Rare Diseases Clinical Trials Toolbox

RISK ASSESSMENT

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

Some academic organisations may not be in a position 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 the 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,  the public health stakeholders, etc.

The risks of a clinical trial 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 a 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.

TRIAL MANAGEMENT PLAN

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 the 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)

DATA MANAGEMENT PLAN (DMP)

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

TRIAL MANAGEMENT

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 CRO - 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, regardless of 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 for 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.

REGULATORY SUBMISSION

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

1. Compliance with legislation

The first step is to confirm, for international clinical trials in Europe, whether it falls within the scope of European Legislation (Clinical trials Regulation EU No 536/2014, CTR), replacing the Directive 2001/20/EC. Although the Regulation entered into force on 16 June 2014 the timing of its application depended on the development of a fully functional EU clinical trials portal and database (CTIS-EMA clinical trial information system)

The European Commission confirmed the 31 January 2022 as the date of entry into application of the Clinical Trials Regulation (CTR) and the go-live of the Clinical Trial Information System (CTIS).

From the 31 January to January 2023 there is a three-year transition period. Failure to be ready to submit Clinical Trial Applications via CTIS by the end of January 2023 , when new applications will no longer be permitted under the old Directive, will mean organisations will not be able to apply and consequently run new trials within Europe. From the end of January 2025 all clinical trials must be fully compliant with the new CTR and be created via CTIS.

The Regulation aims to ensure a greater level of harmonisation of the rules for conducting clinical trials throughout the EU. It introduces an authorisation procedure based on a single submission via 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.

During the transition period, sponsors can still submit new applications under the old directive under which, for international trials in Europe, an application to the competent authority in each member state is required.

The following steps are applicable to the new application under the old directive. For applications through CTIS these steps are fully handled through the portal as a single entry point.

2. Registration

Prior to submission to the National Competent Authority (NCA) each trial must be registered on the European Clinical Trials Database by obtaining a EudraCT number.  

For CTIS applications, trials are registered obtaining a EU CT Number.

3. Submission to National Competent Authorities

Detailed information on how to submit the application is available on the NCAs websites.  The Heads of Medicines Agencies (HMA) is a network of the heads of the National Competent Authorities (NCA) whose website links to all European NCAs.

4. Submission to an Ethics Committee

In addition to the NCA approval, prior to commencing any trial related activities including screening and recruitment, the trial protocol should be submitted to an ethics committee (EC) for review. Clinical trials might also need to be submitted to other interested parties (Data Protection authorities).

These committees will give their opinion on the proposed participant involvement and whether activities are ethical and safe.

In some countries, the trial´s evaluation is made by more than one ethics committee: one at the country level and another local ethics committee at the Sponsor institution and/or participating sites.

For CTIS applications only one national EC approval is needed.

Ethics Committees requirements can usually be found at the NCAs websites (see above) and/or national legislation for clinical trials.

QUALITY MANAGEMENT

The sponsor should implement a system to manage quality throughout all stages of the trial process, in particularly 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, and GCPs.

• 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 Good Clinical Practice 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 an independent audit of Quality Management Assurance (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, SOP and regulatory requirements. It is the responsibility of the sponsor to ensure the trial is adequately monitored.

According to GCP guidelines, “the Sponsor may choose on-site monitoring, a combination of on-site and centralized (remote) monitoring, or, where justified, centralized monitoring alone. Centralized monitoring processes provide additional monitoring capabilities that can complement or reduce the extent and/or frequency of on-site monitoring and help distinguish between reliable data and potentially unreliable data without the need for total source data verification” (ICH GCP 5.18.3). 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 and in accordance with Good Clinical Practice (GCP) guidelines.

Regulatory authorities and changes to guideline ICH E6 (R2) 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 facilitates 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 standard operating procedures (SOPs), GCP and the applicable regulatory requirement(s)”

The purpose of a sponsor's audit, which is independent of and separate from routine monitoring or quality control functions, should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements. 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 a 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.

SAFETY REPORTING

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

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

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

• Validation, use and maintenance of an internal pharmacovigilance database in which all the events received and managed are recorded and where activities to be performed can be planned.

• Expedited reports

All relevant suspected, unexpected, serious, adverse reactions (SUSARs) that occur during a clinical trial must be reported to the National Competent Authorities (NCAs) and Ethics committees of participating countries. Sponsors may use the current European portal (Eudravigilance website) to submit SUSAR reports in bulk to NCAs.

• Annual safety reports

Development Safety Update Reports (DSURs) are internationally-harmonized, safety documents (which became mandatory in European Union Member States in September 2011) covering the safety summary of medicinal products during their development or clinical trial phase. The Sponsor is responsible for submitting annual DSURs to both NCAs and ECs in the countries involved in the clinical trial. These include:

• Validation, use and maintenance of an internal pharmacovigilance database in which all the events received and managed are recorded and where activities to be performed can be planned.
• Periodical reconciliation of adverse events recorded in the eCRF vs the PV database
• Pharmacovigilance training for investigators and staff involved in the trials.

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

DATA MANAGEMENT

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 describes the procedures for collection and management of data throughout the lifecycle of a clinical trial.

INVESTIGATIONAL PRODUCT/SUPPLY MANAGEMENT

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.

Investigational Medicinal Product (IMP): Regulation (EU) No 536/2014 Article 2 (5) defines an 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 advise 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 make 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 apply to compounds that are 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. This is especially relevant for the rare diseases clinical research, where a good number of investigator-initiated trials aim to generate knowledge on drug repurposing.

LABORATORY PROCESSES

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 apply 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

STATISTICAL ANALYSIS PLAN (SAP)

The SAP is intended to be a comprehensive document that contains a detailed and technical description of the principal features of the analysis outlined in the protocol. It also includes 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.

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 include a brief summary of the trial, which includes the aims and objectives, trial population, design of the trial, sample size calculations (including the justifications and assumptions), and the randomisation method.

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, an SAP must describe in detail the statistical methodology i.e. efficacy analysis, safety data analysis, interim analyses, handling of missing data, reporting conventions, etc

ARCHIVING

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 serve to demonstrate the compliance of the investigator, Sponsor and monitor 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 Trial Master File 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.

Archival Strategy

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 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 files, 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 EMA, the long-term archiving of the TMF can be either through an external archive that provides the preservation of paper documents or through 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, for studies conducted under Directive 2001/20/EC, Sponsor and Investigator must ensure that the documents contained in the TMF are retained for at least 5 years after the end of the trial or in accordance with national regulations.

However, trials in which data are used to support a marketing authorisation have additional requirements and the TMF must be retained for at least 15 years after completion or suspension of the trial or at least two years after the last marketing authorisation has been granted in the European Community (where no marketing authorisation applications are pending or foreseen in the EC) or at least two years after the formal suspension of the clinical development of the investigational product (Directive 2003/63/EC)

As soon as the Clinical trials - Regulation EU No 536/2014 becomes effective the sponsor and the investigator will have to archive the content of the clinical TMF 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.

• 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.
• Trial Master File and Investigator Site File, 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.

TRIAL REPORT

A Clinical Study Report (CSR) 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 to support the information in the product label.

A CSR 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. 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.

Standard components of an ICH-compliant CSR include:

1. Title Page
2. Synopsis
3. Table of Contents (TOC)
4. List of Abbreviations
5. Ethics
6. Study Administrative Structure
7. Introduction
8. Study Objectives
9. Investigational Plan
10. Study Participants
11. Results (Efficacy and/or Pharmacokinetics/Pharmacodynamics)
12. Results (Safety)
13. Discussion & Overall Conclusions
14. End of Text Tables and Figures
15. References
16. Appendices

DISSEMINATION

After each clinical trial, 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 publish 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 Database (EudraCT,) of the European Medical Agency collects information on all clinical trials of medicines performed in Europe. As of July 2014, this database also makes trial summary results available to the public. 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.