Clinical Trial Pathway

The definition of the research question is key to research design. All research must have a primary question, clearly stated in advance, and founded on a systematic review of what is already known. Researchers who plan studies without reviewing what has been done, risk performing research for which the answer is already known or exposing participants to ineffective or an inferior treatment.

Evidence suggests that research protocols often lack important information on study design. The study protocol should provide an adequate explanation for why the proposed study methodology is appropriate for the question posed, why the study design is likely to answer the research question, and why it is the best approach.

The planning of a clinical trial depends on the primary question, and researchers should clearly and simply explain in the study protocol what the trial is aiming to show, why it is worth asking and, through consultation with public and patient groups, why this is worthwhile to patients. The primary question should be consistently stated throughout the study protocol.  

The question should generally include specific information on participants, intervention(s), comparator(s) and outcomes (PICO format):

• Population: what are the characteristics of the patient or population-e.g. condition?
• Intervention: what is the intervention under consideration for this patient or population-e.g. a drug or surgical intervention?
• Comparison: what is the alternative to the intervention-e.g. a different drug or a placebo?
• Outcomes: what are the key outcomes the study would measure and how do they answer the primary question? e.g. mortality, disease progression, surrogate parameter? 

The ICH GCP E6 (R3) (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use- Good Clinical Practice) guideline defines the protocol as “A document that describes the objective(s), design, methodology, statistical considerations and organisation of a trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol-referenced documents”

The research protocol explains how the proposed study methodology is appropriated for the question posed, demonstrate that the design is likely to answer the research question and why it is the best approach. The protocol should explain:

• the rational, background information and literature review
• how the relevant successes and failures of previous studies have been taken into account in the design of the planned trial  
• how the proposed research method is appropriate for the question posed  
• the reasoning behind the choice of any treatment/intervention difference sought, as well as the other parameters used in the determination of the sample size  
• the choice of comparators and end points
• the randomisation and blinding methods  
• the suitability of the statistical tests
• how the sample to be studied is representative to the wider group of patients

The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement 2025 is a guideline for the minimum content of a clinical trial protocol. It includes a 34-items checklist that applies to protocols for all clinical trials and focuses on the content on a clinical trial protocol. 

The ICH for Good Clinical Practice guidelines E6 (R3) and the Clinical Trials Regulation (536/2014), define a sponsor as

“an individual, company, institution or organisation which takes responsibility for the initiation, for the management and for setting up the financing of the clinical trial”

According to this definition, the sponsor is equally scientifically, legally and financially responsible of a clinical trial but the budget can either come from the sponsor itself or from sources external to the research group.

The sponsor is ultimately responsible for the scientific, ethical, regulatory and legal aspects of the trial, and also for financial aspects (i.e., if an external funder withdraws, the sponsor will be responsible for looking for funds to complete the trial).

The latest European regulation for clinical trials on medicinal products for human use (536/2014) introduces the possibility of co-sponsorship in Europe, while for Sponsors located out of the EU a legal representative of the sponsor is needed.

Industry-sponsored trials

In commercial research, the same organization (usually a pharmaceutical company), funds, designs and carries out a trial, acting both as sponsor and funder.

Investigator-initiated trial (IITs)/Academic-sponsored trials

Commercially sponsored clinical trials are responsible for bringing most of the new drugs to the market. However, these clinical trials only assess the safety and efficacy of drugs that are chosen by a commercial entity that funds the entire process. Non-commercial or academic trials have therefore their own additional specific significance, often focusing on refining indications of available treatments and optimizing therapeutic strategies that do not have as much financial gain to the pharmaceutical industry.

A good amount of IITs is driven by questions that generally arise beyond the completion of Phase III studies and which have not been studied during Phases I–III of drug development.

For IITs, academic institutions act usually as sponsor (academic-sponsored trials), but not necessarily as the funder. Only in few cases will academic sponsors be able to conduct trials without external funding, usually coming from different sources. This often leads to complex arrangements with multiple partners joining in international consortia. The setup of a complex multi-national partnership may sometimes be at odds with the concept of “single sponsorship” which was developed for ensuring protection of participants in the context of commercial trials. Single sponsorship is rooted in the need to clearly identify the legal responsibility and does not hinge upon the funding aspect. Noteworthy, most funding agencies are unwilling to take the role of sponsor and often they may not be suitable for it.

Sponsor-Investigator is an individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to, or used by a subject. The term does not include any person other than an individual (e.g., it does not include a corporation or an agency). The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator.

Collaboration with industry- For some IITs, pharmaceutical companies might act as funders. The pharmaceutical company can support IITs with drug supply, funding, material and/or information, as allowed under local laws and regulations, provided that they align with the company defined areas of strategic interest. Some big pharma companies publish guidelines describing the conditions to establish collaborations with academic-sponsors for IITs.

Industry-initiated clinical trials are financially supported by the industry. The principal investigator (PI) salary and the costs associated with running the trial are all covered by the pharmaceutical company that conceived the clinical trial. In investigator-initiated trials (IIT), however, usually is the PI who applies for funding through research programs and government grants to fund their conceived research project.

Industry funded trials

Industry- funded and industry-sponsored clinical research is paid by an industry organization that has contracted with a faculty member to conduct a clinical trial that involves an intervention with, or observation of, a disease or biomedical condition, or a registry/repository related to a disease or biomedical condition. For most industry-funded clinical trials, the industry organization acts as sponsor and designs the study, owns the protocol, data and results.

Academic-sponsored trials funded by industry

Collaboration between industry and academics is common in the development of vaccines, drugs, and devices, as it can be mutually beneficial. Academic institutions/hospitals provide access to trial participants and clinical and methodological expertise, and industry provides funding and expertise. The degree of independence and the roles of academics and industry vary across trials. Trials may be run by academic trial units independently but with unrestricted industry funding, or the only contribution from industry could be free provision of study drugs.

Publicly funded trials

Many national research funding agencies open regularly calls for funding clinical research, supporting academia/investigators to set up clinical trials. This funding is nevertheless usually restricted at national level. Indeed, despite the advantages of multinational clinical trials, just 3% of academic trials (vs. 30% of industry trials) involve more than one country. In Europe, the relative scarcity of multinational academic trials can be explained, in part, by restrictions with current cross-border funding options.

Funding by a central European Budget

Horizon 2020 (H2020) has been the biggest EU Research and Innovation programme ever, with nearly €80 billion of funding available over seven years (2014 to 2020). Most multinational clinical trials have been funded under the H2020 “Health, demographic change and wellbeing” programme. Since 2021, the Program Horizon Europe (HE) is the new Framework Program which will run from 2021 to 2027. with an indicative budget or around €95.5 billion.

European and industry funding combined

The Innovative Health Initiative (IHI) is a Horizon Europe source of funding dedicated to public-private partnership projects. Non-industry partners in consortia receive public funding, while industry contributions can be in cash (financial contributions) and/or in-kind (such as personnel time, laboratory access, data, compounds) depending on the partner. A large share of each project must come from industry contribution (≥ 45%).

Cross-border national funding

In general, national funding agencies do not accept funding crossing borders, limiting international collaboration.

Some national public funding agencies (German DFG, Austrian FWF and Swiss SNSF) have established mechanisms to coordinate national calls for funding, facilitating the creation of “virtual common pots”, through mutual opening of the respective funding procedures that facilitate the implementation of cross-border research projects.

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Founded by the Nordic Council of Ministers, NordForsk funds clinical studies, including clinical trials, following both the “virtual and real common pot” models or mixed models combining both. NordForsk can enter into collaboration with funding organisations/institutions outside the Nordic Region when this is expected to result in high scientific quality and Nordic added value. The virtual common pot model is the preferred funding model for partners from outside the Nordics where NordForsk can act as a broker between national funding organisations in the Nordics and organisations outside the Nordics.

Benefit is a funding initiative involving KCE and ZonMW, national funders for Clinical studies in Belgium and Netherlands. The program funds pragmatic Trials running in both countries, following the “virtual common pot” model.

There are also private initiatives supporting multinational trials, pooling funding sources. The GCRFF (Global cardiovascular Research Funders Forum) facilitates simultaneous request of funding to charities located in different countries. The ATTRACT programme launches single calls pooling funding from charities located in different countries under the virtual common pot model with limited cross-border funding.

Co-funded Partnerships

Co-funded partnerships combine national funding from EU member states and European Commission funding. The co-financing rate is typically 30 % from the EC. They offer opportunities for funding through the launch of Joint Transnational Calls. Joint Transnational Calls are based on the “virtual common pot” funding model. Through this mechanism, each national funder supports the components of the applying consortium located in their own country.

Risk assessment is a systematic process for identifying and evaluating events that could affect the achievement of clinical study´s objectives related to quality, safety, timelines and budget, positively or negatively.

Some academic organisations may not be able to undertake the role of sponsor for clinical trials or may only sponsor trials of a certain risk level. It is essential therefore that a risk assessment is undertaken at the very start. The process could be defined such that the risk assessment is undertaken on the research proposal and then further refined once the protocol has been drafted.

The risk-based approach relies on the identification and assessment of risk(s) and mitigation of these risks.

For years, risk has been interpreted as risk for patient's safety or rights only. However, other types of risk should be considered: the institutions and teams in charge of the study conduct, the governance structures, the target population, and the public health stakeholders, etc.

The risks of a clinical trial on a medicinal product depend on a number of factors but can be broadly categorised as:

• the risks of the investigational medicinal product (IMP)
• the risks associated with the regulatory and legal requirements, the trial conduct, design and methods

The OECD Recommendation on the governance of Clinical Trials introduced a risk-based oversight and management methodology for clinical trials. It combines a stratified approach that is based on the marketing authorisation status of the medical product and can be applied in a common manner across countries’ regulatory frameworks, with a trial-specific approach that considers other issues such as the type of populations concerned by the trial, or the informed consent of the patients. EMA Reflection paper on risk-based quality management in clinical trials (2013) and EC considerations on Risk Proportionate approaches in clinical trials (2017) aim to facilitate the development of systematic, prioritised, risk-based approach to quality management of clinical trials, to support the principles of Good Clinical Practice and to complement existing quality practices, requirements and standards.

Importantly from a risk perspective, ICH E6 (R3) emphasises a risk-based and proportionate approach to monitoring, oversight, trial conduct. The guideline structure (principles & objectives + Annex 1 for interventional trials + Annex 2 for non-traditional trials) further supports tailoring of risk assessment to trial design.

The purpose of a Project Management Plan (PMP) in a clinical trial is to define the scope, outline responsibilities and describe key steps of the clinical trial process. This not only ensures that those performing the tasks have a clear plan of what, when and how trial activities are undertaken, but also enables auditors/inspectors to reconstruct how a trial was managed. Trial management procedures/responsibilities that are common across all trials are usually defined in the sponsor’s research standard operating procedures (SOPs)/policies and for less complex trials, the trial management documentation may simply consist of an index of these SOPs with any trial-specific management described in sufficient detail in the protocol. The level of detail required will depend upon:  

a) The clinical trial risk assessment

b) The organisational structure within which the clinical trial is conducted

c) The design and methods of the clinical trial

The trial management plan should outline procedures regarding:

• Communication
• Documentation (Trial Master File)
• Vendors
• Investigational product
• Site management
• Safety plan
• Data management (Data Management plan) 

DMP is a written document that describes the plans for collection and management of data throughout the lifecycle of a clinical trial. The DMP describes which clinical data will be acquired and how it will be handled, stored, checked for consistency and plausibility, and made available for the final analysis and further research after the end of the project.

For effective data management, planning must begin at the time of trial design. It should consider the collection and management of data during the trial, data sharing and archiving at trial closure. A well-designed DMP will provide a road map on how to handle the data, establish processes to handle unforeseeable conditions and assess potential risks.

As there are various stakeholders and staff members involved in data handling, the key goal of this document is to communicate to each stakeholder the required information to create and maintain a high-quality database that is ready for analysis. In addition to the database specification, DMP should also document CRF (Case report Form) design and development.

It is considered best practice to develop the DMP in collaboration with all stakeholders involved in the trial, to ensure compliance. Institutes and agencies involved in clinical research might consider developing DMP templates, which are customised as per the requirements of the trial.

• Typical data management plan elements:
• Data collection-Types of data, contextual details (metadata)
• Data Storage: Storage, backup and security
• Data Protection: Access, monitoring, provisions for protection/privacy
• Policies for re-use
• Access and sharing
• Archiving

Special attention must be given to data access, sharing and re-use. As of July 1, 2018, manuscripts submitted to ICMJE (International Committee of Medical Journal Editors (ICMJE)) journals that report the results of clinical trials must contain a data sharing statement as described below.

Data sharing statements must indicate the following: whether individual deidentified participant data (including data dictionaries) will be shared; what data in particular will be shared; whether additional, related documents will be available (e.g., study protocol, statistical analysis plan, etc.); when the data will become available and for how long; by what access criteria data will be shared (including with whom, for what types of analyses, and by what mechanism)

Informed consent, access governance, and access technologies are important to realize the benefits of data sharing while mitigating risks and should be taken in consideration while designing a Data Management Plan.

Trial management is the process of ensuring that a trial is run effectively and within budget and timelines. According to ICH, the sponsor should utilize appropriately qualified individuals to supervise the overall conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the trial reports. The sponsor should implement a system to manage quality throughout all stages of the trial process

For industry-sponsored trials, the sponsor usually outsources this activity to a CROs-private Clinical Research Organizations. Although there are different types of CROs and diverse levels of specialization (distinct therapeutic areas for instance), typical CRO services include regulatory affairs, site selection and activation, recruitment support, monitoring, data management, trial logistics, pharmacovigilance, biostatistics, medical writing, and project management, among others.

For academic-sponsored trials, Trial Management is usually performed by an academic Trial Coordinating Centre.

The trial Coordinating Centre is at the heart of the trial, whether it is a single-site or multisite trial and is usually linked to the Sponsor ´s institution (Hospital or University).

The Trial Coordination Center can be referred to by a variety of names and set in many different environments. It can be:

• An academic clinical trials unit (CTU) able to provide all the services
• An office/desk in a clinical department in a hospital/university
• Split over different locations and be set up as a combination of the above for example a CTU can support an academic department in one or more aspects of running a trial (data management, statistics etc).

As responsible of the project management, CROs and Trial Coordinating Centers act as Global coordinators of resources, including, but not limited to:

• Clinical site feasibility
• General coordination of resources
• Preparation and maintenance of sponsor’s trial master file
• Organisation of pathways for central laboratory/biobank with instructions for single sites
• Elaboration of the monitoring manual
• Central clinical research associate (CRA) training (web-based and/or on-site)
• Online, web-based central monitoring
• Review of monitoring reports

The sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO/Trial Coordinating Center but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The CRO/TCC should implement quality assurance and quality control

Prior to initiating a clinical trial, researchers must obtain approval from National Competent Authorities (NCA) and ethics committees. For clinical trials on an Investigational Medicinal Product (CTIMP), there are a number of steps to follow:

a) Compliance with legislation

The first step is to confirm, for international clinical trials in Europe, whether it falls within the scope of European Legislation (CTR-Clinical trials Regulation EU No 536/2014).

The Regulation has introduced an authorisation procedure based on a single submission via a single EU portal (CTIS), an assessment procedure leading to a single decision, rules on the protection of subjects and informed consent, and transparency requirements.

Non-international trials (single-country) would follow national legislation with a single application to the competent authority in the participating country.

b) Submission to National Competent Authorities and Ethics Committees

To obtain authorization for clinical trials under the CTR, clinical trials have to be submitted through the Clinical Trials Information System (CTIS) — the centralized portal established by the European Medicines Agency (EMA) . Clinical Trial Applications (CTAs) are based on the submission of a dossier including:

• Part I: General trial information (design, IMP, safety, scientific data) — evaluated jointly by all Member States Concerned (MSCs)
• Part II: National-specific information (ethics, informed consent, compensation) — evaluated individually by each MSC

MSCs review the application within regulated timelines and once approved, the trial is authorized in participating countries. Summary information is automatically published on the EU Clinical Trials Register (public CTIS interface). After registration After registration, CTIS is also used to:

• Submit substantial modifications
• Report serious breaches, safety events, and annual safety reports (ASRs)
• Upload summary results after trial completion

The sponsor should implement a system to manage quality throughout all stages of the trial process, in particular on trial activities essential to ensuring human subject protection and the reliability of trial results.

Quality management is the overall process of establishing and ensuring the quality of processes, data, and documentation associated with clinical research activities. It encompasses both quality control (QC), and quality assurance (QA) activities.

• Quality control. The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled. Periodic operational checks to verify that clinical data are generated, collected, handled, analysed, and reported according to protocol, SOPs (Standard Operation Processes), and GCP (Good Clinical Practice)
• Quality assurance. ICH Good Clinical Practice guideline defines quality assurance as all those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented, and recorded in compliance with GCP and applicable regulatory requirements.

A quality management system (QMS) provides a framework for all quality management activities, including quality control, quality assurance, quality improvement and the reporting of these activities. Key elements of the QMS are:

1. Documented procedures developed, implemented and kept up-to-date
2. A documentation system that allows for the retrieval of any records or documentation to show actions taken, decisions made and results. All approved documents and records are version-controlled
3. Defined organisational and accountability charts, roles and responsibilities
4. Appropriate documented training of personnel to meet the defined competencies of their role, and familiarisation with GCP
5. Documented evidence to demonstrate that computerised systems are fit for purpose (validation)
6. Quality Control (QC) activities, (review and checking). For example, monitoring of trial sites either on-site or through centralised or remote monitoring techniques
7. Quality Assurance (QA), including independent audit of QMA processes and studies by the QA team
8. A risk-based approach used to determine the extent of trial monitoring activities, processes and trials to audit, and computer validation activities
9. Continuous improvement incorporating Corrective and Preventive Actions (CAPA)

Monitoring and Audit

Many professionals working in clinical research may not appreciate or understand the roles and differences between clinical research monitoring and auditing, two distinctly different functions.

Monitoring is a quality control function where study conduct is routinely assessed on an on-going basis at every step of the trial.

Auditing, a quality assurance function, is an independent, top-down, systematic evaluation of trial processes and quality control.

Quality control: Monitoring of clinical sites

ICH- GCP defines monitoring as the act of overseeing the conduct of a clinical trial, that is ensuring that the trial is conducted according to protocol, GCP, SOPs and regulatory requirements. It is the responsibility of the sponsor to ensure the trial is adequately monitored.

According to GCP guidelines, “Monitoring may include site monitoring (performed on-site and/or remotely) and centralised monitoring, depending on the monitoring strategy and the design of the clinical trial (ICH GCP E6 (R3) 3.11.4)The rationale for the chosen monitoring strategy is documented in the monitoring plan.

The monitoring plan sets out monitoring strategies, the monitoring responsibilities of all parties involved, the various monitoring methods to be used, and the rationale for their use. It also describes monitoring procedures, types of visits, what is involved in the conduct of those visits, and the quantity or percentage of each type of document to be monitored. These procedures can be further defined on a protocol basis depending on the purpose, design, size, complexity, and primary outcome measures of the trial.

In general, on-site monitoring is required and remote monitoring may occur at any given research site before a trial begins, while it is in progress, and after it concludes or is terminated. In many instances, study monitors may visit each site after the first one to two participants are enrolled and then schedule subsequent visits based on multivariate criteria, such as the rate of enrolment, volume of data to review, site performance, and other considerations. Study monitors conduct site visits according to the procedures described in the monitoring plan

Regulatory authorities and changes to guideline ICH E6 (R3) recognized the potential use of a risk-based monitoring approach to improve the conduct of clinical trials of all phases

A well-implemented risk-based monitoring process facilitate efficient and cost effective trial delivery without compromising patient safety or data quality.

Documentation of all aspects of the monitoring process is achieved through monitoring reports from on-site visits providing clear evidence of what was checked and any non-compliance as well as the description of associated actions/resolution. Monitoring activities conducted centrally would be required to provide similar evidence. This also enables auditors/inspectors to reconstruct how a trial was managed.

Quality assurance: audits

Audit is defined by ICH as “a systematic and independent examination of trial-related activities and documents to determine whether the evaluated trial-related activities were conducted, and the data were recorded, analyzed, and accurately reported according to the protocol, sponsor’s SOPs, GCP and the applicable regulatory requirement(s)”

Audits are considered good practice and should be part of the Sponsor´s Quality Management system. There are three general areas of concern in the audit process regardless of which entity is performing the audit: patient safety, including consent forms and ethics committees activities; data collection and records; and the pharmacy and investigational drug supply.

Inspections

The ICH defines “inspection” as “The act by a regulatory authority (ies) of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority (ies) to be related to the clinical trial and that may be located at the site of the trial, at the sponsor’s and/or contract research organization’s (CRO’s) facilities, or at other establishments deemed appropriate by the regulatory authority (ies)”.

Inspections are performed by government regulators to ensure patient safety, welfare, scientific integrity and compliance with regulations. In Europe, regulatory authorities perform regulatory inspections of trial sites or sponsors on a regular basis. The frequency of these inspections is based on the risk associated with the trials being undertaken. They may also perform triggered inspection after a particular event. In most cases the regulatory authority shall inform the main contact (normally sponsor) of an inspection but these may occasionally be unannounced.

The sponsor is responsible for the safety evaluation of the Investigational Medicinal Product(s) used in a Clinical Trial

Sponsors should develop formal, written processes (Safety Management Plan) for the management of adverse events and safety reports, including the handling of both expedited reports and annual safety reporting.

Investigators are responsible for Serious Adverse Events (SAEs) reporting to the Sponsor. SAE reporting includes investigator´s causality and seriousness assessment and it must be done timely according to the protocol specifications.

Pharmacovigilance (PV) is the science relating to the detection, assessment, understanding and prevention of the adverse effects of medicines/vaccines. Some academic Clinical Trial Units (CTUs) and private Clinical Research Organizations (CROs) have PV units to support Sponsors and investigators with Safety reporting, including:

• Validation, use and maintenance of an internal PV database in which all the events can be received, managed, and recorded and where all obligatory legal PV activities can be performed in compliance with the national and global regulatory requirements.
• Expedited reports

All relevant Suspected Unexpected Serious Adverse Reaction (SUSARs) that occur during a clinical trial must be reported to the Regulatory authorities of participating countries as soon as possible but no later than 7 calendar days after first knowledge by the sponsor. The communication has to be followed by as complete as possible a report within 8 additional calendar days. Sponsors may use the current European portal (Eudravigilance website) to submit SUSAR reports in bulk to National Competent Authorities (NCAs).

• Annual safety reports

Development Safety Update Reports (DSURs)/Annual Safety Report (ASR) are internationally-harmonized, safety documents covering the safety summary of medicinal products during their development or clinical trial phase. Sponsor is responsible of submitting annual ASR via the Clinical Trials Information System (CTIS)once per year to inform both NCAs and Ethics Committees (ECs) in the countries involved in the clinical trial.

• Periodical reconciliation of adverse events recorded between the Clinical trial database and the PV database
• Pharmacovigilance training for investigators and staff involved in the trials.

A process that begins with conception and design of the clinical trial, continues through data capture and analysis to publication, data archiving and data sharing with the broader scientific community. The Data Management Plan (DMP) describes the procedures for data collection and management  throughout the lifecycle of a clinical trial. 

An investigational product (IP), as defined by the ICH is a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.

Regulation (EU) No 536/2014 Article 2 (5) defines an “Investigational Medicinal Product (IMP) as “a medicinal product which is being tested or used as a reference, including as a placebo, in a clinical trial”.

To ensure all regulatory and governance requirements are met, it is essential that investigators obtain advice and support from those with specialist knowledge relating to the IMP supplies (Clinical Trial Pharmacists, Clinical Trials Unit (CTU) or Contract Research Organisation (CRO)). These specialists are key to plan and advice on IMP handling. In Europe, IMP handling requires a thorough knowledge of ICH GCP sections on Supply and handling IMPs and Eudralex volumes on Good Manufacturing Practice (GMP).

It is highly recommended to start considering IMP handling from the planning stage of the trial, clearly identify the nature of the IMP and a thorough consideration of the IMP sourcing strategy. The complexity of the process varies greatly from IMPs sourced internally and dispensed according to routine practice to externally sourced IMPs not marketed. The IMP requirements relating to unlicensed drugs also applies to compounds that already marketed, for example when an IMP is used for a new indication outside those for which the drug was licensed, such as for a different group of patients or for a different disease.

The analysis of samples collected from subjects participating in clinical trials forms a key part of the clinical trials process. Sample analysis or evaluation provides important data on a range of endpoints which is used, for example, to assess the pharmacokinetic profile of investigational medicinal products and to monitor their safety and efficacy. Consequently, it is essential that sample analysis or evaluation is performed to an acceptable standard which will ensure patient safety is not compromised and that data is reliable and accurately reported.

It is good practice to have well documented Standard Operating Procedures (SOPs) that define how to conduct each laboratory procedure, whether at the clinic or laboratory (analytical) level from the sampling to the analysis and further storage or destruction as applicable.

These applies to:

• samples collected and analysed as part of routine clinical care, that may also contribute to the study dataset
• samples collected and analysed for study objectives only
• samples prepared and stored before shipping to a specialist laboratory
• samples analysed using a standard clinical assay in laboratory with a functional, audited quality system
• samples analysed using an exploratory/experimental assay
• samples collected for biobanking

The SAP is intended to be a comprehensive document that contains a detailed and technical description of the principal features of the statistical analysis outlined in the protocol including detailed procedures for executing the statistical analysis of the primary and secondary endpoints and other data. As compared to the protocol, the SAP should contain an in-depth description of the statistical methods to be used and a definition of the statistical output which will be included in the clinical study report (CSR).

The SAP is generally developed as a separate document and written after the protocol has been finalised. Ideally, a biostatistician should develop the SAP with the help of the principal investigator and in alignment with the protocol. The SAP should be finalised prior to data analysis and before treatment un-blinding. Any changes between the methods in the protocol and analysis plan, should be explained in the SAP.

The SAP must properly explain the statistical analysis following the aims and primary objectives, secondary objective, exploratory objectives, primary/secondary/exploratory endpoints, trial population, design of the trial, sample size calculations with justifications/assumptions and the randomization methods. Additionally, a SAP must describe in detail the statistical methodology i.e. efficacy analysis, safety data analysis, interim analyses, handling of missing data, reporting conventions, etc

A Clinical Study Report (CSR) is a is a key document that describes the methodology and results of a clinical trial in drug development.

The full CSR represents a comprehensive clinical and statistical description of a sponsor’s study conduct. Additionally, a full CSR includes efficacy and safety data. This report is required if the study is to be used to support approval by a regulatory agency, such as the FDA (Food and Drug Administration-USA) or European Medicines Agency (EMA), or that support the information in the product label.

A CRS should also provide enough individual patient data, to allow the key analyses of data to be repeated, should the regulatory authorities wish to do so.

In the European Union, sponsors must submit the CSR summary within one year of the end of their clinical trial to regulatory authorities and ethics committees through the Clinical Trials Information System (CTIS). The end of a clinical trial is usually defined as the date of the last patient last visit (LPLV). The results of most clinical trials are published in the EU clinical trials registry and are therefore accessible to the general public. For trials exclusively involving minors, the CSR deadline is 6 months after the end of the trial. This accelerates transparency for paediatric research.If a CSR is not required for regulatory submission (e.g., exploratory early-phase trials), the sponsor may submit only the summary results within the same 12-month window.

The Clinical Trials Regulation (CTR) allows deferral of CSR publication (not submission) in certain cases:

• Sponsors can request deferral of the public disclosure of CSR or summary results in CTIS to protect commercially confidential information.
• However, the CSR itself must still be submitted to CTIS within the 12-month (or 6-month) timeline.

Standard components of an ICH-compliant CSR include:

• Title Page and Synopsis
• Table of Contents, List of Tables/Figures
• Ethics and Administrative Structure
• Introduction
• Study Objectives
• Investigational Plan (Protocol Overview)
• Study Population and Methods
• Efficacy Evaluation
• Safety Evaluation
• Discussion and Overall Conclusions
• References
• Appendices
• Protocol and amendments
• Sample CRFs
• Investigator CVs
• Audit certificates
• Individual patient data listings 

The documents which individually and collectively permit evaluation of the conduct of a clinical trial and the quality of the data produced are defined as essential documents according to the ICH Good Clinical Practice.

These documents demonstrate the compliance of the investigator, sponsor and trial monitors with the standards of GCP and with applicable regulatory requirements. It is the responsibility of the sponsor to ensure that the documents are filed in an organised way in the so-called Trial Master File (TMF) which will facilitate management, audit and inspection of the clinical trial.

Essential documents must be retained (archived) for sufficient periods to allow for audit and inspection by regulatory authorities and should be readily available upon request.

The TMF should be set up at the beginning of a trial and maintained throughout the trial. Archiving applies to both the investigator sites and the central trial coordinating office.

Prior to initiation of a trial, an archiving strategy must be developed, which addresses the regulatory requirements. It should include the following elements:

• Documents/material to be archived

The plan/strategy must identify the documents, data, supplies, specimens, etc. that are to be archived. Some examples are: source documents, case record forms, informed consent documents, investigator site file, biological samples (if applicable), trial supplies (if applicable), etc.

• Destruction of documents

The reasons for destruction of essential documents should be documented and signed by a person with appropriate authority. The sponsor/someone on behalf of the sponsor should notify investigators in writing when their trial records can be destroyed

• Period of archiving

The plan must indicate for how long the documents will be archived in compliance with the regulatory guidelines. It is also important that access to documents and data is maintained throughout the storage period. This includes ensuring system maintenance (hardware and software) to access data in the original archived format, or the use of a new system to emulate old software, or the migration of data into a new format to ensure continuous access with new software. This issue should be addressed through written procedures by the organisation responsible for long-term archiving

According to the European Medicines Agency (EMA) the long-term archiving of the TMF can be either through an external archive that provides the preservation of paper documents or through an electronic archiving (e.g., cloud data center). When an external repository is used, the sponsor must still make an assessment of the suitability of the solution used both before use and periodically during the long-term archiving period.

In Europe, according to the Regulation EU No 536/2014 (CTR), sponsor and investigator must archive the content of the clinical Trial Master File (TMF) and Investigator Site File (ISF) for at least 25 years after the end of the clinical trial. However, the subject’s medical records at the trial site shall be archived in accordance with national law. Indeed, the CTR leaves the exact retention period for medical records to each Member State’s legislation, which often exceeds 15 years (and may be linked to hospital or data protection laws).

Location and access

Essential records should be maintained in a legible condition and prompt retrieval should be possible. Adequate and suitable space should be provided for the secure storage of all essential records upon trial completion. The facilities should be secure, with appropriate environmental controls and adequate protection from fire, flood and unauthorized access. The storage of the sponsor's documentation may be transferred to a sub-contractor (e.g. a commercial archive) but the ultimate responsibility for the quality, integrity, confidentiality and retrievability of the documents resides with the sponsor.

The plan must specify that the documents will have a restricted access. It is advisable to identify the details of personnel that can access the archival facility. However, it should be clarified that the regulatory authority or ethics committees may request access to these documents.

The archiving plan should include a disaster management plan, to recover the documents in case of an emergency. For example, electronic copies can be made of all documents and data that are archived. However, these electronic copies must be stored at a location other than the archival facility and comply with confidentiality requirements.

• Procedure

It should be specified that the process of archiving should only be commenced after:

• The final visit has been completed by the last trial participant
• TMF and ISF, are complete
• The data has been verified for accuracy
• All queries pertaining to data have been resolved, database is locked, and the data has been analysed
• Final report has been submitted
• Any other pre-requisite specified by the sponsor, regulatory authority, ethics committee, etc.

After each clinical trial finishes, the trial sponsor will compile a detailed clinical study report (CSR), which follows a format laid down by the regulatory authorities. Access to the complete CSR is usually limited to the sponsor and the regulatory authorities that are assessing the marketing authorisation application.

However, information that has been summarised from the CSR is likely to come into the public domain by different means:

Journal papers-The classic route for publication of clinical trial results is a research paper in a specialist medical journal, by which the results are published as an article subject to a peer-review process. Current practice usually involves the publication of the full study protocol as well.

Conferences-CT Results are usually presented at international medical conferences. Nevertheless, access to this information is often restricted to those who are attending the conference and it is not easily available to those who are not.

Clinical trials registries-. In Europe the European Clinical Trials register (https://euclinicaltrials.eu/) allows to search clinical trials initiated in the European Union and European Economic Area since 31 January 2022. For trials taking place in the EU starting after 1st January, 2015, all such results must be published, regardless of their positive or negative implications. The World Health Organisation (WHO), through its International Clinical Trials Registry Platform, is setting international standards for registering and reporting on all clinical trials. In the United States (US), the ClinicalTrials.gov registry does so similarly.

EPAR-When authorisation for a new medicine is sought via the Centralised Procedure (CP), an assessment report (EPAR) is written by the European Medicines Agency (EMA), published on EMA website after a decision has been made either to approve or reject the authorisation application. The EPAR provides public information on a medicine, including how it was assessed by the EMA committees

Lay summary report- The European Union Clinical Trials Regulation (EU CTR) 536/2014 includes a requirement for the submission of lay summaries. As a complement to other forms of clinical study disclosure such as registry postings and scientific publications, lay summaries may aid the transparency of a sponsor’s clinical study results, thereby promoting trust, partnership, and patient engagement throughout the clinical study process.