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International Clinical Trials

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Clinical investigation reports for medical devices are essential for achieving CE approval. What information should be included in order to demonstrate clinical compliance with European standards? When bringing a medical device to market in Europe, or after modifying the function of a device already CE-approved, it is essential to meet the requirements of either the EC Medical Device Directive (93/42/EEC) or the Active Implantable Medical Devices Directive (90/385/EEC) (1,2). This includes submission and acceptance of a clinical investigation report demonstrating clinical compliance with this Directive (see Figure 1). The structure of this report is shown in Figure 2 (3,4). This report is important, especially for Class IIb and III medical devices, because it rates safety and performance.

On 1st February 2011 the International Organization for Standardization published the second edition of international standard ISO 14155, clinical investigation of medical devices for human subjects – good clinical practice (5). This highly readable 58-page document addresses “good clinical practice for the design, conduct, recording and reporting of clinical investigations carried out in human subjects to assess the safety or performance of medical devices for regulatory purposes.” It provides guidance for the content of the clinical investigation report.

According to ISO 14155, the need to conduct a clinical investigation is determined by the applicable national regulations (5). This medical study should evaluate whether the device is suitable for the purpose and the population(s) for which it is intended. The investigation should be designed to ensure that the results obtained have clinical relevance and scientific validity. At the end of a clinical investigation, a clinical study report should be completed, even if the investigation was terminated prematurely. This report describes the design, execution, statistical analysis and results of the investigation.

Opening Pages

The clinical investigation report should begin with a cover page that states the title of the investigation and clearly identifies the investigational device, including name and model number. If not clear from the title, a single sentence describing the design of the investigation, any comparisons with other devices, the time period of the investigation, the method of using the device, and the subject population should be included. It should also provide the name and contact details of the sponsor(s) or sponsor representative(s), the clinical investigation plan (CIP), the name and department of the coordinating investigator, and names of other relevant parties, such as experts, biostatisticians and laboratory personnel. Further, the cover page should indicate whether the clinical investigation was performed in accordance with ISO 14155 and any other applicable guidelines and regulations. It must also contain the date and the authors of the final report (5). An example cover page is shown in Figure 3 (page 58).

The report should include a table of contents that lists the page number of each section, including summary tables, figures, graphs and appendices. This should be followed by a summary enumerating the title of the investigation, a short introduction, the purpose of the investigation, a description of the subject population, the investigative method used, the results of the investigation, the conclusion, and the dates of the investigation initiation and completion or, if the investigation is discontinued, the date of premature termination (5).

The introduction should contain a statement placing the investigation in the context of the development of the device and relating the critical features of the investigation (for example, objectives and hypotheses, target population, treatment and follow-up duration) to that development. Any guidelines that were followed in the development of the CIP, or any other relevant agreements or meetings between the sponsor and regulatory authorities, should also be identified or described (5).

 

Investigational Device and Methods Section

  • This should be followed by an investigational device and methods section, in two parts: the investigational device description and a summary of the clinical investigation plan (CIP) (5). The device description includes its intended use; previous intended uses or indications for use, if relevant; any changes to the device during the investigation or any changes from the investigator’s brochure including raw materials, software, components, shelf-life, storage conditions, instructions for use, and any other changes. The CIP summary includes any subsequent amendment(s) with a rationale for each amendment. It should briefly describe:
  • The clinical investigation objectives
  • Its design, including the investigation type and endpoints
  • The ethical considerations
  • The data quality assurance
  • The subject population, with the inclusion and exclusion criteria, and sample size
  • The treatment and treatment allocation schedule
  • Any concomitant medications or treatments
  • The duration of follow-up
  • The statistical analysis, including the investigation hypothesis or pass/fail criteria, a sample size calculation, and the statistical analysis methods used

Results Section

The results section should include the clinical investigation initiation date, and the completion or suspension date, and should discuss the disposal of subjects and investigational devices, subject demographics, and CIP compliance. It ought to present data analysis, including the performance analysis provided for in the CIP. A summary of all adverse events and adverse device effects should be given, including a discussion of the severity, treatment needed, resolution, and relevant principal investigator’s judgment concerning the causal relationship with the investigational device or procedure. A table compiling all observed device defi ciencies that could have led to a serious adverse device effect, and any corrective actions taken during the clinical investigation should be included. Any needed subgroup analyses for special populations (that is, gender, racial, cultural or ethnic subgroups), as appropriate, should also be described. An accountability of all subjects with a description of how missing data or deviation(s) were dealt with in the analysis, including subjects not passing screening tests, being lost to follow-up, or having withdrawn or discontinued for the clinical investigation and the reason for this is also given (5). Publication of both positive and negative results of the clinical investigation is encouraged to help guide future research, device development and medical treatment.

Discussion and Overall Conclusion Section

In the discussion, conclusions including the safety or performance results and any other endpoints, an assessment of risks and benefits, and the clinical relevance and importance of the results in light of other existing data should be presented (5). Further, any specific benefits or special precautions required for individual subjects or groups at risk, any implications for the conduct of future clinical investigations, and any limitations of the investigation ought to be discussed.

 

Closing Pages

Any abbreviated terms and defi nitions of specialised or unusual terms should be enumerated in a separate section of the report. Next, the ethics report should include a confi rmation that the CIP and any amendments to it were reviewed by the ethics committee (if required), and a list of all the ethics committees consulted.

Then, the overview of the administrative structure of the clinical investigation should include a brief description of the organisation of the investigation and a list of investigators, including their affi liations (5). Also, the names and addresses of any third parties (such as core laboratories, CROs, consultants or other contractors) that contributed to the investigation, and the names and addresses of the sponsor(s) or sponsor representative(s) should be given.

Before finalising the report, it should be made available to the coordinating investigator and all principal investigators for review and comments (5). The sponsor should maintain reports confirming that the report has been provided for review. If a reviewer does not agree with all or part of the report, their comments should be recorded and communicated to the other principal investigators. On the signature page, the signatures of the sponsor and coordinating investigator(s), indicating their agreement with the contents of the report, should be provided. If no coordinating investigator has been appointed, then the signature of the principal investigator(s) should be obtained. The signature pages may be separate from the clinical investigation report itself.

There may be appendices to the report which contain the following: the CIP including amendments; the instructions for use of the device; and the list of principal investigators and their affiliated investigation sites, including a summary of their qualifications or a copy of their CVs. Also, the list of names and addresses of any third parties (such as core laboratories, CROs, consultants or other contractors) that contributed to the clinical investigation; the list of clinical monitors; and the list of ethics committees could be provided. All relevant data sets including CIP deviations that could have affected the rights, safety or well-being of the subjects or the scientific integrity of the clinical investigation, all adverse events, adverse device effects and device deficiencies, and any withdrawals and discontinuations, must be provided, as well as the audit certificate, if applicable. During data merging, while the entire data set from all investigation centres and from all subjects should be listed, the anonymity of individual subjects must be maintained (5).

Conclusion

Frequent omissions in clinical investigation reports include the date, signatures, literature citations within the report, name of the device, and qualifications of the author(s). A risk-benefit assessment, the discussion necessary to reach the stated conclusion(s), and/or a discussion of negative outcomes (for example, those that originate from pre-clinical studies), are also often lacking. These omissions slow the evaluation and potential acceptance of the report. The authorities also value reading that: the investigation was conducted in accordance with ISO 14155, the design was appropriate, the results have relevant clinical meaning and are statistically signifi cant, all relevant functional and safety aspects were recorded and evaluated accordingly, the results of the investigation relate to the relevant literature, and that the identifi cation of the medical device is the same as indicated in the clinical results. A complete report will speed the CE approval process, and get the device on its way to market.

References:

  1. European Commission: Medical Device Directive 93/42 EEC, pp1-160, 2007
  2. European Commission: Active Implantable Medical Devices Directive (AIMD) 90/385 EEC, pp1-35, 2007
  3. Study Group 1 of the Global Harmonization Task Force: Summary Technical Documentation for Demonstrating Conformity to the Essential Principles of Safety and Performance of Medical Devices (STED), 2008
  4. Co-ordination of Notifi ed Bodies Medical Devices (NB-MED) on Council Directives 90/385/EEC, 9A9, Technical Documentation, 2.5.1 Conformity assessment procedures, 2000
  5. International Organization for Standardization: ISO 14155, 2nd Edition: Clinical investigation of medical devices for human subjects – Good clinical practice, 2011

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Karen Lunde is a Research Associate at CERES, Clinical Evaluation & Research, where she writes articles and clinical evaluations for medical devices. She holds a BSc in Biomedical Engineering and a BA in Biochemistry from the University of Iowa, and has a PhD in Biology from the University of California at San Diego. She moved to Germany in 1999, and worked as a postdoc in Developmental Biology at the University of Freiburg for over six years.

Stephan Joeken is the founder and CEO of CERES, Clinical Evaluation & Research. He works with a network of physicians in the areas of electrophysiology, cardiology, cardiovascular surgery, and neurology in both European and non-European countries, to conduct clinical trials on medical devices for the European market. Prior to founding CERES in 2005, Stephan headed research and development departments in the medical device industry. He holds a PhD in Neurophysics.

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