Clinical investigations are crucial in the process of bringing a medical device to market. Although they are often seen as challenging and complex, having a solid understanding of the relevant standards can simplify the experience. Familiarity with ISO 14155:2020 is vital, as it serves as a guide for Good Clinical Practice (GCP) in clinical investigations involving human subjects.

What is ISO 14155?

ISO 14155:2020 provides specifications and requirements for the clinical investigation of medical devices. Published in 2020, this standard serves as a guide for clinical research professionals involved in the design, execution, documentation, and reporting of clinical trials focused on assessing the safety and efficacy of medical devices.

The main objectives of ISO 14155 are to:

– Safeguard the rights, safety, and welfare of human subjects.

– Ensure that clinical investigations are conducted scientifically, maintaining the integrity of results.

– Clarify the roles and responsibilities of sponsors and principal investigators.

– Support sponsors, investigators, ethics committees, regulatory bodies, and other entities engaged in the conformity assessment of medical devices.

The 2020 version of ISO 14155 includes various updates from prior editions. In the United States, the FDA acknowledges clinical trials conducted in accordance with ISO 14155, even if the clinical data is collected internationally, provided it adheres to the standard.

What updates are present in the 2020 edition of ISO 14155?

The ISO 14155:2020 version introduces significant changes compared to the ISO 14155:2011 edition. The 2020 revision places a greater emphasis on incorporating risk management principles throughout the entire clinical investigation process for medical devices. Annex H of ISO 14155 establishes a clear connection between ISO 14971 and the clinical investigation process, featuring a useful graphic for integrating ISO 14971 into the management of potential safety issues during medical device trials.

Several other key updates are included in the 2020 standard, such as:

– A concise overview of Good Clinical Practice (GCP) principles in Section 4

– A mandate for the registration of all medical device clinical investigations in publicly accessible databases like EUDAMED

– The incorporation of clinical quality management in Section 9.1

– The addition of statistical considerations in Annex A

– Enhanced guidance for ethics committees in Annex G

– Requirements for risk-based monitoring in Section 6.7

– Guidance regarding clinical investigation audits in Annex J

– Guidance on how to apply ISO 14155 during both pre-market and post-market stages in Annex I

How can ISO 14155 be applied in post-market clinical activities?

Clinical investigations come in various forms, and the terminology can often lead to confusion. Additionally, these activities can take place at any point in the product lifecycle, ranging from pre-market to post-market phases. The previous version of the standard did not clearly articulate how it applied to different types of clinical investigations at these various stages. In ISO 14155:2020, the standard writers have made an effort to address this ambiguity by introducing Annex I. This annex provides clarity on the different kinds of clinical investigations as they relate to regulatory status, the stage of clinical development, study design, and the burden placed on subjects.

Which sections of ISO 14155 are applicable to your clinical study?

Annex I offers important insights regarding the various types of medical device clinical studies and includes a section (I.7) that discusses how the principles in the document relate to different types of clinical investigations. The standard indicates that “Depending on the clinical development stage and the type of clinical investigation design, the principles of this document can be applied in full or in part.” For example, for a pre-market confirmatory (interventional) clinical investigation, “all principles in this document apply.” In contrast, if you are conducting a post-market observational investigation—which is non-interventional—you may not be required to follow every requirement outlined in the standard. It is essential to remember that if you think you can omit any part of this standard for your medical device clinical investigation, you must provide a rationale for that decision in your clinical investigation plan (CIP).

What is Good Clinical Practice (GCP)?

Good Clinical Practice (GCP) encompasses a collection of ethical and scientific quality standards. It is utilized in the design, execution, documentation, and reporting of medical device trials involving human participants. GCP is recognized internationally, ensuring the protection of the rights, safety, and well-being of participants while also guaranteeing the credibility of clinical data. ISO 14155 summarizes GCP principles in Section 4 of the standard, which outlines essential guidelines for research involving human subjects, forming the foundation of any valid clinical study.

There are 14 guiding principles of Good Clinical Practice, which include:

1. Clinical trials must adhere to ethical principles, robust scientific evidence, and well-defined protocols.

2. The potential benefits of conducting trials should outweigh any associated risks.

3. The rights, safety, and well-being of participants are of utmost importance; this is upheld through informed consent and confidentiality.

4. Care should be provided by qualified personnel with appropriate experience.

5. Records must be readily accessible and retrievable for accurate reporting, verification, and interpretation.

6. Investigational products must be manufactured following Good Manufacturing Practices.

Familiarizing yourself with all the principles outlined in Section 4 of the standard is crucial for planning and executing a compliant clinical study for medical devices. Notably, in the Ethical Considerations section (Section 5), it is stated that Good Clinical Practices “shall be understood, observed, and applied at every step in the clinical investigation.”

Section 5 also covers several significant ethical considerations, such as:

– Prohibitions against improper influence or inducement of participants.

– Guidelines for communication with the ethics committee (EC), including requirements for initial submissions and ongoing communication throughout the clinical investigation.

– Detailed requirements for obtaining informed consent and the necessary information to provide to participants. This section is particularly important, as ensuring proper informed consent is vital for conducting an ethical clinical study in line with GCP.

According to the ISO standard, the Good Clinical Practices for ‘Responsibilities’ are divided into two sections: Responsibilities of the Sponsor (Clause 8) and Responsibilities of the Principal Investigator (Clause 9). The sponsor, which in this context refers to the manufacturer of the device, is tasked with planning and executing the clinical investigation in accordance with established quality assurance and quality control standards. It’s crucial to understand that even if the sponsor delegates the clinical investigation to a qualified third party, the sponsor still holds ultimate responsibility.

On the other hand, the Principal Investigator is responsible for:

– Implementing and overseeing the daily operations of the investigation according to the Clinical Investigation Plan (CIP),

– Ensuring the integrity of the data collected during the investigation,

– Protecting the rights, safety, and well-being of the human subjects participating in the study.

How to plan a clinical investigation following ISO 14155:2020

When planning your clinical investigation, it’s essential to recognize that a standard like ISO 14155 doesn’t provide a step-by-step guide. Instead, it outlines critical components and considerations that must be addressed in your planning process. While it’s important to review the standard and verify each requirement, as well as to develop the necessary documentation, this is not the end of your efforts. Regulatory authorities will seek explanations for your decisions. They will want insights into how you structured your study, the rationale behind your sample size, and the origins of specific numerical choices.

For more details on how to justify your study design, refer to Section 6.3 (Justification for the design of the clinical investigation). Keep this in mind as you draft the various planning documents, which include:

Clinical Investigation Plan (CIP): The CIP serves as the primary document for all individuals involved in the clinical study. It outlines the objectives and design of the study, providing justifications for its structure and a benefit-risk analysis. A list of what to include in your CIP can be found in Annex A of the standard.

Investigator’s Brochure (IB): The IB aims to equip the principal investigator with enough data to support the clinical investigation proposed in the CIP. It should summarize all preclinical testing performed on the investigational device along with any available clinical data. A full outline of the IB’s contents can be located in Annex B of ISO 14155:2020.

Case Report Forms (CRFs): CRFs serve a dual purpose. First, they collect information about each participant’s condition at the start of the study. Second, they gather data on each participant as stipulated by the CIP. The details of what should be included in a CRF can be found in Annex C of the standard.

Although the description of CRFs may seem straightforward, they are a crucial tool for collecting clinical data throughout the study. Relying on paper or general software for CRFs increases the risk of data omissions or entry errors, which can considerably delay your study.

How to conduct a clinical investigation in compliance with ISO 14155:2020

Your clinical investigation can only begin once you have received “written approval/favorable opinion” from both the ethics committee and the appropriate regulatory authority in the countries where the investigation will be conducted. You can find the requirements for conducting a clinical investigation that adheres to ISO 14155 in Section 7 of the standard. There are a few key points in this section that I want to emphasize.

Notably, a significant portion of Section 7 is dedicated to adverse events and device deficiencies. It is crucial to properly document and report any adverse events or device deficiencies related to medical devices. A table for categorizing adverse events can be found in Annex F of the ISO standard.

Risk management in clinical investigations

The ISO standard addresses risk management in Section 7, particularly focusing on risk assessment for potentially unacceptable risks in subsection 7.4.4, which examines risks that may arise during clinical investigations. This isn’t the only section that discusses risk management; Section 6.2 also outlines additional requirements for clinical investigations. This section highlights that risk management activities “shall be performed throughout the clinical investigation” and emphasizes the need to apply risk management principles during both the planning and execution phases of the study.

The focus on utilizing ISO 14971 and integrating risk management principles into all aspects of the clinical investigation reflects a broader industry movement towards embedding risk management throughout the entire medical device lifecycle. This approach may even involve documenting risk management activities for clinical investigations within your Quality Management System (QMS). Furthermore, risk management practices during a Post-Market Clinical Follow-Up investigation can significantly impact the device and should be documented and monitored within the QMS.

Electronic data capture and ISO 14155:2020 compliance

It’s essential to closely examine Section 7.8, which pertains to Document and Data Control, particularly subsection 7.8.3 which discusses electronic clinical data systems. If you are utilizing an electronic data capture (EDC) system for clinical data collection in your study, be aware that ISO 14155 mandates the validation of any electronic system to assess the authenticity, accuracy, reliability, and consistent performance of the data system.

The standard stipulates that 12 written procedures must be followed when using an EDC system. These procedures include the following requirements:

– Verify and validate that the EDC system consistently meets the necessary requirements

– Ensure the data entered is attributable, complete, reliable, consistent, and logical

– Document any changes made to the data and maintain an audit trail

– Establish a security system to prevent unauthorized access to the data, both from internal and external sources.

Managing risks during a clinical investigation

Section 7 of the ISO standard also touches on risk management—specifically, the risk assessment process for potentially unacceptable risks in 7.4.4. This subsection looks at risks that can occur during the clinical investigation.

Section 7 isn’t the only place that risk management is mentioned in the standard, however. Section 6.2 provides more risk management requirements for clinical investigations. Here, the standard states that risk management activities “shall be performed throughout the clinical investigation”. And that risk management principles must be applied during both the planning and the conduct of the investigation.

The emphasis here on using ISO 14971 and applying risk management principles throughout the clinical investigation is part of a larger, industry-wide move toward integrating risk management into every part of the medical device lifecycle. Taking this kind of holistic approach to risk means you may even want to document risk management for clinical investigations within your quality management system. Risk management activities during a Post-Market Clinical Follow-Up investigation may have important implications for the device. These should be documented and tracked in the Quality Management System.

Electronic data capture and compliance with ISO 14155:2020

You’ll also want to pay close attention to Section 7.8 (Document and data control). In particular, Section 7.8.3, covers electronic clinical data systems. If you’re using an electronic data capture (EDC) system for clinical data collection during your study, you should know that ISO 14155 requires any electronic system to be validated “to evaluate the authenticity, accuracy, reliability, and consistent intended performance of the data system.”

The standard requires 12 written procedures to be followed and implemented when using any EDC system. These include requirements to:

Verify and validate that the requirements for the electronic clinical data system can be consistently met
Ensure attributability, completeness, reliability, consistency, and logic of the data entered
Ensure that data changes are documented and an audit trail is maintained
Maintain a security system to prevent unauthorized use of data, both internally and externally