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Breaking Down ISO 14155: Best Practices for Clinical Investigations of Medical Devices

ISO 14155 is a critical standard for anyone involved in the design, conduct, monitoring, recording, auditing, analysis, and reporting of clinical investigations carried out in human subjects to assess the safety or performance of medical devices. This article provides a comprehensive breakdown of ISO 14155, highlighting best practices and key considerations for ensuring that clinical investigations are conducted in accordance with both ethical principles and regulatory requirements. Understanding and implementing the guidelines of ISO 14155 is essential for medical device manufacturers and researchers to ensure patient safety, data integrity, and regulatory compliance.

Key Takeaways

  • ISO 14155 establishes a framework for clinical investigations ensuring the protection of human subjects and the credibility of clinical data.

  • Ethical considerations, including informed consent and ethics committee review, are paramount in clinical investigations of medical devices.

  • Careful planning and robust study design, including endpoint selection and statistical analysis, are crucial for the success of a clinical investigation.

  • Effective conduct of the clinical investigation requires meticulous participant recruitment, data management, and adherence to quality assurance protocols.

  • Post-study activities such as data analysis, reporting, and post-market surveillance are vital for the ongoing evaluation of medical device safety and performance.

Understanding the Scope and Purpose of ISO 14155

Defining the Standard's Reach

ISO 14155 is a global standard that delineates the requirements for the design, conduct, recording, and reporting of clinical investigations carried out in human subjects to assess the safety or performance of medical devices. The standard's reach extends to all phases of clinical research, from the initial conception of the study to the post-market surveillance after the product's release.

Clinical investigations under ISO 14155 encompass a wide range of study types, including but not limited to pilot studies, post-market clinical follow-ups, and randomized controlled trials. The standard is applicable regardless of the medical device's classification or the nature of the clinical investigation.

The following list outlines the key areas covered by ISO 14155:

  • Ethical considerations

  • Study planning

  • Study conduct

  • Data management

  • Statistical analysis

  • Final reporting

By setting a benchmark for clinical trials involving medical devices, ISO 14155 helps harmonize regulatory requirements across different jurisdictions, facilitating international collaboration and data sharing.

Objectives for Clinical Investigations

The primary objective of clinical investigations in the context of ISO 14155 is to assess the safety, performance, and effectiveness of medical devices. These investigations provide critical data that support regulatory submissions and inform clinical practice. Ensuring the reliability of data and protecting the rights and well-being of trial participants are paramount.

Clinical investigations aim to answer specific research questions related to a medical device's use. For instance, they might evaluate how a new heart assist device compares to existing treatments or measure the impact of an innovative surgical robot on procedure times and patient recovery. The objectives are often multi-faceted, encompassing both clinical and technical aspects of device performance.

To illustrate the diverse objectives of clinical investigations, consider the following points:

  • Determining the clinical benefits and risks of a medical device

  • Establishing the technical performance specifications

  • Comparing the device to current standard of care

  • Assessing long-term safety and effectiveness

Aligning with Regulatory Requirements

Ensuring that clinical investigations of medical devices are in alignment with regulatory requirements is a critical aspect of ISO 14155. Regulatory compliance is not only about adhering to the standards but also about understanding the nuances of regional and international regulations. The ISO 14155 standard provides a framework that can be adapted to meet the specific requirements of different regulatory bodies, such as the FDA in the United States, EMA in Europe, and PMDA in Japan.

To effectively align with these requirements, it is essential to identify the key regulatory milestones and documentation needed for a successful clinical investigation. Below is a list of common regulatory elements that should be considered:

  • Submission of an investigational device exemption (IDE) or equivalent

  • Approval from competent authorities and ethics committees

  • Adherence to Good Clinical Practice (GCP) guidelines

  • Regular reporting of study progress and adverse events

By integrating regulatory considerations into the planning and execution phases of a clinical investigation, researchers can ensure that the study outcomes will be recognized and accepted by regulatory authorities, facilitating the path to market approval for the medical device.

Ethical Considerations and Participant Safety

Informed Consent in Clinical Trials

Informed consent is a cornerstone of ethical clinical research. Participants must be fully informed about the study's purpose, procedures, risks, benefits, and their rights before agreeing to take part. This process ensures respect for individual autonomy and decision-making.

Informed consent is not a one-time event but an ongoing conversation between the researcher and the participant. It is crucial to document this process meticulously, as it serves as evidence that participants have been adequately informed and have agreed to the study terms voluntarily.

  • Ensure the consent form is clear and understandable.

  • Provide ample time for participants to consider their decision.

  • Revisit consent throughout the study to address any new information or changes.

By adhering to these practices, investigators can avoid common problems associated with informed consent and uphold the integrity of the clinical investigation.

Risk Management and Adverse Event Reporting

Effective risk management and thorough adverse event reporting are critical components of clinical investigations. Adverse device effects must be meticulously documented to ensure the safety of participants and the integrity of the study results.

Adverse events related to the use of an investigational medical device, or a comparator if it is also a medical device, should be classified and reported according to their severity and causality. This process is essential for identifying potential risks and implementing appropriate measures to mitigate them.

The following table outlines the categories for reporting adverse events:

Each reported event must be evaluated to determine if it warrants a corrective action or if it is an expected outcome of the clinical investigation. Continuous monitoring and periodic review of adverse events are necessary to ensure ongoing risk management throughout the study.

Ethics Committee Review and Approval

Once a clinical investigation plan is in place, obtaining Ethics Committee review and approval is a critical step. This committee, often comprising medical professionals, ethicists, and laypersons, ensures that the study adheres to ethical standards and protects participant rights and safety. The review process includes a thorough evaluation of the study protocol, informed consent forms, and the methods for data collection and management.

Ethics Committees play a pivotal role in maintaining the integrity of the clinical investigation. They are responsible for the ongoing review of the study, which may include amendments to the protocol and monitoring of adverse events. Their approval is not just a one-time checkpoint but a continuous oversight throughout the study duration.

The following list outlines the typical responsibilities of an Ethics Committee:

  • Review and approve the study protocol

  • Assess the risk/benefit ratio for participants

  • Ensure the adequacy of informed consent

  • Monitor the study for compliance with ethical standards

  • Approve any modifications to the study

It is essential for investigators to engage with the Ethics Committee proactively and respond promptly to any queries or concerns raised. This collaboration fosters a culture of ethical vigilance and participant safety in clinical investigations.

Planning and Designing a Clinical Investigation

Developing a Robust Study Protocol

The foundation of any clinical investigation is a robust study protocol. A well-structured protocol ensures that the study's objectives are met and that the data collected are reliable and valid. It outlines the methodology, including the inclusion and exclusion criteria for participants, the interventions to be used, and the methods for data collection and analysis.

Key elements of a study protocol include:

  • Objectives and hypotheses

  • Study design

  • Selection and withdrawal of participants

  • Treatment of subjects

  • Methods of assessment

  • Adverse event reporting

  • Data management and record keeping

  • Statistical methods

The protocol should be developed in collaboration with experts in clinical research, statisticians, and other stakeholders. This ensures that the study design is scientifically sound and that the study can be conducted efficiently. The protocol must also be flexible enough to allow for modifications in response to unforeseen circumstances without undermining the study's scientific rigor.

Selecting Appropriate Study Endpoints

The selection of study endpoints is a critical step in the design of a clinical investigation. Endpoints must be clinically meaningful and directly related to the research question. They should reflect the objectives of the study and be sensitive enough to detect the expected effects of the medical device.

Endpoints can be classified into primary and secondary categories. The primary endpoint is the main result that will determine the effect of the intervention. Secondary endpoints provide additional information about the intervention's effects. Here's a simple categorization:

  • Primary Endpoint: The main outcome measure, often related to efficacy or safety.

  • Secondary Endpoints: Additional outcomes that provide supportive information.

Statistical considerations must also be taken into account when selecting endpoints, as they will influence the study's sample size and the power to detect a difference or change. The endpoints should align with the study's objectives and be capable of providing clear, actionable results.

Statistical Considerations for Trial Design

The design of a clinical trial is critically dependent on the statistical considerations that underpin the validity of its results. Proper sample size calculation is essential to ensure that the study has enough power to detect a clinically significant effect if one exists. This involves understanding the expected variability in the data and the magnitude of the effect being measured.

Randomization is another key statistical tool used to minimize bias and confounding factors. It ensures that each participant has an equal chance of being assigned to any of the intervention groups. Blinding is often used in conjunction with randomization to further reduce bias.

Here is an example of how statistical considerations might be structured in a clinical trial design:

  • Define primary and secondary endpoints

  • Determine the level of significance (alpha)

  • Calculate the required sample size

  • Choose appropriate statistical tests

  • Plan interim analyses and stopping rules

It's important to involve a biostatistician early in the planning process to address these and other statistical challenges.

Conducting the Clinical Investigation

Recruitment and Selection of Study Participants

The recruitment and selection of study participants are critical steps in ensuring the validity and reliability of a clinical investigation. Proper participant selection is not only a matter of meeting the study's inclusion criteria but also of ensuring a representative sample of the population for which the medical device is intended.

Recruitment strategies should be designed to attract a diverse pool of candidates, while also considering the ethical implications of the recruitment process. It is essential to avoid any form of coercion or undue influence that could compromise voluntary participation.

  • Ensure clear communication of study details

  • Obtain informed consent from all participants

  • Screen candidates against inclusion and exclusion criteria

  • Maintain a balance in participant demographics

Data Collection and Management

Effective data collection and management are critical to the success of clinical investigations. Accurate and systematic recording of data ensures the integrity of the research and the reliability of the results. To achieve this, investigators must use standardized data collection forms and electronic data capture systems that comply with regulatory standards.

  • Develop standardized case report forms (CRFs)

  • Utilize electronic data capture (EDC) systems

  • Ensure data is collected in real-time

  • Maintain data confidentiality and security

The use of advanced technology, akin to the facilities provided by SOMA Design Lab in San Francisco, can greatly enhance the efficiency and accuracy of data management in clinical trials. Leveraging such technology can lead to more innovative and effective approaches to handling complex clinical data.

Monitoring and Quality Assurance

Effective monitoring and quality assurance are critical to the success of clinical investigations. These processes ensure that the study is conducted, recorded, and reported in compliance with the protocol, ISO 14155, and applicable regulatory requirements.

Monitoring activities are designed to safeguard the rights and well-being of study participants and to verify the accuracy of the data collected. Regular audits and checks are part of a robust quality assurance system, which also includes training for study personnel and the establishment of standard operating procedures (SOPs).

The following table summarizes key aspects of monitoring and quality assurance:

Post-Study Activities and Reporting

Analysis and Interpretation of Data

The analysis and interpretation of data in clinical investigations are critical for drawing meaningful conclusions about the safety and efficacy of medical devices. Statistical analysis should be performed according to the pre-defined plan outlined in the study protocol. This ensures that the results are reliable and can be attributed to the effects of the device rather than chance.

Key findings should be summarized in a way that is both comprehensive and accessible to stakeholders. For instance, primary and secondary endpoints can be presented in a table to highlight the most significant outcomes:

Data integrity is paramount, and any deviations from the protocol must be documented and justified. The interpretation of the results should consider the context of the study, including the population, the disease being treated, and the clinical setting.

Finally, the conclusions drawn from the data should guide future research and development, as well as inform any necessary changes to the product or its intended use.

Preparing Clinical Study Reports

The culmination of a clinical investigation is the preparation of a comprehensive clinical study report. This document synthesizes all the data and findings from the investigation, providing a clear and detailed account of the study's conduct and outcomes. The clinical study report is a critical component in the process of obtaining regulatory approval for a medical device.

When preparing the clinical study report, it is essential to adhere to the guidelines set forth by ISO 14155. This ensures that the report meets the necessary standards for a Notified Body review, which is a crucial step beyond the Medical Device Regulation (MDR). A well-prepared report should include, but is not limited to, the following sections:

  • Executive Summary

  • Study Objectives and Endpoints

  • Methodology

  • Results

  • Discussion and Conclusions

  • References to standards and guidance documents

The references section should include a detailed list of every standard, technical report, or Medical Device Coordination Group (MDCG) guidance document that the study adheres to. This demonstrates compliance with the relevant regulatory framework and supports the credibility of the study.

Post-Market Surveillance and Follow-Up

Following the completion of a clinical investigation, post-market surveillance (PMS) becomes a pivotal aspect of ongoing device assessment. ISO 14155 outlines the principles for PMS to ensure that any long-term risks or unforeseen issues are identified and managed effectively. This phase is crucial for maintaining the safety and efficacy of medical devices throughout their lifecycle.

A structured approach to PMS may include several components, such as periodic safety update reports (PSURs), post-market clinical follow-up (PMCF) surveys, and feedback mechanisms from healthcare professionals and patients. Below is a list of key elements typically involved in PMS:

  • Regular monitoring of device performance

  • Analysis of adverse events and device deficiencies

  • Updates to clinical evaluation reports

  • Engagement with regulatory authorities

The ultimate goal of PMS is to ensure that any potential safety concerns are swiftly addressed and that the device continues to meet its intended purpose effectively.


In summary, ISO 14155 establishes a robust framework for conducting clinical investigations of medical devices, ensuring the protection of human subjects and the credibility of collected data. Adhering to these standards is not only a regulatory requirement but also a best practice that facilitates market approval and fosters trust with stakeholders. As we have explored throughout this article, from planning and design to execution and post-study activities, each aspect of ISO 14155 is critical for the success of clinical trials. Manufacturers and researchers are encouraged to stay informed and compliant with these guidelines to enhance the quality and safety of medical devices. The deep dive into the 75 most important standards for medical device development, as referenced in the provided link, further underscores the importance of comprehensive knowledge in this field. Ultimately, the diligent application of ISO 14155 can lead to innovative medical solutions that improve patient outcomes and advance healthcare globally.

Frequently Asked Questions

What is the main purpose of ISO 14155?

ISO 14155 provides guidelines for the design, conduct, recording, and reporting of clinical investigations carried out in human subjects to assess the safety, performance, and effectiveness of medical devices.

How does ISO 14155 align with regulatory requirements?

ISO 14155 is internationally recognized and designed to harmonize with regulatory requirements for medical devices in various jurisdictions, helping manufacturers comply with laws and regulations for market approvals.

Why is informed consent important in clinical trials for medical devices?

Informed consent ensures that participants are fully aware of the risks, benefits, and procedures involved in the clinical trial, and that they voluntarily agree to participate, protecting their rights and well-being.

What are the key elements of a robust study protocol according to ISO 14155?

A robust study protocol should include clear objectives, methodology, criteria for participant selection, safety and efficacy assessments, statistical considerations, and compliance with ethical standards.

What is the role of an ethics committee in clinical investigations of medical devices?

An ethics committee reviews and approves the clinical investigation plan, ensuring that the study is ethical, that participants' rights are protected, and that the benefits outweigh the risks.

What is expected in post-market surveillance according to ISO 14155?

Post-market surveillance involves ongoing monitoring of a medical device after it has been marketed to detect any long-term adverse events or changes in performance, ensuring continued safety and effectiveness.


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