Overview of the European Union Regulatory Framework for Clinical Trials

>>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.