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Jón Bergsteinsson

FDA Compliance

The Ultimate Guide to ISO 14155:2020 for Medical Devices

Understanding the standard is essential

Published: Tuesday, November 21, 2023 - 12:02

Clinical investigations play an important role in your journey of bringing a medical device to market. While the relevant standards are often perceived as difficult and complex, having a good grasp of them makes the process less confusing.

Understanding ISO 14155:2020 is essential. It’s a guide to good clinical practice for clinical investigations of medical devices for human subjects.

This ultimate guide provides an overview of both the standard and good clinical practices (GCP). It further explains important aspects of planning and conducting clinical investigations as per ISO 14155:2020.

(Note: “Clinical investigation,” “clinical trial,” and “clinical study” are all synonymous, and I’ll be using them interchangeably.)

What is ISO 14155?

ISO 14155:2020 provides the general specifications and requirements for clinical investigations of medical devices. The latest version of the standard was published in 2020 and is intended to serve as a guide for clinical research professionals during the design, conduct, recording, and reporting of clinical trials related to the safety and effectiveness of medical devices.

The purpose of ISO 14155 is to:
• Protect the rights, safety, and well-being of human subjects
• Ensure scientific conduct of the clinical investigation and credibility of the clinical investigation results
• Define the responsibilities of the sponsor and the principal investigator
• Assist sponsors, investigators, ethics committees, regulatory authorities, and other bodies involved in the conformity assessment of medical devices

ISO 14155:2020 is the latest version of the standard. It includes several updates from the previous version. The U.S. Food and Drug Administration (FDA) recognizes clinical trials that have been run in accordance with ISO 14155, including clinical data collected outside of the U.S., as long as they maintain compliance with the standard.

What’s new in the 2020 edition of ISO 14155?

The ISO 14155:2020 and ISO 14155:2011 differ significantly. The 2020 version puts more emphasis on applying risk management principles throughout the entire medical device clinical investigation process.

Annex H of ISO 14155 (Application of ISO 14971 to clinical investigations) explicitly lays out the connection between ISO 14971 and the clinical investigation process. It includes a helpful graphic for applying ISO 14971 to managing potential safety concerns during a medical device clinical investigation.

There are other important changes in the 2020 version of the standard, including:
• A summary of good clinical practice (GCP) principles in Section 4
• Requirement for the registration of all medical device clinical investigations in a publicly accessible database like EUDAMED
• The inclusion of clinical quality management in Section 9.1
• The inclusion of statistical considerations in Annex A
• Additional guidance for ethics committees in Annex G
• Requirements for risk-based monitoring in Section 6.7
• Guidance on clinical investigation audits in Annex J
• Guidance on the application of ISO 14155 in premarket and postmarket stages in Annex I

How to apply ISO 14155 in postmarket clinical activities

There are numerous types of clinical investigations, and the different language used to describe them can quickly become confusing. On top of that, clinical activities can occur at any stage in the product life cycle, from premarket to postmarket.

The previous version of the standard didn’t do a great job of explaining how the standard applied to different types of clinical investigations at different stages in the product life cycle. The standard writers have attempted to clear up some of this confusion in ISO 14155:2020 with the addition of Annex I, which clarifies the different types of clinical investigations based on regulatory status, clinical development stage, study design, and burden to subject.

As the chart above makes clear, clinical investigations of medical devices don’t just happen during the premarket phase. The standard applies to postmarket clinical investigations as well, including observational (noninterventional) investigations.

Which parts of ISO 14155 will apply to your clinical study?

In addition to clarifying the different types of medical device clinical studies, Annex I also includes a section (I.7) on the applicability of the document’s principles to different clinical studies.

As the standard states, “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, the standard states that for a premarket confirmatory (interventional) clinical investigation, “all principles in this document apply.” On the other hand, if you’re undertaking a postmarket observational investigation—which is noninterventional—you might not be required to apply every requirement in the standard.

The important thing to remember is that if you believe you’re exempt from applying any part of this standard to your medical device clinical investigation, you must justify that decision in your clinical investigation plan (CIP).

What is good clinical practice?

Good clinical practice (GCP) is a set of ethical and scientific quality standards. It’s used for designing, conducting, recording, and reporting trials of medical devices that involve human subjects.

GCP is an internationally recognized standard. It ensures the protection of subjects’ rights, safety, and well-being. Additionally, it ensures that all clinical data are credible.

ISO 14155 provides a summary of GCP principles in Section 4 of the standard. These principles are essential for conducting research with human subjects. They form the basis of any good clinical study.

Overall, there are 14 guiding principles of GCP, including:
• All clinical trials should be conducted in accordance with ethical principles, sound scientific evidence, and clear detailed protocols.
• The benefits of conducting trials should outweigh the risks.
• The rights, safety, and well-being of trial participants are of paramount importance, and these should be preserved by obtaining informed consent and maintaining confidentiality.
• The care must be given by qualified personnel with adequate experience.
• Records should be easily accessible and retrievable for accurate reporting, verification, and interpretation.
• Investigational products should be manufactured according to good manufacturing practice.

You’ll want to familiarize yourself with all the principles laid out in Section 4 of the standard. They are essential to planning and conducting a compliant clinical study for medical devices.

In fact, in Section 5, the ethical considerations portion of the standard, the first requirement states that the good clinical practices “shall be understood, observed, and applied at every step in the clinical investigation.”

Section 5 also lays out several other important ethical considerations, including:
• Rules against improper influence or inducement of subjects
• Requirements for communication with the ethics committee (EC), including requirements for your initial submission and continuing communication throughout the clinical investigation
• Requirements for obtaining informed consent and the information that must be provided to the subject

This section is particularly in-depth, as getting informed consent appropriately is critical to conducting an ethical clinical study in accordance with GCP.

What are the key responsibilities of the sponsor and principal investigator during a clinical investigation?

The ISO standard separates GCP for “Responsibilities” into two clauses:
• Responsibilities of the sponsor (Clause 8)
• Responsibilities of the principal investigator (Clause 9)

The sponsor (in our case, the device’s manufacturer) is responsible for planning and conducting the clinical investigation within prescribed quality assurance and quality control principles.

It’s important to note that even if the clinical investigation is contracted out by the sponsor to a qualified third party, the sponsor still retains overall responsibility.

The responsibilities of the principal investigator include:
• Implementation and management of the investigation’s day-to-day activities in accordance with the CIP
• Ensuring the integrity of investigation data
• Safeguarding the rights, safety, and well-being of the human subjects involved in the study

How to plan a clinical investigation according to ISO 14155:2020

As you plan your clinical investigation, it’s important to understand that a standard like ISO 14155 is not telling you exactly what to do. It’s telling you what you need to include and consider while planning a clinical investigation.

It’s important to go through the standard and check off boxes, as well as create necessary documents. However, this is not where your work ends. Regulatory authorities will want to see the justification for your decisions. They’ll want to know why you’ve decided to structure your study a certain way, why you’ve chosen that sample size, or how you came up with a specific number.

Section 6.3, “Justification for the design of the clinical investigation,” has more information on providing that justification. Keep that in mind as you create the various documents for the planning stage. These documents include:
• The clinical investigation plan (CIP): The CIP is the go-to document for everyone involved in the clinical study. It will include the objectives and design of your clinical study, a justification of the study’s design, and a benefit-risk analysis. You can find the full list of what to include in your CIP in Annex A of the standard.
• The investigator’s brochure (IB): The purpose of the IB is to provide the principal investigator with sufficient data to justify the clinical investigation proposed in the CIP. The IB will include a summary of all the preclinical testing performed on the investigational device, as well as any existing clinical data. You can find the full list of what to include in the IB in Annex B of ISO 14155:2020.
Case report forms (CRFs). The purpose of CRFs is twofold: First, they provide information on the condition of each subject entering the study. Second, they capture data for each subject as required by the CIP. You can find the full list of what should be included in a CRF in Annex C of the standard.

Now, that basic description of CRFs is deceptively simple. Case report forms are one of the chosen methods of collecting clinical data during a study. Using paper or general-purpose software for your CRFs puts you at risk of missing data or data-entry mistakes. These can slow down your study significantly.

Greenlight Guru’s modern eCRF is built for the unique needs of the medtech industry. When you use Greenlight Guru Clinical, you can get started quickly and enjoy prevalidated software, regulatory templates, and a user-friendly study builder.

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

Your clinical investigation may only commence once you have “written approval/favorable opinion” from the ethics committee and the relevant regulatory authority in the countries where your clinical investigation is taking place. 

You’ll find requirements for conducting an ISO 14155-compliant clinical investigation in Section 7 of the standard. There are a couple points within this section that I want to highlight. 

First, you’ll notice that a large part of Section 7 is given over to adverse events and device deficiencies. Documentation and reporting of adverse events or device deficiencies pertaining to medical devices is extremely important. You can find a table for adverse event categorization in Annex F of the ISO standard.

Greenlight Guru Clinical offers an adverse event (AE) module for EU MDR and ISO 14155-compliant reporting. The customizable module is fully integrated into an eCRF and provides automatic notifications to users and sponsors as well as an AE specific-data export.

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. It also includes a written version of the flowchart at the top of this article.

Section 7 isn’t the only place where 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.” 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, industrywide move toward integrating risk management into every part of the medical device life cycle. 

Taking this holistic approach to risk means that you may even want to document risk management for clinical investigations within your quality management system. Risk management activities during a postmarket clinical follow-up investigation may have important implications for the device. These should be documented and tracked in the quality management system.

Because risk is a fundamental part of bringing a medical device to market, Greenlight Guru built its risk management workspace to be traceable and compliant with ISO 14971:2019 and ISO 13485:2016. This ensures that a workspace meets the risk-based requirements of both standards.

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,” and in particular, Section 7.8.3, which 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 that any electronic system be validated “in order 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

While that may seem daunting, Greenlight Guru Clinical is a system that comes prevalidated to all the requirements in ISO 14155:2020. That includes out-of-the-box compliance with the requirements in Section 7.8.3, along with a suite of compliance document templates available to all customers.

Final thoughts

Planning and conducting an ISO 14155-compliant clinical investigation is difficult enough without having to worry about your data collection tools—but Greenlight Guru Clinical was specifically built for the needs of the medtech industry. It enables you to collect and manage data during premarket and postmarket clinical studies, including registries, cohorts, surveys, human factor testing, design validation, and more.

Greenlight Guru Clinical meets the regulatory requirements of the FDA, EU, and most other countries. It also ensures out-of-the-box compliance with GCP and ISO 14155:2020.

Published Sept. 15, 2023, on the Greenlight Guru blog.

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About The Author

Jón Bergsteinsson’s picture

Jón Bergsteinsson

Jón Ingi Bergsteinsson, with a master’s degree in biomedical engineering, is the co-founder of Greenlight Guru Clinical (formerly SMART-TRIAL). He was also the technical founder of Greenlight Guru Clinical, where he paved the way for the platform’s quality standards, data security, and compliance.