
and the investigator site will never be published.
To finalize this lecture, I would like to provide you
with some information on an ongoing E.U.
initiative to transform the E.U. clinical research environment,
the so-called Accelerating Clinical Trials in the E.U.
Since 2022, the E.U. is building on the momentum
generated by the Clinical Trial Regulation
and the Clinical Trials Information System
to transform all clinical trials are initiated,
designed, and run in the E.U.
This transformation is carried out
under this ACT E.U. initiative.
This is a joint initiative of the European Commission,
European Medicines Agency, and Heads of Medicines Agencies
who represent national regulatory authorities
in the E.U. The Accelerating Clinical Trials
initiative includes an ambitious program
of 10 priority actions,
which aim to further strengthen E.U. clinical trials
and to promote the development
of high-quality, safe, and effective medicines.
The priority actions include, for instance,
the modernization of GCP, to adapt GCP inspections methods
to take into account for innovation
in clinical trial tools and processes.
Other area, it's clinical trials methodologies.
For instance, guidance in areas
such as complex and decentralized trials.
This is just an overview of what is foreseen
in terms of actions for the next four years
on these Accelerating Clinical Trials E.U. initiative.
So, ensure effective operation
of the Clinical Trials Regulation.
Simplify governance and align the clinical trials
approval with scientific advice. Support academic sponsors
to conduct impactful clinical trials.
And we have mentioned it during the presentation,
for instance, in the use of multinational trials.
Establish the place of novel methodologies
like decentralized trials. Enable decentralized approach.
Lots of investment in terms of training.
Align internationally in GCP, for instance.
Optimize use of data about clinical trials
for better research and decision making.
And create a multi-stakeholder platform.
And this last one is something that is already ongoing.
And in fact, there will be a meeting this month.
And this multi-stakeholder platform,
it will include representatives from all stakeholders
on the clinical trials area.
Meaning patients, healthcare professionals, academics,
clinical trial investigators, clinical research organizations,
sponsors, ethics committees' representatives.
And they all come together to discuss
how to improve the clinical research environment --
how to improve the conduct of clinical trials in the E.U.
This is just a wrap up slide to show you
how accelerating clinical trials in the E.U.,
the Clinical Trial Regulation,
and the Clinical Trials Information System
is impacting the clinical research environment in Europe,
and which benefits it's bringing for patients.
This is just a summary.
I will not go through it because in fact,
this is just wrapping up what I have shown in this presentation.
And before I finalize, just a few questions
to see where is your knowledge
in terms of the clinical trials in Europe.
In the E.U., the European Medicines Agency is responsible
for the authorization of clinical trials?
True or false? This is in fact false.
The authorization of clinical trials in the European Union
is under the responsibility of the Member States.
In each E.U. Member State, both the regulatory authority
and the ethics committee need to issue decisions
on the authorization of a trial? This is false as well.
One of the advantages of the Clinical Trial Regulation
is that it brought this single decision
by each Member State concerned.
So, the decision of a Member State
is the common decision from the ethics committee
and the national competent authority.
A tacit approval of a clinical trial in a Member State
concerned is possible if the Member State doesn't issue
a decision within the established timelines?
This is true. And this is, again,
an advantage brought by the Clinical Trial Regulation.
So, there are strict timelines
which brings pre-visibility to the sponsors.
And if a Member State concerned does not issue a decision,
then the decision in that Member State
will be the one of the reporting Member State
for the assessment of Part I of the dossier.
The sponsors of a clinical trial
need to draft a summary of results for laypersons
which will become publicly available?
This is true. And again, it's one of the tools
brought by the Clinical Trial Regulation
with the aim of increased transparency.
12 months after the end of the clinical trial in the E.U.,
this sponsor needs to submit this laypersons summary.
And this is it for this lecture.
I hope you have learned a bit about E.U. regulatory framework
for the authorization and supervision of clinical trials.
Many thanks for your attention.