ECRIN - European Clinical Research Infrastructure Network

RARE DISEASES CLINICAL TRIALS TOOLBOX (END OF THE TRIAL)

Toolkit Outline

 

Define a question Risk Assessment Trial Management Statistical analysis plan Archiving
Develop a protocol Data Management Plan Regulatory submission   Trial report
Identify a Sponsor Trial Management Plan Quality management   Dissemination
Identify a Funder   Safety reporting    
    Data Management    
    Investigational Products    
    Laboratory processes    

 

 

 

 

 

 

 

 

 

 

 

End of the trial

Each subsection below includes two parts. The subsection opens with an explanation of the subject and guidance on how to address it. This is followed by a list of tools that have been identified in relation to this subsection. The tools listed may not be unique to clinical trials in rare diseases, this is specified in the table to better understand the use of the tool. You can visit the different section by clicking on the buttons above or return to the full toolkit here.

 

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.

 

Tool Name Relevance Year RD/ Paediatric specific Type
Guideline on the content, management and archiving of
the clinical trial master file (paper and/or electronic)
The EMA guideline on the content, management and archiving of the TMF provides  guidance relating to the media used for storage of documents (including requirements when original records are transferred to electronic media for the purpose of archive). 2018 No Guideline

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

 

Tool Name Relevance Year RD/ Paediatric specific Type
ICH E3 guideline on Structure and Content of Clinical Study Reports (ICH E3) The objective of this guideline is to allow the compilation of a single core clinical study report (CSR) acceptable to all regulatory authorities of the ICH regions 1995 No Guideline
CONSORT statement CONSORT Statement is an evidence-based, minimum set of recommendations for reporting randomized trials. It offers a standard way for authors to prepare reports of trial findings 2010 No Checklist
CONSORT statement on N-of-1 trials
 (extension of the CONSORT Statement)
A CONSORT extension for N-of-1 trials that provides guidance on the reporting of individual and series of N-of-1 trials 2015 Yes Checklist

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.

 

Tool Name Relevance Year RD/ Paediatric specific Type
EUPATI tutorial: Reporting and recording clinical trial results EUPATI tutorial about recording and reporting clinical trial results Regular updates No Training
EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) European Clinical Trial CT Database. Since 2014, it is the responsibility of sponsors to ensure that the protocol information and results of all clinical trials is submitted in EudraCT; this information is publicly available through the EU Clinical Trials Register (EU CTR). Regular updates No Registry
Technical guideline on the format of the data fields of results-related information on clinical trials Technical guideline on the format of the data fields of results-related information on clinical trials to publish on the EU Clinical Trials Register 2013 No Guideline
Tutorials on posting results on EudraCT Tutorials on posting results on the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) Regular updates No Training
Summaries of clinical trial results for laypersons Guideline provides sponsors and investigators with guidelines and templates for the production of summaries of clinical trial results for laypersons Regular updates No Guideline