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A clinical investigation plan (CIP) is an essential part of any medical device clinical trial. The CIP is a standalone document that includes everything investigators and research staff need to know to successfully undertake the clinical investigation.
It’s important enough that ISO 14155:2020, Clinical investigation of medical devices for human subjects — Good clinical practice, includes a nine-page annex that covers all the information you’ll need to provide in a CIP.
There are 18 sections in Annex A. And while you’ll need to read through Annex A carefully on your own, it may help to have some context as you do. This guide will point out some of the most important sections of Annex A and provide some context to help you better understand the purpose of the CIP and its contents.
The first section of Annex A in ISO 14155:2020 deals with the general information you’ll need to include in your CIP. This includes:
Identification information related to the clinical investigation (such as title, reference number, and abbreviations and acronyms) (A.1.2)
Information on the sponsor and their funding source (A.1.3)
Identification of the principal investigator, coordinating investigator, and investigation site(s) (A.1.4)
A synopsis of the clinical investigation that includes relevant information such as inclusion/exclusion criteria, number of subjects, duration, follow-up, and objectives and endpoints (A.1.5)
Something to note here is the second paragraph of Section A.1.3, which states:
Certain national or regional regulations can require that if a sponsor is not resident in the country (countries in which the clinical investigation is to be carried out, the name and address of a local representative who acts as the sponsor fulfilling responsibilities of the sponsor in that country (those countries) are provided.
In other words, if you are performing this investigation in a country outside of where your company is incorporated, you may be required by local regulations to have a local representative acting on your behalf.
Keep in mind that there may be other local regulations in the country where you are carrying out this investigation. For instance, EU MDR includes requirements for a CIP in Annex XV, Chapter III (3) of the regulation.
For more information on EU-specific requirements, check out MDCG 2021-08, the guidance document on clinical investigation application and notification documents.
Section A.2 covers the information regarding the investigational device that you’ll be required to provide in your clinical investigation plan. This includes information such as the intended purpose of the device in the study and its intended indications and patient populations.
You’ll also be required to provide specifics regarding the manufacturer of the device, name and number of the model or type (including any software), and how you’ll achieve traceability of the device(s) during and after the clinical investigation.
This device information is to ensure that you aren’t using multiple versions or types of the device during the investigation, which could impact both subject safety and the quality of the data you obtain from the clinical study.
If your medical device’s clinical trial uses a comparator device, then you will also be required to provide this information for the comparator, as well.
Section A.3 of Annex A is short, but what it describes is extremely important. The scientific and rational justification for the design of your study is crucial to getting it approved. You must be able to provide a sound rationale for conducting this clinical investigation in your CIP.
ISO 14155:2020 requires the justification of the design to be based on the conclusion of the clinical evaluation, and the justification should consist of:
Section A.4 of Annex A lists the information you’ll need to provide about the investigational device’s benefits and risks. It’s important to remember here that risk management must be applied at every stage of the medical device lifecycle, which includes clinical trials.
Along with the anticipated clinical benefits of the device, you’ll be required to provide information on any anticipated adverse effects from the device and any risks to subjects associated with participating in the clinical investigation. You can find more information about both of these topics in sections 6.2.2 and 6.2.3 of the standard.
You’ll also be required to provide any steps that will be taken to control or mitigate these risks. This ties in with Annex H of ISO 14155:2020, which provides a roadmap for applying the risk management principles of ISO 14971 to clinical investigations.
At Greenlight Guru, we understand that risk management isn’t something you perform once and forget about. It has to be integrated throughout a medical device’s lifecycle. That’s why we built Risk Solutions to be a complete risk management solution for integrating risk-based thinking into your entire device ecosystem, keeping you in compliance with ISO 14971:2019 and the risk-based requirements of ISO 13485:2016.
Ready to learn more? Then get your free demo of Greenlight Guru’s Risk Solutions today.
Section A.5 outlines the information you’ll need regarding the clinical objectives and statistical hypotheses for the study. This is an important section of your CIP because it can influence how regulators will review and potentially accept the results of the study when it comes time to submit your market application.
You’ll begin by writing the purpose of the clinical investigation. This is the claims for clinical performance, effectiveness, or safety about this device that the study is intended to verify.
You’ll also note the objectives, primary and secondary, in this section, which may be described as “superiority,” “non-inferiority”, or “equivalence”. In other words, are you attempting to prove that this device is better, equivalent to, or simply non-inferior to another device or treatment?
Depending on your answer to that question, you may need to provide the scientific justification and clinical relevance for effect sizes, non-inferiority margins, or equivalence limits.
Section A.6 of the annex covers the design of your clinical investigation, and the information you’ll need to include here is fairly extensive. This should be a detailed description of your clinical investigation design and will cover everything from general study design to specific elements such as data capture procedures, forms, visits, and inputs/outputs.
As you’ll see, there is a lot to cover in A.6 alone, which is why it’s critical to have a clinical expert along with a device clinical affairs professional on your team, as their participation can make or break the study.
A.6 begins with the general information about your study design, including the type of investigation to be performed (such as randomized, blinded or open label, parallel groups or crossover, etc.). You also need to include the control group and the comparator and give a rationale and justification for these choices.
The statistical element of your study design is an essential part of writing a solid CIP. Statistical design and analysis will cover items such as:
Sample size, in particular, requires careful determination, as it will directly affect the quality of the data you get from your clinical trial.
Sample size calculation is the process of determining the minimum number of samples that would make a study outcome statistically significant—which would make your clinical evidence more reliable in statistical terms.
However, not all medical device companies have the privilege of employing a biostatistician or a data scientist in-house to assist with sample size calculation.
If you’ll be getting expertise from an external source like a consultant, then you’ll want to check out our Sample Size Cookbook for Medical Device Clinical Investigations. It will help you understand the process of sample size calculation and the statistical methods that you’ll use as you work with your consultant.
Another important section in the CIP will cover your plans for managing the data you collect from your clinical investigation. This is about more than just making sure you collect it—you’ll need procedures for CRF (case report form) tracking, data review, database cleansing, and more.
You’ll also need procedures for verifying, validating, and securing any electronic clinical data systems you use.
Your ability to properly collect, store, and manage all the data from your investigation is essential to your ability to use that data later on for regulatory purposes. And while you may want to begin your study and start collecting data as soon as possible, it’s best to take the time to carefully plan your data management setup before the study begins.
If you’re concerned about how you’ll plan your data management setup (and put it in your CIP), then check out our eBook on How to Plan a Clinical Data Management Setup for Electronic Data Capture. It has everything you need to know about data management to eliminate delays, reduce errors, and increase the quality of your clinical data.
While A.13 is relatively short, this section of the CIP is extremely important, as it deals with the informed consent of study participants. You’ll need to provide a description of the general process you’re using to obtain informed consent, including the process for providing subjects with any new information later on.
Today, it’s common for study participants to give consent electronically, known as eConsent. And while this may be easier for everyone involved, eConsent still requires you to present the objects of the trial or study, make sure participants understand all rights, risks, and ethics regarding the trial, and only then obtain the participants' acceptance.
If you plan on using eConsent in your clinical investigation, I highly recommend you check out this webinar on efficiently using eConsent in a medical device study.
Section A.14 deals with the possible adverse events (AEs) related to the study and the use of your device, as well as the reporting process you will have in place specifically for adverse events, adverse device effects, and device deficiencies.
It’s crucial that you’re prepared for possible adverse events in your study, but it’s just as important that you have a robust reporting process in place if any adverse events should occur.
That’s why at Greenlight Guru, our electronic data capture (EDC) system can be customized with an ISO 14155:2020-compliant AE reporting module. The Adverse Event module comes with ready-to-use templates, customizable AE forms, automatic email notifications, and a clear overview of all safety events in your study.
Writing a great clinical investigation plan is an undertaking, but putting in the necessary time and effort up front to create your Clinical Investigation Plan will save you a lot of trouble down the road. It may even save your clinical investigation altogether.
Likewise, thinking about how you’ll capture the data your study generates ahead of time will pay dividends both during and after the study. With Greenlight Guru Clinical, you can collect clinical evidence and safety and performance data for any activity throughout your entire medical device lifecycle.
Greenlight Guru Clinical comes pre-validated for both FDA and ISO 14155:2020 requirements to ensure you’re in compliance from the very beginning of your clinical investigation.
If you’re ready to see how a MedTech-specific clinical data solution can streamline your clinical investigation, then get your free demo of Greenlight Guru Clinical!
Stephanie Hinton is a Clinical Medical Device Guru with over a decade of combined experience working in human subjects research. Her expertise includes recruitment strategy, protocol development, IRB submissions and amendments, preparing for NIH grant applications, as well as coordinating and planning for DSMB...