Applications to begin clinical studies

Before a new medicinal product is studied in humans, the sponsor applies for approval: in the United States through an investigational new drug application, and in Europe through a clinical trial application with its investigational medicinal product dossier. The application brings together what is known about the product and argues that the first participants will not be put at undue risk. In the European Union it is submitted and assessed under the Clinical Trials Regulation through a single information system, and the Regulation sets which trials it covers, what the application contains, how it is assessed, and the transition from the Clinical Trials Directive between its entry into force in 2014 and the move of the last trials onto it in 2025.

Approval to begin studies in humans

The initiation of studies in humans is a major milestone in drug development, and studies with a new medicinal product require approval by regulatory authorities and by ethics committees or institutional review boards. ¹ No ICH guideline covers the initiation of clinical studies. ¹ Broadly, European countries require a clinical trial application and the United States an investigational new drug application, and the investigator's brochure and the relevant protocols should be submitted as well. ^{1, 2} The investigator's brochure and the protocol are the key submission documents. ¹ One reviewer finds the content of the investigational medicinal product dossier relatively unfamiliar compared with more commonly authored medical writing documents such as clinical study reports and investigator's brochures. ²

ICH E6(R3) recommends that, before a trial begins and in accordance with applicable requirements, the sponsor, or the sponsor and the investigator, submit any required application to the appropriate regulatory authorities for review, acceptance or permission to begin the trial, and that any submission be dated and contain enough information to identify the protocol. ³ In most regions where a submission to the regulatory authority is required alongside the one to the ethics committee, the two may be combined into a single submission in accordance with applicable requirements. ⁴

What the application must show

The key information needed to begin studies in humans covers the target profile and the drug development programme, the nonclinical data, the galenics and the human data. ¹ The target profile describes the characteristics a new drug should have to be approvable and financially viable after launch, and the development programme lists the studies required to show that the drug fulfils the target profile. ¹ The nonclinical data cover safety, efficacy and pharmacokinetics, and the galenics cover the formulation, stability and bioavailability applicable to the target population and route of administration. ¹ For the first study in humans no human data on the drug will be available, but if the drug belongs to a known class, human data on drugs in that class should be reviewed, and the application should indicate how the new drug could add value, such as a better safety profile or a more convenient dosage and route of administration. ¹ Besides the nonclinical data, the submission should clearly reflect what the drug development plan foresees. ¹

The information in the application should reflect the current state of knowledge about the drug and show a rationale for developing it in terms of the indication and the medical need. ^{1, 2} The nonclinical safety data should show an acceptable benefit–risk ratio for starting human studies. ^{1, 2} The nonclinical efficacy and safety data should be sufficient to identify a safe starting dose, the rate of dose escalation and the maximal dose to be given in the studies, and the safety parameters to be monitored should be identified. ^{1, 2} At this early stage there is rarely any direct benefit to the participants, so their safety is the overriding concern. ¹ With certain drug classes, such as cytotoxic drugs, a high safety risk might make the drug unacceptable for studies in healthy volunteers, so that studies can only be done in the target population, such as patients with cancer. ¹

For planning studies in humans, whether in healthy volunteers or patients, the available data should show a clear rationale, in terms of the benefit–risk ratio based on the nonclinical data, for conducting the trials, and that the safety issues have been thoroughly investigated and adequate safety precautions incorporated in the protocol. ⁵ A European application with its dossier, like a US investigational new drug application, seeks approval of the submitted protocol, is written for the regulatory authority, and draws on the investigator's brochure and the literature. ⁶ The key messages suggested for it are that there is a clear rationale for studies in humans with the new medicinal product, that there are sufficient nonclinical data to make a clear benefit–risk assessment, that adequate safety precautions have been built into the protocol, and that the galenics, or quality, of the new drug are acceptable. ⁶

The US investigational new drug application

In the United States an investigational new drug application must be submitted to the Food and Drug Administration before a sponsor can begin any trial in humans and can legally ship the drug product across state lines. ⁷ It includes everything the sponsor knows to date about the product, and the FDA regulations describe all the information and documents it must include before the sponsor will be allowed to start human trials. ⁷ Its components are administrative documents, among them a cover sheet form with information about the investigators, sponsors, monitors and institutional review board, and a table of contents that should make it easy for readers to find what they need; an introductory statement and general investigational plan; the investigator's brochure; the protocol; chemistry, manufacturing and controls documentation; the nonclinical study reports with a summary of their results; pharmacology and toxicology information, based on nonclinical and clinical data; and previous human experience with the drug, if any studies were done. ^{7, 8}

The general investigational plan describes how the clinical research will progress over time. ⁷ It includes the drug's characteristics, the broad objectives and planned duration of the proposed investigations, a brief summary of previous human experience, investigational or marketing, any countries where the drug was withdrawn, a brief description of the investigational plan, its rationale and the indications, the general approach to evaluating the drug, with the trials in the first year and the estimated number of patients, and any anticipated risks of particular severity, based on toxicological data in animals or prior studies in humans with the drug or related substances. ⁸ The protocol defines the who, what, how, when and where of the first proposed trial, and the investigator's brochure summarises the information relevant to the clinicians who will conduct the trials. ⁷ The drug's manufacturing process should be of acceptable quality and conform to good manufacturing practice, whose requirements are discussed in the FDA guidance on current good manufacturing practice for phase I investigational drugs. ⁸ The FDA recommends a pre-IND meeting to discuss the intended submission, so that issues are identified in time and delays in approval are avoided. ⁸

The primary objective of an investigational new drug application is to demonstrate that the product will not put the initial human subjects at undue risk. ⁷ The regulatory writer needs to know enough about the regulations and the drug development process to ensure that the application's documents are written concisely and clearly, with enough information to demonstrate that the sponsor has exercised due diligence to protect the health of the subjects exposed to the new product. ⁷

The European clinical trial application

A European clinical trial application comprises a covering letter, the application form, the protocol, the investigator's brochure, data on the investigational medicinal product, and an overall risk and benefit assessment. ⁹ The covering letter's heading should include the allocated EudraCT number, the protocol number and the title of the trial, and its text should draw attention to any special issues in the application, such as special trial populations, first administration to humans, unusual medicinal products or unusual trial designs. ⁹

The headings for the product data are a guideline and may be modified if necessary. ⁹ The quality data include summaries of the chemical, pharmaceutical and biological data on the product, a copy of the manufacturing authorisation, certification of the good manufacturing practice status of any active biological substance, and a copy of the importer's authorisation. ⁹ The nonclinical pharmacology and toxicology data should be given as summaries, preferably in a table with limited text, with a reference list of the studies conducted and of appropriate literature. ⁹ They should comply with good laboratory practice and be critically assessed in the context of the proposed trial, deviations and omissions from the detailed guidance should be justified, and the test material used in the toxicity studies should be representative of that proposed for the clinical trials. ⁹ The human data should include summaries of all available data from previous clinical trials and human experience with the product, and all the studies should be conducted in accordance with the principles of good clinical practice. ⁹ In certain circumstances, for example when information on the product has been submitted previously, a simplified investigational medicinal product dossier can be submitted, and it should include a benefit–risk assessment of the proposed trial. ⁹

In the overall risk and benefit assessment, the nonclinical and clinical data should be summarised critically in relation to the potential risks and benefits of the proposed trial, and the nonclinical pharmacology, toxicology and kinetic results should be used to predict possible risks in humans. ⁹ All available data should be used to suggest possible mechanisms and the exposure required to produce them. ⁹ Safety margins should be discussed in terms of relative systemic exposure, preferably based on AUC and Cmax data, and recommendations should be made for further monitoring of effects and safety. ⁹

The EU Clinical Trials Regulation

The Clinical Trials Regulation was made to harmonise the assessment of clinical trials across the European Union. ¹⁰ Its main content is a harmonised clinical trial application procedure through a new EU database, which documents the procedure, the assessment and the timelines for each trial. ¹¹ Under the Clinical Trials Directive, wide interpretation by different member states led to disharmony in trial application procedures, including the documentation required, the approval timelines and the assessments performed, and this was one of the main drivers for replacing the directive with a regulation. ¹² The Regulation aims to harmonise clinical trial applications and simplify and harmonise the rules for trials in the EU, to bring more innovation to Europe and support innovative clinical trials, to improve the transparency of conducting clinical trials, and to enable faster approval of clinical trials. ^{13, 14} It aims to harmonise the submission, assessment and supervision processes for clinical trials throughout the EU. ^{15, 16} In the agency's announcements, its application streamlines the application and supervision of clinical trials and their public registration and strengthens Europe as an attractive location for clinical research. ^{17, 16, 15}

The Regulation aims to create an environment favourable to conducting clinical trials in the EU, with the highest standards of safety for participants. ^{18, 11} It makes the rules for conducting clinical trials consistent throughout the EU. ¹⁸ Alongside simplifying clinical trial approvals, it foresees transparency on the conduct of trials in the European Economic Area from their authorisation to the publication of their results. ¹⁹ When it was published in May 2014, the European Medicines Agency (EMA) expected it to open a new era for the conduct of clinical trials in the EU, keeping Europe an attractive centre for clinical research, fostering European competitiveness and innovative capacity, and facilitating swifter development of new medicines for patients. ¹⁹

The Regulation and the trials it covers

An EU regulation is directly applicable under EU law and automatically becomes part of the national law of the member states and of the EEA states, so it is likely to achieve the law's purpose quickly and in a harmonised way. ^{20, 21} Regulations are binding, inflexible legislative acts that must be applied in their entirety across the EU and leave no room for interpretation. ¹² A directive sets out a goal that all member states must achieve but is not directly applicable: member states must implement it, but they choose the form and methods themselves. ^{20, 21, 12} This can be a protracted process, and it often leads to imbalanced interpretation and realisation of the law among the states. ^{20, 21}

The Regulation instructs trial sponsors on the organisational, reporting and disclosure aspects of clinical trials. ²² Public disclosure is one of many aspects it addresses. ²³ Its 19 chapters with 99 articles describe the procedure for the submission, assessment and evaluation of requests for authorisation of clinical trials by the concerned member states, safety reporting during the trial, the protection of subjects, and informed consent. ²³

The Regulation applies to all interventional clinical trials performed in the EU, and not to non-interventional studies or to studies of medical devices, unless the devices are part of a clinical trial involving a medicinal product. ²³ It distinguishes clinical trials, which are interventional clinical studies, from clinical studies: a clinical study is the broader concept, and a clinical trial is a specific type of one. ²³ In practice a clinical trial is characterised by specific elements, including the presence of an investigational medicinal product, an active human intervention in defining the treatment, a treatment assignment that does not fall within the normal practice of health care, and monitoring of the subjects throughout the trial. ²³

The Regulation covers investigational medicinal products irrespective of their marketing authorisation status. ²⁴ The trials it covers are those conducted in the EU or EEA, non-paediatric trials included in a paediatric investigation plan, paediatric trials performed outside the EU or EEA that are included in such a plan, and paediatric trials of an investigational product covered by an EU marketing authorisation and sponsored by its holder, whether or not included in such a plan and wherever performed. ^{24, 25}

Submission through the Clinical Trials Information System

An application is submitted online through the Clinical Trials Information System, which the European Medicines Agency programmed and audited and which holds the data and databases for the trials submitted to it. ^{26, 10} The Clinical Trials Information System is the single entry point for clinical trial application submission, authorisation and supervision in the EU and in the EEA countries Iceland, Liechtenstein and Norway, through which sponsors and regulators submit and assess clinical trial data. ^{15, 16, 27, 28} Every sponsor uses the same system and follows the same procedures to apply for authorisation of a trial, wherever it is located and whichever national competent authority or ethics committee it deals with. ^{17, 16}

Before the system, a clinical trial application was national: sponsors had to submit applications separately to the national competent authorities and the ethics committees of each country, and registration and results posting were separate processes. ^{14, 28, 15, 16} A sponsor wanting to run a multinational trial in 20 EU/EEA countries had to submit 20 national applications and adapt the documentation to each country's legislation. ¹⁴ Under the Regulation the application is submitted centrally through the system, so a sponsor can apply for authorisation in up to 30 EU/EEA countries at the same time with a single application and the same documentation, and the publication of trial information is built into the system. ^{14, 28, 15, 16, 29} The competent authority and ethics committee assessments can run in parallel, and the member states communicate validation and assessment questions to the sponsor as a request for information. ¹⁴ The Regulation also introduced a winter clock stop from 23 December to 7 January, during which the procedure timer stops and no due date can be set for a request for information. ^{14, 30} The Regulation applies to national trials too, so smaller companies and academic sponsors, which usually run a trial in a single country, carry the same documentation burden, though they may cope better with the tight timelines. ³⁰

What the Clinical Trials Information System does

Sponsors and the authorising authorities each have a dedicated secure workspace, and the authorities can interact with the sponsor and exchange information with other authorities. ¹⁶ The system facilitates interactions between sponsors and the regulatory authorities of the EU/EEA countries throughout a trial. ²⁹

The system stores all documents related to a trial, such as clinical study reports and protocols, and replaced the EudraCT database on 31 January 2023. ^{29, 27} It does not accept or evaluate marketing authorisation applications, which must be made separately. ²⁹ Ahead of go-live the agency announced that, with other agency IT tools, the system would support the coordinated assessment of safety reporting in clinical trials, and so contribute to the understanding of the benefits and risks of medicinal products planned for or already on the EU market. ¹⁵ It also announced that the system would facilitate recruitment by letting sponsors and researchers expand trials to other EEA countries, and support collaboration across borders for better results and knowledge sharing. ¹⁵ It includes a public searchable database for healthcare professionals, patients and the general public, at euclinicaltrials.eu, which is to contain prospectively detailed information on, and the outcomes of, all clinical trials authorised through the system. ^{15, 16, 27} The agency therefore encouraged sponsors to present data in a user-friendly, searchable format. ²⁷

Authorisation and oversight of clinical trials remain the responsibility of the member states. ^{31, 19, 15, 17, 16, 32, 33} The legislation mandated the agency to prepare the IT platforms that support sponsors and member state experts in authorising trials, supervising them, safety reporting and compliance activities, and that enable public access to information on clinical trials. ¹⁹ In the agency's account of 2015, the Regulation makes the agency responsible for developing and maintaining the portal and database. ³¹ In the agency's announcements, the agency maintains the system and the European Commission oversees the implementation of the Regulation. ^{15, 17, 16, 32, 33} A 2018 account instead puts the Regulation's implementation under the agency's responsibility, with the agency also managing the EU portal. ³⁴

The submission package

For one writer on the transition, the submission package is where harmonisation really makes sense. ³⁵ Under the Directive the general requirements were set in the CT-1 guidance in EudraLex volume 10, yet each competent authority had its own recommendations and naming conventions for the submission package, as the requirements of Austria, Germany and Belgium show. ³⁵ Austria asked for five numbered parts — general information with the cover letter and EudraCT form; the current protocol with its synopsis and signature pages; the investigator's brochure; the full or simplified dossier for the investigational product or its summary of product characteristics; and the patient information with any paediatric investigation plan or scientific advice summary. ^{36, 35} Germany asked for fifteen numbered items running from the cover letter and the EudraCT form in PDF and XML through the protocol, brochure and product dossier to benefit-risk, the non-investigational medicinal product dossier, good manufacturing practice, labelling, administrative documents, scientific advice, genetically modified organisms, xenogeneic products, other documents and reporting. ^{36, 35} Belgium required no numbering but defined the document names strictly, and added items such as the list of competent authorities already applied to, manufacturing and import authorisations, viral safety studies, TSE certificates and labelling examples in the national languages. ^{35, 36} The channel differed too — email or EudraLink in Austria, the Common European Submission Portal in Belgium and Germany — and using the right one was essential to approval. ³⁵

Under the Regulation the documentation is the same in every country and divided in two, with a different review level for each. ^{37, 38} Part I, on scientific, quality and technical aspects, holds the core scientific documentation and goes to the competent authority, with the reporting member state assessing it: the cover letter, the EU application form, the protocol, the investigator's brochure, good manufacturing practice documentation, the investigational and auxiliary medicinal product dossiers, scientific advice, any paediatric investigation plan decision and the labelling. ^{38, 37, 39} Part II, on national and ethical aspects, holds the more country-specific and patient-related material and is assessed by each member state's ethics committee: the recruitment arrangements, the informed consent form and subject information leaflet, compensation arrangements, the suitability of investigators and site, proof of insurance or indemnity, data protection, financial agreements, proof of payment and other administrative forms — and each member state can still define or request its own Part II documents. ^{40, 38, 37, 39}

Procedure and timelines

The sponsor proposes one member state as reporting member state; if there are no objections the proposal is accepted, and if the proposed state declines, another may step up or be appointed. ^{26, 36} Validation takes place within ten days; the reporting member state raises validation issues as a request for information, the other member states have seven days to pass their requests to it, and no contact means validation is complete. ⁴¹ Timelines are defined for three types of application — the initial application, a substantial modification such as a protocol amendment or brochure update, and the addition of a member state to an approved trial — each passing through validation, assessment and decision, with selection of the reporting state only in the initial application and no validation phase when adding a state. ^{42, 43} For an initial application, Part I is assessed in up to 45 days, or 76 if requests for information are raised, with Part II in parallel; for a substantial modification, Part I or Parts I and II in up to 38 days (69 with requests) and Part II alone in up to 33 (64); for an added member state, depending on the assessment, Part I or Part II in up to 47 days (78); and in every case a decision within up to five days. ⁴⁴

Advantages and disadvantages for sponsors

One writer on the transition counts these as the Regulation's advantages: ³⁰

• a single submission to the countries, their ethics committees and their competent authorities at once
• consistent documents in every member state concerned
• questions channelled through one country, the reporting member state
• defined timelines and faster approval
• a lower documentation burden for multinational trials
• harmonised rules for conducting trials across the EU
• simplified safety reporting, with a single report for all investigational medicinal products
• the winter clock stop

³⁰

The same writer counts these as its disadvantages: ³⁰

• a new system with new challenges
• a procedure that may be complicated for smaller and less innovative trials
• only one substantial modification per trial at a time, the next possible only once the first is approved
• tight timelines in general
• other member states concerned can still contact the sponsor and request documents

³⁰

From entry into force to full application

The Clinical Trials Regulation was adopted on 16 April 2014, repeals the Clinical Trials Directive 2001/20/EC, and fulfils most of the requirements the Paediatric Regulation (EC) No. 1901/2006 had set for clinical trials in paediatric subjects conducted in the EU. ²³ It was published in the Official Journal in May 2014 and entered into force in June 2014. ^{19, 45} The Regulation is intrinsically connected to the EU portal and database, and its application depended on their being fully functional. ^{45, 46}

The expected date of application moved repeatedly:

• In May 2014 the agency put the legislation's coming into force at no earlier than mid-2016. ⁴⁷
• In January 2015 the agency stated that the Regulation would apply to clinical trials registered once it was in operation, not before 28 May 2016. ³¹
• Other accounts of 2015 expected it to become effective not earlier than 28 May 2016, or once the new EU database had become available. ^{11, 12}
• In 2018 its provisions were reported as not taking effect before mid-2020, because of the complex technical demands of the single EU portal and database regarding data entry, storage and the information flow between the agency and the member states. ^{23, 46}
• In September 2020 the system, whose launch had initially been planned for December 2015, was still not functional; its earliest planned go-live was 2022, and the Regulation was expected to be implemented in 2023. ^{45, 48}
• In June 2021 the agency postponed the launch of the Clinical Trials Information System to 31 January 2022 because of technical difficulties. ⁴⁹

Until the Regulation applied, the existing law stayed in force: the Clinical Trials Directive 2001/20/EC and the Paediatric Regulation (EC) No. 1901/2006, whose relevant items are Articles 41, 45 and 46, which deal with situations that may occur in clinical trials involving children. ^{23, 46} The Regulation's contingency measures kept the previous Directive's provisions in use, so the existing EU Clinical Trials Register at www.clinicaltrialsregister.eu continued to be used for prospective registration and for posting clinical trial results. ^{45, 46} The new system was to replace the existing EU Clinical Trials Register and the EudraVigilance database. ⁴⁵ Despite the delay, sponsors of clinical trials in the EU and EEA were urged in 2018 to learn the Regulation's requirements, assign staff and set up internally tested standard operating procedures so as to be ready for the effective date. ⁴⁶

In June 2019 the agency revised its methodology for developing the Clinical Trials Information System, the IT system that would enable the Regulation to come into force, to engage stakeholders. ^{50, 51} Member states and stakeholders, including business experts, became directly involved in its development so that their expectations were taken into account, and business expert representatives could continuously review, select and verify its functionalities. ⁵⁰ One regulatory public disclosure editor hoped the change would improve delivery. ⁵⁰ One 2020 account understood the delays to the system, as to the device database Eudamed, to be due to technology-related challenges, but held that the change went well beyond an IT-driven initiative, since organisations had to prepare for it. ⁵² The delay led some organisations to take an observational approach, while many others had started preparing their processes for the transition. ⁵² As planned in June 2021, eight years would separate the Regulation's adoption and entry into force in 2014 from its full application in 2022, a span that also took in a pandemic and the innovations in trial design, conduct, reporting and authorisation that came with it. ⁴⁹ An account of 2023 puts the release of the submission platform in January 2022, after an implementation planned for December 2015, down to technical difficulties, strategic changes and the audit of the new system. ¹⁴

On 31 July 2021 the European Commission officially published and confirmed 31 January 2022 as the date of application of the Clinical Trials Regulation and the go-live date of the Clinical Trials Information System. ^{53, 15} As the Regulation sets out, its entry into application is set by the publication of a notice in the Official Journal confirming that the EU portal and database, the key component of the system, has reached full functionality, and the Regulation's application and the system's go-live take place six months after that notice. ^{15, 12} The full functionality of the system was linked to the Regulation's full application. ⁴⁹

The Regulation came into application on 31 January 2022 with a three-year transition. ^{16, 27, 28} The final rollout of the system and its functionality were confirmed on that date, after various delays. ²⁶ Member states work in the system immediately after it goes live. ^{15, 16} Until 31 January 2023 sponsors could still choose to submit an initial clinical trial application under the Directive or under the Regulation. ^{15, 16, 28} From that date submission of initial applications through the system is mandatory, and every sponsor has to use it and follow the same process to apply for authorisation in the EU/EEA. ^{15, 16, 27, 54, 28, 38} As of that date the Clinical Trials Directive was completely superseded by the Regulation, while the transition for ongoing trials run under the Directive continued until 2025, except for non-interventional studies. ¹⁴ By 31 January 2025 all ongoing trials approved under the Directive must be governed by the Regulation and transitioned to the system. ^{15, 16, 27} As the transition was described in 2018, a trial could in the first year be submitted under either the Regulation or the Directive; in years two and three trials authorised under the old system remained under it while all new trials had to be submitted under the Regulation; and in year four all ongoing trials running under the Directive had to switch. ⁵⁵ The first clinical trial authorisation through the system was issued on 31 March 2022, for a trial originally registered under the Directive and in EudraCT and moved under the Regulation and into the system. ⁵⁶

Challenges and support for users

For one writer on the transition, clinical trial research requires companies to respect rules and to be precise and accurate, and the Regulation pushes companies and health authorities one step further, to be more flexible and collaborative. ¹³ In its early stages, however, the new application process was fraught with technical and logistic challenges. ¹³ In its October 2022 Clinical Trials Highlights the EMA acknowledged technical difficulties with the system, reporting that challenges in the workflow for some very large multi-member-state applications were being managed through workarounds to minimise the impact on applications, and articles in December 2022 expressed great concern about the system's functionality and roll-out. ⁵⁷ For one local point of contact on transition projects, collaboration was the key: portal problems could go to the system's helpdesk, but when deadlines were too tight contacting the reporting member state was sometimes the fastest solution, and good relationships with all internal and external stakeholders were important for finding solutions to technical challenges. ⁵⁷ For the same local point of contact, both the agency and the sponsor have an interest in the procedure running smoothly. ⁵⁷

In the agency's account of 2023, the move from the Directive to the Regulation was not without challenges and involved far-reaching changes to how medicine developers, the agency and member states operate, so the agency was working closely with users during the transition on training, support and technical difficulties. ²⁷ It expected the Regulation to facilitate sponsors' applications and streamline assessment and supervision, making it easier to run larger trials in several member states, and ultimately to benefit all those involved, especially patients, through more transparent trial data and stronger patient involvement. ^{27, 58} The agency was monitoring the Regulation's implementation within Accelerating Clinical Trials in the EU, an initiative to transform how clinical trials are designed and run, with monthly metric reports on progress. ²⁷ By September 2023, in the view of one regulatory public disclosure editor, regional and country agencies and sponsors were becoming familiar with the Regulation and the system, and were sharing knowledge effectively enough to save stakeholders time. ⁵⁹ The same editor counted the agency's information sessions and posted documentation as key resources that help sponsors with their applications, and noted that results had not yet emerged from the system, because trials conducted under the Regulation were still active. ⁵⁹ For individual companies, using the system made changes to and enhancements of processes necessary at the application stage of a trial. ⁵⁴

The agency created a training programme of modules covering the full lifecycle of clinical trial submission, authorisation and supervision, on a webpage progressively updated as more materials became available, and published a sponsor handbook on getting ready for and using the system and easing the transition to the new application process. ^{15, 57} Most training was online, with a few virtual classroom sessions aimed at sponsors. ⁴⁹ In March 2023 the agency published a guidance document to help users identify the latest updated training materials and those developed since they last consulted them, and in April 2023 version 3.02 of the sponsor handbook added information about multi-factor authorisation in the system and links to its bitesize talks. ⁶⁰ In 2022 the agency's page on the system's development carried updates and links to reference materials, with CTIS Newsflash articles appearing regularly, module 13 of the training catalogue covered clinical study report submission, and the agency had support initiatives to help universities and hospitals use the system. ⁵⁶

In March 2023 the Clinical Trials Coordination Group published a question-and-answer document to support sponsors submitting complex trials to the Clinical Trials Information System or transitioning them to it. ⁶⁰

In June 2024 Accelerating Clinical Trials in the EU (ACT EU) launched two advice pilots to improve the quality of applications for clinical trials in Europe. ⁶¹ The first offers scientific advice on clinical trials and on the requirements for a marketing authorisation application. ⁶¹ The second is coordinated by the Clinical Trials Coordination Group and provides technical and regulatory support on the dossier of a clinical trial application before it is submitted through the Clinical Trials Information System. ⁶¹