Writing appropriate documents for Competent Agencies in EU and CH for compliant MR-research
Ethics proposal — The Clinical Investigation Plan (CIP)
Introduction
Navigating the bureaucracy behind clinical trials in Switzerland is no small feat. As a researcher preparing the SIGNATURES2023study, I quickly found that working with both the localCantonal Ethics Commission (CEC) and Swissmedic / EMA — two independent bodies with their own rules and regulations — requires a level of coordination and compliance that can be both time-consuming and frustrating. Each iteration of the proposal, whether it’s addressing concerns from the ethics committee or responding to feedback from Swissmedic , must be submitted to both instances on the same day. The regulatory dance of managing two different approval processes means that any delay on one side causes the entire process to stall, even though both entities are supposed to operate independently. In my case both procedures took 25 months time, to my opinion, way to long compared to the duration of an SNF project of 48 months..
Compounding the challenge, if resolving one instance’s critiques takes longer than the maximum waiting time permitted by the BASEC system, I am forced to restart my application from scratch—requiring me to resubmit all documents again, including the Clinical Investigation Plan (CIP). To make matters worse, Swissmedic [or your local EU-CA]and the CEC use two separate web submission systems that are often user-unfriendly, with Swissmedic’s IT system feeling like a relic from 25 years ago—a nostalgic throwback to what was considered cool in the early days of the internet. Welcome to the digital age, Switzerland.
Navigating the CIP Template: Start Right, Stay Updated
When preparing a Clinical Investigation Plan (CIP), starting with the most recent template is crucial to avoid unnecessary work. The latest version of the CIP template is available on the official swissethics website and should always be downloaded directly from there. Using outdated versions can lead to discrepancies that result in additional revisions or even a complete restart of the submission process.
Why Use the Latest Template?
Ethics committees and regulatory bodies, such as Swissmedic [or your local EU-CA], regularly update their templates to reflect the latest legal, procedural, or administrative requirements. Submitting an obsolete version can lead to avoidable delays, as your application may not meet the current standards or expectations. Furthermore, the template itself contains detailed guidance and clarifications tailored to current regulations, which can greatly aid in constructing a compliant CIP.
Key Instructions in the CIP Template
The CIP template includes several instructions that must be followed meticulously to ensure a smooth submission process. Here are the most important points applicants should keep in mind:
Consistency Across Submissions: Ensure that the information provided in the CIP aligns with the details in other documents submitted to both the ethics committee and Swissmedic [or your local EU-CA]. Inconsistencies can result in time-consuming requests for clarification.
Comprehensive Details:
Investigational Device Description: Provide detailed technical specifications, the intended use, and evidence supporting its safety and performance.
Study Objectives and Design: Clearly outline the purpose, endpoints, and methodology of your investigation.
Risk Management: Include a thorough risk analysis, highlighting mitigations for identified risks. Notably, the CIP contains (in my opinion) a significant overlap with the Investigator’s Brochure (IB) in this section. To avoid redundant work, focus first on completing your risk analysis and associated documents, and then summarize these findings in both the CIP and IB.
Participant Information: Specify the inclusion and exclusion criteria, recruitment strategy, and informed consent process.
Monitoring Plan: Describe how the study will be monitored to ensure participant safety and data integrity.
Data Management: Explain how data will be collected, stored, and analyzed while maintaining confidentiality and compliance with regulations.
Adherence to Deadlines: Both Swissmedic [or your local EU-CA]and the ethics committee must receive your submissions on the same day. Delays in one submission can jeopardize the entire process.
Clear Formatting: Follow the formatting guidelines provided in the template. This ensures readability and reduces the likelihood of overlooked sections.
Use of Plain Language: For participant-facing sections, such as informed consent forms, use language that is easily understandable to non-specialists.
Submit in English or National Language: Depending on the canton and target audience, submissions can be made in English or one of Switzerland’s national languages (German, French, or Italian).
Attach Required Appendices: The CIP must include appendices such as investigational device manuals, risk analyses, and data collection forms.
Advice for Efficient Preparation of CIP
For MR scientists and clinical researchers, the CIP and IB overlap significantly in areas such as risk management and device safety evaluations. To streamline your workflow:
Begin by drafting your risk analysis and related documents thoroughly.
Use these documents as a basis to populate the corresponding sections in both the CIP and IB. This approach not only saves time but ensures consistency across your submissions.
Use this blog as a resource to address detailed questions early in your preparation process. Gaining clarity upfront can save you months of unnecessary effort and prevent frustrating delays caused by misunderstandings or overlooked requirements.
Additionally, ensure that all safety considerations, including SAR (Specific Absorption Rate) evaluations and device-specific simulations, are well-documented and harmonized with the information provided in supplementary materials.
By adhering to these guidelines and leveraging the instructions embedded in the CIP template, applicants can streamline their submission process and minimize the risk of setbacks. Taking the time to thoroughly understand the template before beginning your CIP can save significant effort and frustration down the line. Phone or mail your CEC if you are in doubt what category your trial is, since writing a whole proposal based on the wrong assumptions on your project (which happened to me) is quite frustrating, and be sure you don’t want to repeat that.
A Deep Dive into the CIP: Context and Project Overview
Before delving into the structure of the Clinical Investigation Plan (CIP) itself, it’s essential to set the stage for the project it supports. The CIP detailed in this blog relates to the complex study entitled “Non-Invasive Monitoring of Brain Metabolites Using Novel and Adapted Proton AND Deuterium MR Techniques (SIGNATURES2023).” This innovative clinical trial represents a significant step forward in medical imaging and metabolic research, leveraging cutting-edge MRI and MRSI technologies.
Key Characteristics of the SIGNATURES2023 Study
The SIGNATURES2023 project is a medical device clinical trial designed to push the boundaries of non-invasive metabolic imaging. Below are its defining features:
Ultra-High-Field MR and MRSI Utilizing advanced 7 Tesla MRI technology, this study explores the capabilities of ultra-high-field imaging to deliver unprecedented spatial and metabolic insights.
MR and MRSI Measurements on Healthy and Patient Groups The project involves meticulous MR imaging and spectroscopy on both healthy volunteers and four distinct patient groups, each with specific metabolic conditions.
Cutting-Edge MR-Pulse Sequence Development A highlight of the study is the development and application of non-CE-marked MR pulse sequences, including:
Externally developed pulse sequences provided by [your scanner manufacturer], which are called C2P sequences
Non-CE-Marked Hardware Integration The trial employs a non-CE-marked, dual-tuned 1H/2H head coil, tailored for the study’s specialized imaging requirements.
In Vivo Metabolic Response Studies A significant focus is placed on measuring the metabolic response after administering specific substrates, such as:
Deuterated D-glucose
Standard alpha-D-glucose
This combination of novel technologies, metabolic substrates, and innovative imaging protocols is designed to unravel the complexities of brain metabolism in health and disease.
The Scale and Scope of the CIP
The Clinical Investigation Plan (CIP) for SIGNATURES2023 reflects the complexity of this ambitious project. Spanning 77 pages, the document meticulously outlines the study’s objectives, methods, and risk management strategies. The CIP balances technical precision with compliance, ensuring alignment with both Swissmedic [or your local EU-CA]and ethics committee requirements.
In the next section, you’ll find the table of contents (TOC) of the final CIP of SIGNATURES2023, which provides a roadmap for how this comprehensive document is structured to support such a complex clinical trial.
CIP Table of Content of the SIGNATURES2023 Project
The acronym SIGNATURES2023 stand for “Non-Invasive Monitoring of Brain Metabolites Using Novel and Adapted Proton AND Deuterium MR Techniques 2023”. The 2023 stands for the year the project should start, but the delays in getting an approval from the responsible local CEC and Swissmedic caused a delay of the project to 02-2025 as starting date. The Clinical Investigation Plan or CIP was a quit big document in the end, and had the following table of content (TOC) listed below. Each TOC entry is a hyperlink to a section below where you find example text which could be used as starting point for your own MR-project.
Please note that quoted texts are literal pieces of text of the approved CIP and are in rust red.
This is an example how literal texts from the approved CIP submitted to the CEC and Swissmedic are formatted.
The full texts are provided, but one should note that these texts are highly project dependent, and need to be adapted. You can consider to have your CIP being AI-generated by means of a chatbot operated by me. Or create a chatbot yourself with the provided texts.
Making the Synopsis of your CIP: Lessons for MR Scientists
Filling out the Clinical Investigation Plan (CIP) template can be a daunting task, especially for MR scientists undertaking complex clinical trials. From my experience with the SIGNATURES2023 project, I can say that how you approach the first few pages of your CIP can set the tone for the entire document—and potentially save you from costly inconsistencies later. So take care.
Do not Start with the CIP Summary
The Summary Section on page 1 may tempt you to fill it out first. After all, it feels like the natural starting point. However, this approach can backfire. The summary is meant to provide an accurate overview of the trial, but if you complete it first and then start working through the rest of the document, you risk introducing inconsistencies. As the details of your project evolve while filling out the full CIP, it becomes easy to forget to update the summary (as happened to me). If you have the final text, you can use Chat-GPT to create the Synopsis from it. Believe me, this is much faster, and error free.
Instead, fill out the summary section only after you’ve completed the rest of the CIP. This ensures alignment between the summary and the detailed sections, particularly for a complex study involving novel MR techniques, new devices, or multiple study groups. Save the summary for last—it’s worth the effort to avoid discrepancies that could raise questions from regulators or ethics committees.
Know Your Study Type — Consult the Ethics Committee
The first table on page 1 is deceptively simple but critically important. It asks you to categorize your study type, and you must get this right. Misclassifying your study here can lead to significant setbacks, including resubmissions or delays if your study doesn’t align with the category you claim. If you have experimental pulse sequences and/or non CE-marked RF-hardware, the category is C2.
To avoid such pitfalls:
Call the ethics committee (CEC) early in the process. They are incredibly helpful and responsive, and their guidance can be invaluable in correctly classifying your study.
Take the time to understand how your study fits within the existing framework of medical device categories and clinical trial types. If in doubt, err on the side of overcommunicating with the CEC—they would much rather clarify things upfront than deal with a misclassified study later.
Balancing Complexity and Clarity
For MR scientists, one of the biggest challenges is dealing with the complexity of advanced trials. My trial, for instance, involved:
Novel MR pulse sequences (non-CE-marked).
A non-CE-marked dual-tuned RF coil.
Patient and healthy volunteer studies across multiple groups.
While it’s tempting to cram all these details into one application to save time, this can lead to a bloated and inconsistent document. Be strategic: break your trial into manageable components within the CIP, ensuring every section is aligned. If necessary, consult a statistician or experienced clinical trial advisor to help streamline your approach.
Read the Instructions Carefully
On page 2, the CIP instructions emphasize paying attention to detail, particularly when describing the objectives, design, and safety measures of your study. Don’t skim these instructions. They often contain nuanced guidance that can help you frame your application more effectively. For instance:
When describing your investigational device or intervention, provide clear, concise, and consistent details. Overly technical jargon can confuse reviewers.
Make sure your risk management section aligns across the CIP and related documents, like the Investigator’s Brochure. This avoids conflicting statements that could undermine your application.
Build a Strong Foundation
Starting your CIP with clarity and precision on pages 1 and 2 lays the groundwork for the entire application. Here’s my advice for MR scientists embarking on this journey:
Categorize your study correctly. Call the ethics committee for guidance if you’re unsure.
Leave the summary section for last to avoid inconsistencies.
Balance clarity with detail. Include enough information to justify your trial but avoid overwhelming reviewers with technical minutiae.
Learn from my mistakes. Taking the time to get it right at the start will save you months of revisions and resubmissions.
Use my paid service and generate you CIP using a developed GPT (not necessary, but it might save you very much time!).
By carefully addressing the foundational elements of your CIP, you set yourself up for a smoother journey through the rest of the document—and the regulatory review process.
ABBREVIATIONS
Tip: use Chat-GPT to collect them and list them with explanation from your finished CIP. That will take you less than a minute. I started to write the CIP before Chat-GPT was available. Count your blessings!
SUMMARY OF THE REVISION HISTORY IN CASE OF AMENDMENTS
Complete this table during each stage of the submission and review process. With the insights and tips provided in this blog, we aim to help you achieve approval within just one or two iterations at most.
INVESTIGATION SCHEDULE
The investigation schedule is highly dependent on your project. For me it was, despite the complex nature of the trial, still quit overviewable.
You need to fill out one or multiple tables with the actions and timepoints of your trial. Here is an example from the SIGNATURES2023 project for one single MR-scan of one of the patient groups:
Table 1 : Example of the investigation schedule for one single subject.
Investigation Periods
Patient information
Consent (ICF) Screening
MR Scans
Time points
0
1
2
3
Time (hour, day, week)
> -2d
-0.5h
0
1.5h
Patient Information
x
Patient consent (ICF)
x
x
In- /Exclusion Criteria
x
Pregnancy Test
x
Medical Device application
x
x
(Serious) Adverse Events, Adverse device effects
x
x
Device Deficiencies
x
x
Depending on the complexity of your MR-medical device study, you can have multiple tables.
1. INVESTIGATION ADMINISTRATIVE STRUCTURE
1.1 Sponsor-Investigator
The Sponsor-Investigator is an individual who takes on the dual responsibility of both the sponsor and the principal investigator in a clinical trial. As a sponsor, they are accountable for the initiation, management, and financing of the study. As an investigator, they also oversee the conduct of the investigation, ensuring it complies with ethical, regulatory, and safety standards. This dual role is common in academic or small-scale clinical investigations, particularly in areas like MR-medical device trials, where the principal investigator often has the resources and expertise to act as the sponsor as well.
The SIGNATURES2023 study is an SNF funded study in which the PI (see 1.2) is also the sponsor-investigator. This is not necessarily always the case, but for typical MR-medical device trials, in which non-CE-marked pulse sequences and/or RF-hardware is used, this will mostly apply.
1.2 Principal Investigator(s)
The Principal Investigator (PI) is the person responsible for the overall conduct of the clinical investigation at a specific site. Their primary role is to ensure that the study is carried out according to the Clinical Investigation Plan (CIP), ethical guidelines, and applicable regulations. Unlike the sponsor, the PI is not responsible for funding or initiating the trial but focuses on managing day-to-day operations, patient safety, and data integrity. In multi-site studies, there may be multiple PIs, each leading the investigation at their respective sites under the coordination of the sponsor.
Please define for you medical device MR-study who has this responsibility.
1.3 Statistician (“Biostatistician”)
The nature of the SIGNATURES2023 is such that we will not perform typical bio-statistics like in drug studies and studies to test one medical device against another. Therefore we wrote:
Given the exploratory nature of most of the investigations with MR-expert decisions on how to proceed, no statistician is needed. Statistical evaluations are done by the sponsor-investigator, and/or project collaboration partners, and/or employees of the project. In case of any potential open issues in evaluations, the statistic support service of the clinical trials unit (in our case the [your local CTU or equivalent]) will be consulted.
If you need help with statistics in your study, please contact the CTU which is responsible for your institute.
1.4 Laboratory
Here you can add the location where your medical device relevant investigator initiated trial (IIT) is performed. In the case of SIGNATURES2023 we added the following:
All MR investigations will be performed at:
[Your Imaging Center] [Your address] [Your city]
1.5 Monitoring institution
The monitoring institution in a (medical device related) clinical trial is responsible for ensuring that the investigation is conducted in compliance with the approved Clinical Investigation Plan (CIP), ethical standards, and regulatory requirements. Its duties include overseeing the quality and accuracy of the data collected, verifying adherence to protocols, and safeguarding participant safety throughout the study.
Often, this responsibility is assigned to a local Clinical Trial Unit, which is equipped with the expertise and infrastructure to perform these tasks effectively. However, involving the CTU comes with a price, a quit high price (according to my recent information around CHF 130 per hour). Alternatively, this role can also be fulfilled by a qualified individual. For example, in the SIGNATURES2023 study, monitoring responsibilities were undertaken by a highly experienced MR-scientist, demonstrating the flexibility in assigning this critical role to appropriately skilled personnel.
1.6 Data Safety Monitoring Committee
We added the following to the application. The reasons for this are threefold:
the safety of the study has been clarified by Swissmedic [or EMA or your local responsible administration]beforehand.
the nature of the study is an investigative one with minimal numbers of persons scanned. This means that either the MR-methodology proposed works, or not. This can be done best by the investigators themselves at the end of the trial.
All acquired data will be stored on password protected computers, and won’t leave the institute.
Therefore we wrote:
No data safety monitoring committee is implemented for this study. The conclusion of the safety analysis is that, although this study contains non-CE-marked components, the risk for human participants is extremely low (see IB and safety report submitted to Swissmedic [or EMA or your local responsible administration]). Therefore this clinical investigation, as the risks from the MR examinations are judged to be minimal (see §3.7), in particular since the MR acquisitions will be without use of contrast agents. No interim analyses are planned.
1.7 Any other relevant Committee, Person, Organisation, Institution
Here we referred to the person who conducts the monitoring in our trial, instead of the CTU.
Depending on the exact nature of your ClinO-MD trial (e.g. involvement of medical device manufacturers), you have to give here more detailed information.
2. ETHICAL AND REGULATORY ASPECTS
This chapter outlines the ethical principles and regulatory requirements governing the clinical investigation. It addresses key aspects such as compliance with ethical standards, regulatory approvals, participant safety, and reporting obligations to ensure the study is conducted responsibly and transparently.
2.1 Registration of the investigation
Clinical investigations must be registered in publicly accessible databases to ensure transparency and compliance with ethical standards. Common platforms for registration include ClinicalTrials.gov, the EU Clinical Trials Register, or national registries, depending on the scope and regulatory requirements of the investigation.
Registration is typically completed or finalized after obtaining approval from both the Competent Ethics Committee (CEC) and Swissmedic / [or EMA or your local responsible administration], ensuring that all necessary regulatory and ethical prerequisites are met. For the SIGNATURES2023 study, the investigation was registered on ClinicalTrials.gov (approval of them is still pending), following these approvals. This process involved providing comprehensive details about the study design, objectives, and methodology, promoting accountability and global visibility of the research.
2.2 Categorisation of the investigation
The SIGNATURES2023 study will be registered in a registry listed in the SWISS National Clinical Trial Portal (SNCTP via BASEC) with SNCTP number: SNCTP000006108. The study is entered on the ClinicalTrials.gov website but, awaiting their approval, does not have a registration number yet. The NCT number is: SNCTP000006108.
We wrote concretely in the CIP
The investigation is categorized as C2 (non-CE marked operation [as foreseen and prepared by the manufacturer] of a CE-marked device (pulse sequence package), not truly off-label use in the common sense). The device is classified as class IIa according to rule 11 of Annex VIII of the MDR.
2.3 Competent Ethics Committee (CEC)
The following text we submitted for our SIGNATURES2023 trial:
The Sponsor-Investigator will submit the investigation to the [your local CEC] and obtain ethical committee approval before the start of the investigation. The sponsor-investigator ensures that approval from the CEC is obtained and filed in the Investigator site file before the investigation starts.
2.3.1 Reporting duties to the Competent Ethics Committee
Here we submitted the more or less standard text:
Amendments are reported according to Art. 15 ClinO-MD (see also 2.10). The regular or premature end of the investigation as well as the interruption of the investigation is reported to the CEC within 15 days (within 24 hours if it is due to security reasons) (Art. 36 ClinO-MD). The reasons for a premature end or an interruption have to be explained. A final report shall be submitted within one year after the regular end of the investigation and within 3 months after a premature end of the investigation (Art. 37 ClinO-MD).
2.4 Competent Authorities (CA)
Here we submitted the more or less standard text of the template:
The Sponsor-Investigator will submit the investigation to the CA and obtain regulatory approval before the start of the investigation. The Sponsor-Investigator ensures that approval from the CA is obtained and filed in the Investigator site file before the investigation starts.
Verify if this is still valid in the newest CIP template you have to use for your ClinO-MD trial.
2.4.1 Reporting duties to the competent authorities
Here we submitted the more or less standard text of the template:
Reporting duties and timelines are the same as for CEC, except of non-substantial amendments that shall be reported as soon as possible (Art. 20 ClinO-MD). See chapter 10 for safety reporting. Amendments are reported according to Art. 20 ClinO-MD (see also 2.10).
Verify if this is still valid in the newest CIP template you have to use for your ClinO-MD trial.
2.5 Ethical Conduct of the Investigation
Here we submitted the more or less standard text of the template:
The investigation will be carried out according to the CIP and with principles enunciated in the current version of the Declaration of Helsinki, the European Regulation on medical devices 2017/745 (MDR), the Norms ISO14155 and ISO14971, the Swiss Human Research Act (HRA) and its Ordinances and Swiss regulatory authority’s requirements. The CEC and the CA will receive the Annual Safety Report (ASR) and interim reports and be notified about investigation stop/end in agreement with local requirements.
Verify if this is still valid in the newest CIP template you have to use for your ClinO-MD trial.
2.6 Declaration of interests
Change to what applies for your study.
No conflicts of interest to be reported.
2.7 Patient Information and Informed Consent
This section is a mix of instructions and given text you have to use in your CIP. In bullet form these are the most important things to keep in mind when writing this section, and preparing informed consent forms (ICFs):
Use Swissethics Templates: Swissethics strongly recommends using their templates for patient information and consent forms, as they meet Swiss legal requirements. Templates are available in German, French, and Italian on swissethics.ch/templates. Staying close to the provided text ensures compliance and clarity.
Guidance and Resources:
Review the guidance document on writing comprehensible patient information and consent forms before starting.
Utilize the glossary for medical terms and abbreviations to ensure clarity.
For electronic ICFs, refer to the Swissethics guidance on eIC development.
Content Requirements:
Clearly explain the study’s purpose, procedures, risks, benefits, and voluntary nature of participation.
Provide information on participant rights, including the ability to withdraw at any time without affecting medical care.
Highlight compensation, if applicable.
Address privacy concerns and who may access medical records (e.g., authorized personnel).
Special Considerations:
Use inclusive and epicene language, and consider issues related to sex, gender, contraception, and pregnancy.
Allow participants enough time to consider their decision based on the study’s risks and complexity.
Consent Process:
Participants must read, understand, and voluntarily sign the ICF, with the signed form retained as part of the investigation documents.
Inform personal physicians about participation, where applicable, with participant approval.
Ensure procedures are in place for emergencies and incidental findings, if relevant.
Vulnerable Populations:
For minors or subjects under legal representation, obtain both the legal representative’s consent and the subject’s assent if capable of judgment.
Exclude participants showing unwillingness to take part.
Emergency Situations:
Outline how a subject’s will is determined without delay and how consent is obtained from legal representatives.
Ensure the subject’s interest is safeguarded by an independent physician not involved in the study.
Important Note: Stay as close as possible to the text in the templates to ensure the forms meet legal and ethical requirements while maintaining clarity and compliance.
By following these summarized steps and using the templates provided, you can ensure that the patient information and informed consent forms adhere to the highest ethical and regulatory standards.
An example of an ICF for our study you find in another post in this blog. Our submitted final in the CIP text was:
The investigators will explain to each participant the nature of the investigation, its purpose, the procedures involved, the expected duration, the potential risks and benefits and any discomfort it may entail. Each subject will be informed that participation in the study is voluntary and that he/she may withdraw from the investigation at any time and that withdrawal of consent will not affect his/her subsequent medical assistance and treatment. The subjects are informed that he/she can ask any question, and consult with family members, friends, their treating physicians, or other experts before deciding about their participation in the investigation. Sufficient time will be given to the subjects, i.e. normally more than 24 hours. If participants want to sign up within less than 24h, they will document that they consciously declined their right to time for consideration on the consent form. Eligibility criteria will be evaluated based on the subjects’ statements during the recruitment interaction and again before the examinations. For patients included in the study, medical records may be examined only to assess the inclusion criteria. All subjects are given a subject information sheet and a consent form describing the investigation and providing sufficient information for the subjects to make an informed decision about their participation in the investigation. The formal consent of a subject, using the approved consent form, will be obtained before the subject is submitted to any investigation procedure. The subject should read, understand, and voluntarily agree before signing and dating the informed consent form, and will be given a copy of the signed document. The consent form will be signed and dated by the subject and the PI (or her/his designee). The signed consent form will be retained as part of the investigation records.
2.8 Subject privacy and confidentiality
Most of text is defined by the CIP template. We submitted following text to the [your local CEC] deining what identification for all participants will be used:
The Sponsor and the PI affirm and uphold the principle of the subjects’ right to privacy and that they shall comply with applicable privacy laws. Especially, anonymity of the subjects shall be guaranteed when presenting the data at scientific meetings or publishing them in scientific journals. Individual subject medical information obtained as a result of this investigation is considered confidential and disclosure to third parties is prohibited. Project data will be handled according the data management plan. The uttermost discretion is warranted, and the data is only accessible to authorized personnel for project related tasks who require the data to fulfil their duties within the scope of the research project. On the CRFs and other project specific documents, participants are only identified by a unique participant number. Participants` encrypted IDs will be created in a format using a volunteer number, the age and gender, e.g. a 73-year-old male patient who was examined for the first time focusing on deuterium spectroscopy: 005_1_73_p_m_2H. Examination IDs are formed from the institution name, examination date, the scanner used and a running number, e.g. 4th exam on the 7T scanner on 17th July 2022:xw_DIN_220717:7004. The participant list will be accessible to the investigators only. If any health or disease related data will be needed for precise evaluations, those data will be obtained from the involved physicians. The key list will be stored in the office of the PI on a password protected computer, within a password protected excel file. Direct access to source documents will be permitted for purposes of audits and inspections. Access to documents, datasets, source codes, etc. during and after the study will otherwise only be granted to the investigators and their designees. For data verification purposes, authorised representatives of the Sponsor, the CA or a CEC may require direct access to parts of the medical records relevant to the investigation, including subjects’ medical history.
2.9 Early termination of the investigation
Here we used the standard formulation of the CIP template:
The Sponsor may terminate the investigation prematurely according to certain circumstances, for example:
ethical concerns,
insufficient subject recruitment
when the safety of the subjects is doubtful or at risk, respectively.
alterations in accepted clinical practice that make the continuation of the investigation unwise
early evidence of benefit or harm of the experimental intervention.
2.10 Clinical investigation plan amendments
Here we also used the standard formulation of the CIP template:
Substantial amendments are only implemented after approval by the CEC (Art. 15 ClinO-MD) and, for category C investigations, after approval by the CA also (Art. 20 ClinO-MD). The use of waivers from the CIP is prohibited (Annex XV, Chapter 2, Art. 3.10 MDR). Under emergency circumstances, deviations from the CIP to protect the rights, safety and well-being of the subjects may proceed without prior approval by the Sponsor and the CEC (and for category C investigations without prior approval by the CA). Such deviations shall be documented and reported to the Sponsor and the CEC (and to the CA for category C investigations) within 2 days (Art. 34 ClinO-MD). All non-substantial amendments are communicated to the CEC together with the Annual Safety Report (ASR) (Art. 15 ClinO-MD), and for category C clinical investigations to the CA as soon as possible (Art. 20 ClinO-MD). The ASR shall include any deviations from the CIP that may have affected the rights, safety or well-being of the subject or the scientific integrity of the investigation (ISO14155).
2.11 Deviation from the Clinical Investigation Plan
We took the CIP template text without any changes:
The use of waivers from the CIP is prohibited (Annex XV, Chapter 2, Art. 3.10 MDR).
3. BACKGROUND AND RATIONALE
3.1 Background and Rationale for the Clinical Investigation
The template gives the following summarized instructions for this section:
Relevance and Context:
Explain the relevance of the investigation in relation to the current state of clinical practice.
Highlight the proposed benefits of the new device (per Annex XV, chapter 2, Art. 3.2 MDR).
Research Question:
State the research question clearly.
Summarize previous investigations (published and unpublished) examining benefits and harms.
Disease Background:
Provide information on disease epidemiology and current standard of care, if applicable.
Knowledge Gaps:
Identify gaps in current knowledge and justify why the investigation is necessary.
Establish the study’s context and purpose with a clear statement.
Sex and Gender Dimensions:
Address whether “sex and gender” are relevant to the study topic.
Specify any genetic/biological or social mechanisms at play, if applicable.
Refer to Swissethics recommendations on equitable research.
If not relevant, provide a clear justification.
The text we uploaded in the end was split into 10 sub-sub-sections, highly precisely defining the background of the study. Whether this is really necessary for your study you have to decide. You can reuse e.g. the text of an SNF or other funding proposal here.
3.1.1 Introduction
The text we submitted here was:
This proposal deals with metabolic imaging using proton as well deuterium magnetic resonance spectroscopic imaging (DMI) applied to humans on an ultra-high field (UHF) MR-scanner. It focuses on (a.) the use of already established (product) pulse sequences (deuterium: 3D-FIDCSI; protons: SLOW-EPSI); (b.) the development of novel pulse sequences for 1H-MRS(I) and 2H-MRS(I) and other so-called X-nuclei; (c.) the application of the sequences on four cohorts of healthy volunteers for establishing age dependent normal metabolic values; (d.) the application of the same sequences to four patient groups: I. 10 patients with Alzheimer’s disease; II. 10 patients with diabetes Type-2; III. 10 patients with mild cognitive impairments (MCI); IV. 10 high- grade carotid stenosis patients. Since most MRI studies have identical basic structure, we allow ourselves to make reuse of text parts previously CEC approved applications (2021-Dxxxx) and corresponding Swissmedic approved application (10xxxxxx; EUDAMED CIV-21-11-xxxxxx). The underlying proposal repeats the most important aspects of the approved proposals KEK-BE/2021-Dxxxx and Swissmedic/10xxxxxx and extends these texts.
3.1.2 Metabolic imaging of the brain
This section will be different in your application and will depend on what exactly you want to do.
In general terms you could address following items in this section and other sub sections which you deem to be relevant for your study:
Introduction to (Brain Metabolism) Imaging:
Discuss the significance of studying brain metabolism and its implications for understanding neurological diseases and conditions.
Highlight the use of Magnetic Resonance (MR)-based techniques as powerful tools for non-invasive metabolic imaging.
Overview of MR Techniques:
Describe how MR techniques, such as Magnetic Resonance Spectroscopic Imaging (MRSI) or other MR modalities, can detect and quantify physiologic and/or anatomic aspects.
E.g. if applicable: Emphasize their ability to provide detailed insights into biochemical pathways and cellular processes.
Relevance of MR Methods:
Discuss the broad applicability of MR methods across various pathologic conditions.
Highlight their capability to measure specific physiology relevant to disease mechanisms or therapeutic effects.
Advantages of MR-Based Methodology the Trial is about:
E.g. Highlight the non-invasive nature of MR techniques compared to methods involving radioactive tracers (e.g., PET).
E.g. Stress their ability to simultaneously capture a wide range of biological parameters without the need for external agents.
Tailoring to Specific Investigations:
Relate the discussion to the specific focus of your study, whether it involves exploring neurotransmitters, energy metabolism, biomarkers for disease progression, or other molecular targets.
Provide context on how MR techniques align with the goals of your clinical investigation.
Innovative Aspects of MR Techniques:
Describe how your approach advances the state of the art, such as through new pulse sequences, advanced imaging protocols, or novel biomarker analysis.
3.1.3 Deuterium metabolic imaging: DMI
This section is too project specific and is not relevant for the general case.
3.1.4 1H-SLOW-EPSI of Neuro-Metabolites, Neurotransmitters
This section is too project specific and is not relevant for the general case.
3.1.5 Glucose metabolism in the brain
This section is too project specific and is not relevant for the general case.
3.1.6 Brain glucose metabolism in normal aging
This section is too project specific and is not relevant for the general case.
3.1.7 Brain glucose metabolism in mild cognitive impairment (MCI) and Alzheimer’s disease (AD)
This section is too project specific and is not relevant for the general case.
3.1.8 Brain glucose metabolism in Type-II diabetes
This section is too project specific and is not relevant for the general case.
3.1.9 Brain glucose metabolism in high-grade carotid stenosis
This section is too project specific and is not relevant for the general case.
3.1.10 Methodological Aspects
This subsection you can focus on the methodological aspect of your MR-related study. You can consider re-using the following text for your MR-pulse sequence development application.
Figure 1 has been copied from the approved application KEK 2021-D0064 dealing with MR pulse sequence development according to the new MDR. It provides a concise overview on how MR-methodology running on MR-scanners is developed. All MRI/MRS developments start with an idea, or with a clinical question to be solved. Using an application framework provided the [your scanner manufacturer], MR-methodology of an existing (CE-labelled) sequence is (further) modified, or a novel sequence can be developed. More generally, whenever new MRS and metabolic imaging (MI) methods are developed (that is the case for the four funded projects connected to this ethics proposal), they undergo four phases of application:
Phase I: they are tested in theoretical ways (i.e., using simulations), then using in vitro metabolite solutions.
Phase II: they are tested in healthy subjects, first just to optimize the methodology in the in vivo situation for single subjects.
Phase III: in order to prove their potential, the newly developed methods need to be explored in larger cohorts (repeatability within the same subject, variability between subjects) and possibly in specific setups, if the physiologic situations may be important.
Phase IV: the methods are implemented in examinations with a pure focus on medical/physiological questions.
Figure1:The four phases of pulse sequence development in MRI and MRS(I).
After these 4 phases of development and testing a successful method would be ready to serve as clinical research tool. If a manufacturer of MR-scanner systems finds these pulse sequences (applications) interesting enough for wider use all day clinical use, the manufacturer may seek CE-labelling or FDA-approval for them.
…. more project specific texts which do not have general relevance …
3.2 Identification and description of the Investigational Medical Device(s)
The difficult issue I had to find a solution for in the SIGNATURES2023 trial is that our “Medical Device” consisted of two non CE-marked components, and the supplementation of deuterated and normal glucose:
Non CE-marked pulse sequences
Non CE-marked RF-hardware
Supplementation of deuterated and normal glucose to patient groups and healthy controls
In a bullet list form, the CIP instructions asks the applicant to provide the information below.
IMPORTANT: Please note that you should first write the IB and the safety documentation etc. of the Swissmedic / [or EMA or your local responsible administration] related documents, and than summarize these documents here.
Device Identification:
List all devices in the system, including brand name, manufacturer, model/type, software version, algorithms, and accessories.
Include a picture of the medical device (MD) if possible.
CE Marking and Intended Purpose:
State whether the device is CE marked and for what use (e.g., medical, electrical, pressure vessels).
Describe the populations for which the MD is intended.
Off-Label Use:
Specify any deviations from the original CE-marked instructions for use or confirm if there are no deviations.
Modular Design:
If the MD has a modular design, identify the modules and specify which module or modification is the focus of the investigation.
Materials and Composition:
Describe materials in contact with body tissues/fluids, including medicinal substances, human/animal tissues, derivatives, or biologically active substances.
Reference compliance with applicable national regulations for these materials.
Training and Experience Requirements:
Indicate the necessary training and experience for using the MD and performing related medical or surgical procedures.
Reference Documents:
Provide references to the Investigator’s Brochure (IB) and Instructions for Use (IFU).
Since this section touches the heart of an MR-research related ClinO-MD (or EU-MDR) trial I will print the text you could consider to re-use and adapt to your MD-study:
The complete study will be performed in the so-called clinical mode of a [your scanner brand/type] system running software version [your scanner software version]. The clinical mode is FDA approved identically to lower magnetic field clinical MR scanners of [your scanner manufacturer]. However, there are two reasons for this study to be categorised as type C2:
The first reason is that the study foresees the use of modified MR pulse-sequences, therefore non-CE-marked. Hence, the description of the medical device is focused on the effects of sequence changes rather than the main scanner hardware used, which is unmodified.
The second reason is the usage of a non-CE-labelled dual tuned 1H/2H-head coil (investigational device meeting IEC standards on safety see Table 1 on page 30; also refer to section 3.7.2 below for details).
NOTE: Although the focus of the SIGNATURES2023 study is not to evaluate the performance of this coil, but to use the coil as investigational device: even for this case, Swissmedic demands that the proof of safety for the non-CE-marked RF-coil MUST BE PART OF THE TRIAL.
Table 1: The used dual tuned RF-coil fulfils according to the manufacturer all standards listed in the table below.
Product standards
IEC 60601-1: third edition (+A12) à standard for Medical electrical equipment
IEC 60601-2-33 / A12: Medical electrical equipment – Particular requirements for the basic safety and essential performance of magnetic resonance equipment for medical diagnosis.
ISO 13485:2016: standard for medical devices – Quality management system
ISO 14971:2019: standard for medical device Risk management
IEC 60601-1-6/A1: Application of usability engineering to medical devices
IEC 62366-1: Application of usability engineering to medical devices
3.2.1 CE-labelled Product Sequences and Research MR Pulse Sequences
IN the SIGNATURES2023 we used the following formulation for this section, which you might be useful for the description for your medical device. If you have a different provider/scanner/software type, please reformulate such that it fits to your situation:
MR-scanners are digital devices like computers. An MR-scanner can perform a nearly infinite number of different measurements. An MR-measurement is defined by a so-called pulse-sequence. An MR pulse-sequence is a piece of software that runs on the digital logic (i.e., a controlling computer and further digital logic) of the MR-scanners. For [your scanner manufacturer] scanners this software is written by the manufacturer in the object-oriented programming language, in most cases C++. These C++-source files can be compiled and be run on MR-scanners. The sequences produced by the manufacturer are referred to as product MR-pulse sequences. These product sequences are sold by the manufacturers and can clinically be used due to the fact that they are CE-marked (green executable file symbol in Figure 5).
However, MR-technology is extremely versatile, and what can be done with the technology is virtually infinite. For MR-scanner manufacturers ([your scanner manufacturer] in this case) it is impossible to develop the millions of ideas that are around on what can be done with the scanners. For this reason, all manufacturers of MR-scanners provide the scientific community with software frameworks which allow scientists to change/extend the product sequence C++ source codes. After compilation of these altered C++ source codes by the users, a so-called research pulse sequence (also called customer pulse sequence) results (orange executable file symbol in Figure 2 below). If the sequence is successful and shows clear advantages over current state of the art sequences, the manufacturer can decide to make a “work in progress” (WIP) package out of the sequence, of which the manufacturer maintains that functionality it considers to be useful for a larger group of researchers. WIP packages can also be understood as “candidate product sequences” for which no CE-labelling is performed yet. Another option is that the research sequence is forwarded to other researchers which can decide to make additional changes to the C++ code. This type of forwarding pulse sequence source code is called C2P (code to peers). It is important to understand that, in the clinical mode of the [your scanner brand/type] scanner, running research pulse sequences impose no additional risk to the patients scanned with these sequences.
For the use of research sequences on clinical scanners, the operator of the scanner has to specifically access research protocols which are stored separate from the vendor-predefined CE-marked sequences. Hence, both CE-marked and research sequences are available in the same examination, but they are chosen from separate directories when devising the examination protocol, hence the research sequences are not used unintentionally for diagnostic clinical use.
The principal workflow and safeguards of MR scanners using CE-labelled sequences or WIP or C2P sequences is illustrated in Figure 6 below. Crudely speaking, an MR-scanner system consists of (a.) central computer on which CE-labelled, C2P and WIP sequences can be loaded, (b.) a real time scanner safety control system that permanently verifies whether the system works in a safe way and halts the execution even before the sequence is applied, as well as halts the system if too much RF-power (potential danger: tissue heating) or gradients are played out with too large slew rates (danger: peripheral neuro-stimulation) (c.) real-time digital electronic control operating system which controls the real time execution of pulse sequences, (d.) an RF-transmit and receive system adapted to different body parts and those transceivers will be used according to the manuals. The underlying study foresees the use of a so-called dual tuned RF head coil (tuneable to proton and deuterium MR-signal) which has no CE-marking but is an investigational device fulfilling all required electronic IEC-standards on safety and is manufactured according to ISO-standards. (e.) a magnetic field gradient system that enables localization of MR-signals.
Figure 2: Presents a visual categorization of pulse sequences used in MRI research, distinguishing between standard product sequences and specialized research sequences. The product sequences, shown in green, are binary executables provided by manufacturers like [your scanner manufacturer]. These sequences are CE-marked and unmodifiable at the binary level, although (neuro)radiologists have the flexibility to adjust certain imaging parameters for diagnostic applications. In contrast, the research sequences, depicted in orange, encompass peer-to-peer (C2P) and work in progress (WIP) sequences. These are primarily developed by researchers who may receive the C++ source code of CE-marked sequences from[your scanner manufacturer] for modification according to specific research needs. Despite their use for research, these sequences undergo rigorous safety checks by the MR-safety system to ensure patient safety during scans. The figure also outlines the development and distribution process of these sequences. If a research sequence shows significant value, [your scanner manufacturer]may transform it into a WIP package for broader distribution within the research community. Alternatively, researchers can share their modified sequences with peers as C2P packages, either as binary executables or source codes .A notable inclusion is the Pulseq package, a unique C2P offering that enables rapid pulse sequence prototyping through MATLAB scripts. Despite its efficiency, Pulseq adheres to the same strict safety protocols as other sequence types. Irrespective of the sequence category — be it WIP, C2P, or Pulseq-C2P — the safety and security of all sequences are guaranteed by the MRI scanner’s superior, independently acting MR-safety system. This system consistently prevents the execution of any sequence that could pose a risk, upholding stringent safety standards across all pulse sequence categories. This illustration underscores the diverse methodologies in MRI pulse sequence development and highlights the crucial balance maintained between innovation and safety in MR spectroscopy research.The applied RF-power that might lead to tissue heating is limited by software and hardware systems (watchdogs) to the specific absorption rates according to international safeguard guidelines. The scanner is also including gradient amplifiers and gradient coils that are used in unmodified fashion and are limited to safe action (in particular gradient ramp times) according to internationally recognized standards and guidelines applicable for the use of clinical MR-scanners: more specific: in compliance with IEC 60601-2-33:2010/AMD2:2015. These regulations demand that all scanners need to have a security system (including the mentioned “watchdog”) that controls the amount of RF-power and the maximum slew rates of switched gradients in order to prevent heating and peripheral neuro-stimulation.The underlying project proposals include an open range of novel MR sequences that by principle cannot be defined in every detail before the research is actually completed, but the modifications can be described in a generic form to cover the potential increased risks:All MRI and MRS sequences consist of a series of RF pulses, magnetic field gradient pulses and periods of data acquisition. The exact shape and mutual timing of these events is designed to create images and localized spectra of specific contrasts and reflecting various tissue properties. The main items of concern for safety of the investigated subjects are the steepness and maximum amplitude of the gradient field pulses (peripheral nerve stimulation) as well as the power deposited in the tissue by the RF pulses as a time average and in terms of peak power (tissue heating, characterized as specific absorption rates).All sequences used in this proposal are derived from [your scanner manufacturer] product sequences (in particular the [your scanner manufacturer] MRS product sequences (FID, 2H-FIDCSI) that are part of CE-labelled MR scanners.Additionally, we will use the C2P sequence EPSI for which the C++-source code was changed (now named SLOW-EPSI) by us to enable spectral editing and which has been applied successfully in healthy controls and brain tumour patients in a currently running study (covered by CEC ID 2019-xxxxxx). Additionally, if it turns out to be necessary, the C2P package called Pulseq may also be used. This C2P package enables fast prototyping of novel sequences. The modifications will include changes of timings, removal/addition of further RF pulses (e.g., to create additional echo signals or to suppress specific spurious signals) and addition of gradient pulses, as well as changes in the shape, duration and/or amplitude of such gradient and/or RF pulses. The modifications of the sequences are done in the [your scanner manufacturer]s programming environment IDEA that was developed to allow such modifications, without offering the possibility to change any safety relevant features. The derived sequences thus conform to the same safety restrictions as the original codes that the CE-marked sequences are based on. In particular, ramp times are restricted to the safe and allowed times and RF pulses are integrated to not exceed the allowed SAR limits. Both properties are in addition checked in real time by so-called watchdog systems that cannot be circumvented.Operation of the MR scanners with standard sequences or modified sequences is virtually identical and is restricted to trained personnel. The modified sequences need knowledge in terms of settings of the newly programmed features for proper operation, though without any safety risks in case of inappropriate settings.More details of the scientific background and the intended modifications of the MR sequences, as well as further risk evaluations are provided in the IB. MR sequence programming is taught in [your scanner manufacturer software pulse programming IDE], programming courses of [your scanner manufacturer] which are taken by all programmers in this study before they implement any sequences on the scanners.We would like to emphasis here that in a currently running SNF-study approved by the local competent ethics committee (Basec ID 2019-00xxx) we developed a SAR minimized 1H-tuned EPSI variant (named SLOW-EPSI) for in vivo spectral editing of GABA, Glutamate/Glutamine, 2HG and also for glucose. For the further use, reuse, and further development of this mentioned SLOW-EPSI sequence we need, according to the new Medical Device Regulatory (MDR) also a Swissmedic approval as well. The SLOW-EPSI sequence will be further developed to perform 2H-EPSI (or DEPSI) as well and is one of the goals of the SNF-funded study.
Figure 3: Simplified scheme of a [your scanner manufacturer]MR-scanner, emphasizing (in red) the watchdog system that will block (X) any non-conforming action before being played out. Besides the Software monitoring system, the sequence output is also verified by hardware control at the position of the red X. It should become evident that both, CE-marked sequences, as well as modified sequences, are equally monitored by the safety components of the scanner. It is also illustrated that the modified sequences are programmed outside the actual scanner and essentially only timetables of well-known events.
Finally, we would like to state that phantom safety tests have been conducted with the non-CE-marked RF-coil (to be described below) in combination with the non-CE-marked 1H-SLOW-EPSI pulse sequence which will be used in this study. These tests are described in detail in two documents submitted to Swissmedic [or EMA or your local responsible administration](safety report, investigators’ brochure). High SAR stress tests applied on the proton as well as the deuterium channel using the pulse sequences to be used in vivo in this study, where all well within the official SAR guidelines; and no hotspots were found where excessive heating takes place. The conclusion of the report was, we cite, “From these results, it can be concluded that the coil is safe to use.”
3.2.2 Non-CE-marked dual tuned 1H/2H head coil
You could reformulate following text for your MR-related MD-trial:
As already indicated above, the study proposed here involves the use of a non-CE-marked dual tuned 1H/2H head coil. The manufacturer [your RF-coil manufacurer] named this coil as: “BRN0004-Exwa”. Although the CE-marking has not been performed (due to the high cost for the limited amount of coils that can be sold worldwide) this coil is fully safe due to the product standards and process standards used by the manufacturer [your RF-coil manufacturer, address of manufacturer]. See Table 1 above for details.
The word “dual tuned” refers to an RF-coil which can be used at two different frequencies: namely at the 1H (proton) frequency of 297 MHz and 2H (deuterium) frequency of 45.6 MHz at 7 Tesla. All security relevant documents, as well as the user manual of the coil will be provided. Please refer to the Appendix on page 68 for details on the provided documentation.
In parallel to this ethics proposal, a Swissmedic [or EMA or your local responsible administration]proposal will be submitted. All safety relevant documents, proving the safe use of the dual tuned head coil have been provided to Swissmedic [or EMA or your local responsible administration]. The documents, reporting on RF-safety support the claim that the coil can be used safely, with IEC-norms.
3.3 Preclinical Evidence
Please change the text of this section to match to your trial:
Preclinical evidence in this context could be understood as the testing of the functionality of the modified pulse sequences, in this case 1H-SLOW-EPSI (clinically applied in a currently running study) and DEPSI (to be developed) in aqueous phantoms with dissolved metabolites of known concentrations, where performance is tested in comparison to theoretical investigations / simulations, e.g., quantum mechanical spectral simulations using for instance NMRSCOPE-B in jMRUI. Such testing is done extensively for each sequence before use on human volunteers (in the first phase) and on patients (in the second phase). If phantom tests are successful (e.g., we can show that the observed SNR of a glucose solution phantom is sufficiently large that it justifies the use of the sequence in vivo than it is tested in vivo in humans.
3.4 Clinical Evidence to Date
Please change the text of this section to match to your trial:
There is broad scientific evidence that for deuterium labelled glucose Deuterium Metabolic Imaging (based on the results of other research groups) and also for SLOW-EPSI-based for proton based metabolic imaging for the detection of glucose and neuro-transmitters (based on our own results) if applied to the brain. These methods are not only working from a technical point of view, but they are also feasible to be applied in patients within reasonable measurement times. Clinical evidence that the method will have a clinical benefit in diagnosis and treatment of Alzheimer’s’ Disease, high-grade carotid stenosis, Type II Diabetes and Mild Cognitive Impairment patients has still to be shown; the motivation of the project it to establish the foundation for such studies. There is, however, founded reason to assume that DMI using glucose and SLOW-EPSI will have clinical impact for patients in the future. The reason for this optimism is that, for the first time in history, it is possible to scan the whole brain aiming at (deuterated) glucose and follow-up metabolic products within 20 minutes, and simultaneously scan the inhibitory neurotransmitter GABA and excitatory glutamate within 10 minutes. There are numerous scientific indications that alterations may be expected in the pathologies examined in this study.
3.5 Justification for the design of the clinical investigation
You might want to adapt or reuse the following section for your MR-device study, where you give a justification for the design of your clinical investigation:
General — The design of the study is an explorative study. Since the DMI-methodology and SLOW-EPSI methodology which will be (re-)used in the chosen pathologies (AD, Type-II diabetes, high-grade carotid stenosis, MCI) the study foresees different phases described above. After application to phantoms, the sequence will be optimized on healthy test persons. With the final protocols a group of healthy you persons will be scanned, and a group of elderly healthy persons will be scanned to (a.) defined normal reference values and (b.) examine whether there is a brain aging effect noticeable comparing these two groups. In the final stage 4 times 10 patients will be examined and compared to the healthy control groups.
MR-sequences and Scanner choice — The need for and benefit from novel MR sequences is probably undisputed given the success of this method with ever new possibilities thanks to such developments. The only clinical evaluations possible are open exploring/probational evaluations on healthy subjects followed by examinations in a limited number of patients with proven pathologic condition. The scanner to be used is an UHF 7T scanner which benefits from higher signal to noise ratios (SNR-s) enabling equal SNR in shorter measurement times, maximizing the probability that the envisaged patient groups will tolerate the duration of the examination.
Pulse sequences and CE-labelling — One sequence used in this study has CE-labelling namely 3D-FID-CSI to be used for DMI of glucose. Non-CE-labelled but used in healthy controls and brain tumour patients in a currently running project is SLOW-EPSI. The deuterium metabolic echo planar imaging (DEPSI) sequence will be developed during the first part of the project and is therefore also not CE-labelled. It will be a further development of SLOW-EPSI and will not be made from scratch.
MR-examination time — Based on experience from clinical routine, the use of standard MR protocols in patients for patients with Type II diabetes, MCI, and high-grade carotid stenosis (i.e., the duration of the examination) will not pose a serious problem. However, depending on the severity of the cognitive impairment of early-stage AD-patients the examination time may appear relatively long; the examination time of the study protocol is comparable to the total time needed standard FDG or β-amyloid PET examination of AD suspect patients (preparation and scanning). In addition, this study will result in an as efficient as possible protocols that can be performed on MCI and AD patients in the future.
Type of trial — It cannot be stressed enough that the current proposal now legally falls into the category of a “clinical trial”, even though it does not in any way at this stage resemble a standard clinical trial as known in traditional drug research or medical device research , moreover it does not influence any clinical diagnoses, clinical decisions, or clinical treatments, and in addition, it should be considered that for the study participant (be it a patient or a healthy test person) the exact nature of the employed sequence or target organ does not at all alter the general course of the investigation.
Final remark — The MR-community uses non-CE-marked sequences for the last approximately 40 to 45 years. During that time MR-technology from a technological point of view has proven to be extremely safe and poses only an absolute minimal risk to the persons while being in the scanner, and no permanent health risk after having been in the scanner has ever been shown.
3.6 Explanation for choice of comparator
In the context of a medical device (MD) clinical trial, a comparator is a reference device or treatment used to evaluate the safety, performance, and effectiveness of the investigational medical device. The comparator serves as a benchmark to provide meaningful context for the results of the clinical investigation.
Key Characteristics of a Comparator
Reference for Comparison:
The comparator can be an already established medical device, standard treatment, placebo, or even no treatment, depending on the clinical trial design.
It allows researchers to determine whether the investigational device offers equivalent, superior, or additional benefits compared to existing options.
Selection Criteria:
A comparator is typically chosen based on its relevance to the study objectives, its use in the current standard of care, and its approval for the intended application.
Use in Trial Design:
In randomized controlled trials (RCTs), participants are often assigned to receive either the investigational device or the comparator.
The performance, outcomes, and any adverse events are then measured and compared.
Types of Comparators:
Active Comparator: A device or treatment with known efficacy that is part of standard clinical practice.
Placebo Comparator: An inactive device or sham treatment to assess the investigational device’s effect beyond placebo.
No Comparator: Sometimes, trials involve comparing the investigational device to no intervention, especially in exploratory studies.
Regulatory and Ethical Considerations:
The choice of comparator must align with ethical standards to ensure that participants receive appropriate care.
Regulatory bodies may require justification for the selected comparator, ensuring it is relevant and does not expose participants to unnecessary risks.
Comparator in the SIGNATURES2023 Study
In the SIGNATURES2023 study, no comparator is included due to the absence of a gold standard for the dual-tuned head coil used or the experimental pulse sequences being developed. This reflects the innovative nature of the investigation, where no established alternatives exist for comparison. The focus remains on assessing the feasibility, safety, and potential benefits of these novel technologies.
You could adapt/reuse the following text for your own MR-device trial:
No comparator used. The research is probing for new effects not as comparison with specific existing methods (and if such comparisons are used in single situations for establishing improved repeatability they are drawn from the general literature). If, at the end of this study it should turn out that [6,6′2H2] glucose based DMI and/or α-glucose SLOW-EPSI to be sensitive enough marker of brain metabolism with sufficient spatial resolution, comparison could be made to FDG/β-amyloid PET in future. However, this is not foreseen in this study.
3.7 Risk evaluation (Risk-to-Benefits rationale)
This section requires a detailed assessment of the risks and benefits associated with the investigational medical device (MD) and the clinical investigation. It involves risk management, anticipated adverse effects, and measures to control risks, aligned with ISO14971 standards. Write this section after you have written the risk related documents which you need for your Swissmedic [or EMA or your local responsible administration].
Key Points:
Risk Management:
Discuss risk analysis, residual risks, and control measures.
Reference the risk analysis report and describe post-investigation care arrangements.
Anticipated Adverse Effects and Risks:
Detail device-related adverse effects and residual risks.
Include risks from interactions with concomitant treatments or concurrent medical interventions.
Risk-Benefit Rationale:
Provide a rationale for the anticipated clinical benefit versus the associated risks.
Analyze historical safety data, including modifications or recalls of the device or comparator.
Investigations Without Immediate Subject Benefit:
Justify the investigation’s potential to improve future treatments, diagnostic tools, or understanding of the disease.
Specific Risks to Address:
Harm caused directly by the MD.
Risks from invasive procedures.
Consequences of device deficiencies or side effects (e.g., local heating).
Risks of incorrect diagnostic outputs (false positives/negatives).
Delays in correct diagnosis or treatment.
For final SIGNATURES2023 texts we wrote the following introductory text here in reaction to the issue of “hyperthermia” Swissmedic was afraid of as a result of head MR-scanning:
MR-scanning technology is a very safe low risk intervention. This is due to the safety systems which have been implemented by the manufacturers since the beginning of the in vivo MR-technology approximately 40 years ago. Four risks need to be mentioned here, three related to the radio frequent (RF) energy that is applied to the persons in the scanner, namely burns, hotspots, and hyperthermia, as well as one risk related to the switching of magnetic field gradient coils which can lead to (peripheral) nerve stimulation. Since these four risk types are implicit to the use of all in vivo MR-technology, the risks in this study do not pose any additional risk, even in the case that non product sequences are used. This is due to the fact that superior and independent acting security systems are always active (“watchdogs”) and are not changed in the underlying study.
More specific, local burns are prevented in this study by excluding persons with metallic implants and tattoos in the head and neck area, two possible reasons for burns. This is due to the fact that most implants and some tattoo ink types contains metal compounds, which can inductively heat up.
The so called “hot spots” can be prevented by using CP-mode and not pTx technology. A hot spot is defined in this case as a sub-volume of tissue in which, time averaged, a high electric field is induced. The probability of this to happen is in CP-mode extremely low. Therefore, CP-mode is used in this study.
Finally, as heating risk “hyperthermia” is often mentioned. However, for healthy persons head-MRI scanning using a head coil for transmit as well as receive, is not a neglectable risk. This can be motivated followingly:
Assume a worst-case scenario in which a person weights 50 kg and the mass of a head weighs 4 kg (small person with big head). The maximum SAR is limited by the scanner for a head scan to 3.2 W/kg. If we assume that a person is scanned for 60 minutes at a row, and all heat is locally dissipated and remains in the head this would lead to a rise in temperature which can be computed the following way: (60 seconds x 60 minutes x 3.2 J/kg x 4 kg) / (4 kg 4200 J/kg.K) = 2.7 Kelvin. Worst case, valid in the case that the head is not perfused and would not exchange heat with its surrounding. However, the head is the most well perfused organ, and receives approximately 20% to the total blood volume pumped by the heart. A total of approximately 5.5 Liter / minute is pumped through the total body (in rest, which is the case in a person lying in the magnet), which means the head receives 1.1 Liter / minute. In 60 minutes of the MR-exam the head receives 66 Liter of blood. Since thermodynamic equilibrium is maintained due to the very high perfusion, the worst case warming of the (body + head) is ( 60 x 60 x 3.2 J/kg x 4 kg ) / 50 kg x 4200 J/kg.K = 0.21 K in one hour time. Note that this is a not realistic worst-case increase. The criteria for hyperthermia are a body temperature to rise above 37.5°C to 38.3°C, and therefore hyperthermia is NEVER a realistic danger in any healthy adults. Since non healthy persons (e.g., with fever) are excluded from the study, hyperthermia is not an issue. Finally, the risk of peripheral nerve stimulation can fully be controlled, by obeying maximum gradient slew rate limitations. These checks are made by the [your scanner manufacturer] MR-system during compilation and also at runtime. Therefore, no additional measures w.r.t. peripheral nerve stimulation are necessary from our side: the [your scanner manufacturer] application frameworks guarantees that SAR as well as gradient slew rate limitations are met at all times.
In the SIGNATURES2023 we made subsections which follow here now:
3.7.1 Non CE-marked MR-sequences
The risks from the MR examinations are judged to be minimal, also in particular since the MR acquisitions will be performed on CE-marked MR scanners and without use of contrast agents. Given the special type of this MD study, the base safety of normal scanning on the used MR devices does not have to be addressed. This includes the safety of scanning at 7T as reflected by the Food and Drug Administration (FDA) declaring that MRI scans at magnetic fields of up to 8 Tesla constitute a non-significant risk for adults, children and infants aged 1 month and older. Rather, we mainly address any potential risk as originating from the modification of the scanner pulse programs used to run the specific scans.
As described under 3.2 all safety measures (hardware as well as software precautions limiting the energy delivered to safe conditions) of the MR scanner are always in place – also for newly designed pulse sequences to be employed here (see attached letter from the manufacturer [your scanner manufacturer]; file reference names given in appendix). This statement holds irrespective of the exact nature of the alterations of the pulse sequence as long as they are implemented with the company’s development tool IDEA and as long as the hardware is not altered. Both conditions are fulfilled for this project.
Figure 4: This figure should make clear that a research pulse sequence does not pose any additional harm to the person in the MR-scanner. Both the CE-labelled product sequence as well as the research pulse sequence are converted into list of scanner hardware states. Each hardware state has a user definable duration. During each hardware state the user defines which gradients should be switched on/off and whether RF-power should be applied simultaneously. After the operating system created the MR-scanner state table, an independent and superior system performs predictive security tests which contain checks on the expected RF-energy deposited per time unit (SAR) into the patient, and whether gradient slew rates are in safe bounds. If the predictive security system gives its OK a real time operating system starts executing the list of instructions. This real time execution system performs continuous real time tests on the RF-power sent to the patient and the reflected power: if the difference between the sent power and the reflected power exceeds the SAR-limits the pulse sequence will be terminated. From this it may be clear, that these mechanisms work for CE-labelled sequences as well as for research sequences.
For better understanding of why apparently general software modifications – even without strict monitoring of the types of modifications and their implementation details – can easily be safety-controlled by the manufacturers software-environment that has no explicit knowledge of the planned modifications of the user, one should realize the programming – even though performed in a general programming language (C++) – could be viewed as a kind of parameter optimization rather than general programming, since the output it produces is very limited. The produced executables in connection with the CE-marked scanners essentially produce lists of events (broken down into small time-interval elements) that are played out by the scanner (see Figure 7 above, and subscript). Only events known by the scanner can be interpreted. The [your scanner manufacturer pulse sequence IDE]software environment, made available to trusted researchers by [your scanner manufacturer], has to be used, and was/will be used in this study to produce changed RF-pulse sequences. They have the function of magnetic field gradient pulses, RF-pulses (amplitude and phase tables), instructions to record data, and commands for start and stop execution. All these individual events are handled as if being a part of the CE-labelled device in unaltered form and are monitored by all original safeguards, as confirmed by the Confirmation documents by [your scanner manufacturer]:
Risk evaluation and risk management are described in the risk management and the risk analysis documents, while the results of an initial (residual) risk evaluation are provided in the risk management report file (see appendix for a list of file name references).
It may be mentioned that mild temporary side effects may be felt by the investigated persons, such as dizziness and vertigo primarily when people move in/out of the 7T scanner. Given that these effects immediately disappear when the patient table stops moving it is an inconvenience rather than a risk.
The only potential aftermath for the investigated subjects from the MR examination is an incidental finding. This can potentially be lifesaving or a burden in case the finding would hint at incurable disease. Test persons must agree that incidental findings will be reported to them or their physician. If they do not agree with this procedure, they are not included in the study, because the potential psychological burden for the MR operator, who realizes an imminent and preventable danger for the investigated subject, while they would not be allowed to intervene, cannot be accepted.
Given the need for the proposed studies when developing new MR methods to be used in future targeted research or for diagnostic use and the minimal additional risk involved, the risk-benefit ratio is thus judged to be very low, even if the individual subject does not profit from the exams personally (except for the minimal financial reimbursement and unless curable disease is detected in an incidental finding).
3.7.2 Dual tuned 1H/2H-Head Coil
The details are written in the documentation submitted to Swissmedic, [or your local EU-CA]or your local administration. We just summarize here the most important for the ethics committee.
The underlying study foresees the use of a non-CE-marked dual tuned head coil. Both 1H-channel as well as 2H-channel will be operated in quadrature mode (a kind of circular polarization CP-mode), the only mode which is supported in the CE-marked so-called clinical mode of the Terra system. From an occurrence of local hot spots point of view, the CP-mode is the safest mode since local thermal hot spots within the tissue are not an issue; this in contrast to parallel transmit (pTx) techniques, where thermal hotspots may, seldomly however, occur. Quadrature mode and CP-mode technology is the oldest and most robust RF-technology for realizing whole-head volume coils.
The energy deposition of radio frequent energy in biological tissue scales proportional to the square of the resonance frequency. With the resonance frequency of 2H being a factor 6.514 lower than that of 1H the wavelength of the RF-waves is also a factor 6.514 longer, which has a beneficial effect on not only RF-inhomogeneity, but also means a much lower tissue heating (SAR). More specifically, this means that SAR-load of deuterium is only 2.4% of the SAR required for the same RF-pulse applied. Given the fact that 1H-MRSI is feasible at UHF, there is no SAR issue to be expected for the deuterium metabolic imaging. The 1H-SLOW-EPSI sequence 15 to be used in this study was SAR optimized, which means that the SAR-load is low as well. The latter sequence is already used in a currently running KEK approved study (see above).
Though non-CE-marked, the dual tuned 1H/2H-head coil fulfils all technical (IEC) and quality (ISO) production standards needed for qualitative good and safe product. The file names of these four documents are listed on page 70 below. The description of meaning of these five documents is the following:
Required is the ISO-certificate of the coil manufacturer [your RF-coil manufacturer]:
Risk Management File:
General safety and performance requirements checklist (GSPR-checklist)
Instruction for use of the coil
Safety report of the RF-coil
!
This study does NOT aim to show that this dual tuned coil works or works better than other coils. The product is used “as is”. Proper function is guaranteed by the manufacturer [your RF-coil manufacturer], and the safety measurements which have already being performed. Neither is it the aim of this study to obtain CE-marking or equivalent certification for this coil.
The 1H/2H-dual tuned head coil in this study is used as is, the topic of investigation is the development and use of novel/adapted MRSI-pulse sequences. Proper functioning is guaranteed by the manufacturer, as is demonstrated by the documentation attached to the proposal.
3.8 Justification of the choice of the investigation population
Adapt this section to your investigation.
The CIP-template gives following summarized the rationale for choosing the investigation population and its relevance to the study’s objectives and target population.
Key Points
Investigation Population:
Justify the selection of the investigation population and its representativeness in relation to the target population (per Annex XV, Chapter 2, Art. 3.6.3 MDR).
Ensure appropriate representation of gender and age groups relevant to the scientific question.
Inclusion/Exclusion Criteria:
State and justify the exclusion or underrepresentation of any relevant groups (Art. 4a ClinO).
Sex and Gender Considerations:
Describe recruitment strategies to ensure sex and gender balance.
If balance is not possible, explain how this impacts the validity of results and justify the imbalance.
Refer to Swissethics recommendations on sex and gender in research to address these issues.
Vulnerable Subjects:
Provide a rationale for including vulnerable subjects (e.g., minors, subjects incapable of judgment, or those under tutelage), demonstrating why comparable results cannot be obtained from non-vulnerable groups (Art. 11 HRA).
If both vulnerable and non-vulnerable subjects are included:
Describe the specific aspects of the research question relevant to vulnerable subjects.
Refer to Chapter 11 for recruitment stratification and sample size details.
This information is highly project dependent, and therefore more details cannot be given here.
The investigation is performed to develop new MR spectroscopy and metabolic imaging methods to be applied to the human brain studying normal aging of the brain, setting up age and spatial dependent normal value atlases of the human brain, and first tests of the developed methodology to 4 groups of patients: Alzheimer’s disease (AD), mild cognitive impairment (MCI), Type II diabetes (DM), and high-grade carotid stenosis (HGCS).
Note that we did not mention here the non CE-marked RF-hardware for the simple reason that the RF-coil performance is not part of the clinical investigation.
4.2 Primary Objective
Also quite short (adapt to your objectives):
To develop and validate (new) MR-spectroscopy based deuterium and proton based metabolic imaging techniques aiming at the study of spatial resolved glucose metabolism to establish metabolite brain atlases and to develop novel analysis tools to study the effect of brain aging and individual comparisons of these maps of individual cases in patients having Alzheimer’s disease, mild cognitive impairment, Type II diabetes, and high-grade carotid stenosis.
4.3 Secondary Objectives
Quite short as well (adapt to your objectives):
Secondary objectives include the creation of brain atlases of [6,6′-2H2] glucose / α-glucose and their metabolic products in response to specific physiologic situations and the usage of these atlases to individuals of four patient groups.
4.4 Safety Objectives
This section is longer, due to the fact that the safety is a key factor. The key information we provided to the local ethics committee was:
As this study involves a non-CE-marked RF coil and RF pulse sequences, their use has been thoroughly evaluated through preclinical examinations. All safety documentation, including that of the RF coil and scanner software, has been submitted to Swissmedic [or your local EU-CA]alongside this CIP, as required by law.
The preclinical investigations concluded that the coil is safe for in vivo use in its intended applications—namely, 1H-MRI and 1H/2H MRSI of the human head. Simulated SAR levels remained within IEC-defined limits, and temperature increases in a humanoid-shaped phantom were well within safe thresholds, including sensitive tissues like the vitreous humor of the eyes. The SAR measurements included the highest tested power levels: 1H-SLOW-EPSI at 3.2 W/kg over 10 minutes and 2H-3D-FIDCSI at 3.2 W/kg.
While safety validation of the novel sequences is not a primary objective of this clinical investigation, routine monitoring will be performed to prevent accidents due to hardware or software defects. Emphasis will be placed on proper subject screening to mitigate MRI-specific risks (e.g., ferromagnetic implants, tattoos near the face or neck).
Finally, safety measurements of the RF coil and pulse sequences are detailed in the Investigator’s Brochure and the safety report submitted to Swissmedic [or your local EU-CA]. The results affirm that both the proton and deuterium channels can be used safely in combination with the non-CE-marked RF pulse sequences. Importantly, the planned MR examinations pose no additional risk compared to routine MR scanning.
5. CLINICAL INVESTIGATION OUTCOMES
These clinical investigation outcomes are highly dependent on your project. If it is a MR-application where you only want to show that your MR-methodology is working (better) on a group of healthy just write that. In case that you want to show that your method is working better at a field strength of X-Tesla compared to Y-Tesla, you have a comparator which you need to define above. This might have a substantial impact on how you should write the proposal.
5.1 Primary Outcome
These clinical investigation outcomes are highly dependent on your project. I does not make sense to give you details of the SIGNATURES2023 project.
5.2 Secondary Outcomes
These secondary outcomes are highly dependent on your project. I does not make sense to give you details of the SIGNATURES2023 project.
5.3 Other Outcomes of Interest
These other outcomes are highly dependent on your project. I does not make sense to give you details of the SIGNATURES2023 project.
5.4 Safety Outcomes
For the SIGNATURES2023 project the following was written during an early iteration of the application process and not changed afterwards:
No safety outcomes planned. Safety is assured as documented by the statements of the manufacturer of the MRI scanner, only the performance of new MR sequences applied in vivo in healthy persons and a limited group of patients is evaluated.
In fact this text is not correct, since according to the view of Swissmedic, the safety of any MD-investigation involving non CE-marked components always involves safety related outcomes, namely that the non CE-marked overall device is safe to use. In your MR-device application you could either refer to the safety documentation of the Swissmedic / [or your local EU-CA] application, or the safety results of prior investigations that demonstrate safety.
6. CLINICAL INVESTIGATION DESIGN
This section is highly dependent on your proposal, and therefore we do not add here texts on the SIGNATURES2023 trial. The BASEC template gives however clear instructions on what is expected in this section:
Investigation Design and Rationale:
Outline the investigation design (e.g., blinded, comparator type, parallel design).
Specify allocation ratio and framework (e.g., superiority, equivalence, non-inferiority, exploratory).
Procedures and Duration:
Describe the procedures, stages, and sequence of the investigation.
Include the expected duration of each period and total subject participation, including follow-up.
Potential Problems and Limitations:
Discuss known or potential challenges with the chosen design.
Key Information to Include:
Intervention: Describe the medical device (MD) and procedures being studied.
Population: Define the study population and the anticipated number of subjects.
Blinding/Masking: Detail the level and method of blinding (e.g., double-blind, open-label).
Comparator(s): Specify type (e.g., sham, no treatment, active drug) and control group configuration (e.g., parallel, cross-over).
Assignment Method: Describe how subjects are assigned to interventions (e.g., randomization, stratification).
Follow-Up: Include details on any follow-up procedures and their duration.
Addressing all bullet list ensures all critical aspects of the investigation design are addressed succinctly and systematically.
6.1 General clinical investigation design and justification of design
The content of this section is highly dependent on what you want to do in your MD-MR-trial.
The CIP-template gives following clear instructions on what is expected of the investigator:
Note: The scientific integrity of the investigation and the credibility of the data from the investigation depend substantially on the design of this investigation.
Describe the design of the investigation and its rationale, the type (e.g., blind – who is blinded, with comparator, parallel design), allocation ratio and framework (e.g., superiority, equivalence, non-inferiority, exploratory). Provide a description of intended procedures and stages, the expected duration of subject’s participation, description of sequence and duration of all investigation periods, incl. follow-up. Provide a discussion of the known or potential problems and limitations of the design.
The following information should be included in this chapter:
Intervention to be studied (MD and procedures),
Population to be studied and the number of subjects to be included (if known or applicable),
Level and method of blinding/masking (e.g. double-blind, open, blinded evaluators and unblinded subjects and/or PI(s)),
Kind of comparator(s), (e.g. sham, no treatment, active drug, dose-response, historical and investigation configuration (parallel, cross-over)). Describe the control group(s)
Method of assignment to intervention (randomisation, stratification),
Expected duration of subject participation and a description of the sequence and duration of all investigation periods, including follow-up, if any.
Hint: you could add in table form all (experimental) sequences of the MR-exam(s) you plan to perform on the study patient and healthy control population(s) you are planning to perform.
6.1.2 Methodological Aspects: Timing of Glucose Supplementation and MRSI measurements
6.2 Methods for minimising bias
The CIP-template gives following instruction:
Describe measures to be taken in order to minimise or avoid bias; if applicable describe randomisation, blinding and other measures in the chapters below.
For MR-methodology centered studies this section is most likely not relevant.
6.2.1 Randomisation
The CIP-template gives following instruction:
Describe the exact randomisation method (unit, what, allocation ratio, number generation mechanisms, block randomisation, stratification, how it is done and concealment of list). You can refer to chapter 7.3 as appropriate.
Describe how blinding is ensured, and who will be blinded after subjects’ assignment to the intervention(s) (e.g., investigation subjects, care providers, outcome assessors, data analysts).
For the SIGNATURES2023 no blinding was used, but anonymization.
6.2.3 Other methods for minimising bias
The CIP-template gives following instruction:
Describe other methods if applicable (e.g., the use of validated questionnaires).
For the SIGNATURES2023 there were no other methods used to minimize bias.
6.3 Unblinding Procedures (Code break)
The CIP-template gives following instruction:
If the investigation is blinded, describe under which circumstances unblinding is permissible and the unblinding procedures. Describe the unblinding procedure in case of suspension or premature termination of the investigation.
This section is also highly dependent on the MR MD-trial you want to perform, we therefore cannot give details here which generally apply to any MR-oriented MD-trial. The CIP-template is, however, clear on what is expected here:
Describe in the subchapters below the population to be studied; this should include a description of the investigation settings if relevant (e.g., out-patients, community clinic, academic hospital) and list of centres/countries where data will be collected (or reference to where list of investigational sites can be obtained). Provide plan of actions to be taken if the enrolment goals are not met.
7.1 Eligibility criteria
The CIP template presents mandatory text in black and provides guidance on determining eligibility criteria in blue. For the SIGNATURES2023 project, the process proved particularly challenging due to its complexity, involving multiple groups of healthy individuals and four distinct patient cohorts. Additionally, the extensive exclusion criteria mandated by Swissmedic required numerous iterations to refine and finalize these seemingly straightforward details.
The CIP template requires, in summary, the following, to our opinion an easier to apply bullet list:
Inclusion Criteria
List all specific criteria that subjects must meet to participate in the investigation.
Include the following as examples:
Informed Consent: Signed by the subject.
Any additional criteria relevant to the specific study population or intervention.
Exclusion Criteria
Detail all conditions that will disqualify a subject from participation, including:
Device Contraindications: Specific contraindications or limitations of the medical device as described in its instructions for use (e.g., known hypersensitivity or allergies to device materials, clearly naming substances or trade names like Betadine™).
Vulnerable Subjects: Except where the study specifically investigates these groups.
Compliance Issues: Subjects with suspected non-compliance, substance abuse, or inability to follow investigation procedures (e.g., due to language barriers, psychological disorders, or dementia).
Concurrent Investigations: Participation in another investigational study within 30 days before or during the current trial.
Previous Enrolment: Prior enrolment in the current investigation.
Conflict of Interest: Exclude the PI, their family members, employees, or dependent persons.
Disease-specific exclusions relevant to the investigation.
Additional Requirements
Mapping in CRF: Each inclusion and exclusion criterion must be individually mapped in the Case Report Form (CRF). A generic statement (e.g., “Subject meets all criteria”) is not acceptable.
Physician Assessment: A qualified investigator or sub-investigator must assess each criterion and document the decision to include the subject before any intervention begins.
Considerations
Address sex and gender issues as recommended by Swissethics.
Clearly justify all criteria to ensure eligibility requirements align with study objectives and regulatory standards.
In the SIGNATURES2023 trial, for the healthy control person groups we had the following text:
Healthy controls (all sub groups)
The criteria of participations with adhere to ADNI EANM procedure guidelines for PET imaging of the brain glucose metabolism.
Apart from HV-1H-II-Opt and HV-2H-III-Opt, all participants will undergo a pre-screening visit, which will include standard glucose measurement after an overnight fast, and completion of a medical history questionnaire including the use of prescription medications. Healthy volunteers will be defined as person with no known significant health problems, good general health with no diseases precluding enrolment. A small drop of blood, obtained by pricking the skin with a lancet, will be placed on a disposable test strip and inserted into a CE-certified glucose meter to calculate the blood glucose level.
Inclusion criteria:
Informed consent signed by the subject.
Healthy (no neurological, metabolic, or psychiatric diseases as stated by the study participant).
Being able to lie still in the MR-scanner for at least one hour.
No current or life-time drug or alcohol abuse.
Not medication that interferes with cognition.
Normal or corrected to normal vision.
Exclusion criteria (also account for patient groups with indicated exceptions):
<18 years of age
Claustrophobia
Pregnancy or current state of lactation
Active implants (e.g., pacemakers, neuro-stimulators)
Passive ferromagnetic implants
Passive non-ferromagnetic metallic implants > 4 cm inside a region covered by the active RF coils.
Large tattoos inside a region covered by the active RF coils.
Known or suspected non-compliance or claustrophobia.
Underweight < 30 kg body weight.
Body mass index (BMI) > 30.
Overweight > 135kg
Persons with extreme big head circumference and/or extreme astigmatism which cannot be corrected by MR-compatible exe-glasses set.
Persons not able to understand the informed consent form.
Not agreeing with the institute’s policy that the subject must be informed on any incidental findings found during the examination.
Visual and auditory acuity impairing neuropsychological testing (if relevant).
Diabetes or glucose intolerance according to World Health Organization recommendations (excluded the diabetes patient group)
Evidence of overt heart or renal disease.
Evidence of disease of the gastrointestinal tract.
Indication of cognitive impairment (Mini-mental state examination score <26/30, CDR score > 0, memory complaints) (excluding AD, MCI-groups).
Current or life-time drug or alcohol abuse.
Untreated dyslipidemia, hypertension, or thyroid disease.
Antidepressant medications with anticholinergic properties and the regular use of narcotic agents more than 2 doses per week within 4 weeks of screening.
Antiparkinsonian medications used within 4 weeks of screening.
Enrollment in any investigational drug studies within 4 weeks of screening
Immunomodulating or oncological treatment.
The cardiac implantable electronic device (CIED) such as pacemakers, implantable cardioverter defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices.
Metallic intraocular foreign bodies: The patient should be asked if he/she has ever welded without eye protection or had any facial injury with metal; if yes, an orbit x-ray must be taken and reviewed by the radiologist for approval before the MRI.
Implantable neurostimulation systems
Cochlear implants/ear implant: BAHA cochlear implant type can be scanned on a 7-tesla scanner only after the patient removes the battery. Cochlear implant wrapping scheduling must take place before the patient’s MRI appointment.
Drug infusion pumps (insulin delivery, analgesic drugs, or chemotherapy pumps): If possible, the patient has to remove the device.
Catheters with metallic components (Swan-Ganz catheter)
Metallic fragments such as bullets, shotgun pellets, and metal shrapnel
Cerebral artery aneurysm clips
Magnetic dental implants
Tissue expander
Artificial limbs
Non removeable earing aid
Non removable piercing
Metallic intraocular foreign bodies,
Drug infusion pumps,
Catheters with metallic components,
Metallic fragments,
Cerebral artery aneurysm clips,
Magnetic dental implants,
Tissue expander,
Artificial limb,
Non removable hearing aid
Non removable piercing
Implantable cardiocerter defibrillators
Cardiac resynchronization therapy devices
Volunteers taking amphetamines and sedatives
Fever (T > 37.5°C measured prior to entering MR)
Body temperature = . °C
Swissmedic is focussing strongly on “hyperthermia” in test persons and patients. Swissmedic insisted that of all persons participating in SIGNATURES2023 the body temperature should be measured before entering the magnet. All my arguments that any MR-scanner controls the maximum (local)-SAR independently of what pulse sequences, or what RF-hardware (fulfilling the IEC-60601-2-33 standard) is used did not bring them off the demand that temperatures in all subjects must be measured.
Since the inclusion and exclusion criteria of our 4 different patient groups (Alzheimers’ disease; minimal cognitive impaired, diabetes type 2, and patients with a single sided carotid stenosis) are such specific for our trial, we will not mention them here.
7.2 Recruitment and screening
To give you an impression how this section can be handled we add the following example text:
Healthy controls will be recruited through flyers posted on analog and virtual message boards. After initial contact, potential participants will receive oral and written information about the study, with exclusion criteria emphasized early.
A designated study team member (e.g., a technician or local investigator) will explain the study’s nature, purpose, procedures, duration, potential risks, benefits, and any possible discomfort. Participants will be informed that participation is voluntary and that they can withdraw at any time without affecting their future medical care or treatment at [your institute/hospital].
For the MCI and AD patients we had the following (shortened) text:
Patients with mild cognitive impairment (MCI) or Alzheimer’s disease (AD) will be recruited through the memory clinic, collaborators, or newspaper and social media advertisements. Prospective participants will be contacted by telephone and undergo an initial screening to assess eligibility.
An investigator will explain the study’s purpose, procedures, duration, potential risks, benefits, and any discomfort involved. Participants will be informed that participation is voluntary, they may withdraw at any time without affecting their future medical care, and their medical records may be reviewed by authorized personnel outside their treating physician.
Each participant will receive a participant information sheet and consent form with sufficient details to make an informed decision. Consent will be formally obtained using the approved form before any study procedures begin. Both the participant and the investigator (or their designee) will sign and date the form, with a copy provided to the participant and the original retained in the study records.
For the DM type 2 patients we had the following (shortened) text:
Patients with type 2 diabetes will be recruited through referrals from the diabetes clinic at the [your institute] or collaborating external physicians.
For this patient group, it is important to note that participants will have an HbA1c of no more than 7.5%, with or without treatment involving a maximum of two oral glucose-lowering agents. These inclusion criteria ensure that participants have early-stage type 2 diabetes with preserved endogenous insulin production. As a result, the glucose load used in the study poses no risk to participants, and no additional medical follow-ups outside of routine care will be required.
And finally, for the carotid stenosis patients we had following text:
Patients with high-grade carotid stenosis will be identified through the weekly neurovascular board, which involves close collaboration between the Departments of Neuroradiology, Neurosurgery, Vascular Surgery, and Angiology. Recruitment will take place within the dedicated Neurovascular Consultation at the Department of Neurology, [your institute].
The following general text followed valid for all groups:
All participants in the study will receive a participant information sheet, a consent form, and an MR screening form. They will have the opportunity to ask any questions via telephone, email, or in person. Five distinct participant information and consent forms will be used: one for the healthy control group and four for the respective patient groups.
Formal consent should be obtained well in advance—at least two days before any study procedure. Participants will be given ample time to review the information and consider their participation. Once they decide to participate, they will sign and date the informed consent form, and a copy will be provided to them. The form will also be signed and dated by the investigators, with the original retained as part of the study records.
7.3 Assignment to investigation groups
The instructions for this section are the following:
Requirements for Describing Randomization and Treatment Assignment
Randomization Process:
Specify the tools used for randomization (e.g., software, random number generator).
Identify who will perform the randomization and at what stage of the process.
Treatment Assignment:
Describe how treatment assignments will be determined and allocated.
Allocation Sequence:
Explain the mechanism for implementing the allocation sequence (e.g., central telephone system, sequentially numbered opaque sealed envelopes).
Detail measures to conceal the allocation sequence until interventions are assigned.
Reference to Relevant Sections:
Refer to Chapter 6.2.1, if applicable, for further details.
This SIGNATURES2023 does not contain any randomization, therefore we could leave this section empty.
7.4 Criteria for withdrawal / discontinuation of subjects
The CIP instructions for the section can be summarized in a list like follows:
Criteria for Subject Withdrawal:
Define when and how subjects may be withdrawn from the investigation.
Specify circumstances under which subjects will be replaced.
Reasons for Withdrawal or Discontinuation:
List possible reasons for subject withdrawal, such as:
Voluntary withdrawal.
Non-compliance with study protocols.
Disease progression.
Safety concerns.
Intervention Discontinuation:
Outline conditions under which the intervention will be discontinued.
Follow-Up Procedures:
Refer to Chapter 9.2.5 for follow-up procedures addressing situations like:
Withdrawal of informed consent.
Non-compliance.
Safety concerns or disease progression.
Stopping the investigation or routine procedures due to safety issues.
For the SIGNATURES2023 this section had the following content:
Participants, both patients and healthy volunteers, may withdraw from the study at any time. Upon withdrawal, data collected up to that point may be used in coded form, and after analysis, it will remain coded. The following criteria apply for withdrawal or discontinuation of participants:
Withdrawal of informed consent.
Changes in health condition that make continued participation unwise or meet any exclusion criteria.
Safety concerns or risks to the participant for any reason.
Alterations in accepted MR safety guidelines for 7T scanning.
Evidence or suspicion of harm from any planned intervention or action.
Inability of the participant to remain still for the required duration of scanning.
Participants who drop out will be replaced by other volunteers or patients. Replacing healthy volunteers is straightforward, though it may require repeating a series of scans. However, replacing patients may be more challenging.
To comply more with the given instructions, one could also consider to write for your proposal:
Consider explicitly referring to follow-up actions if participants withdraw due to non-compliance, safety concerns, or disease progression, as mentioned in the instructions (e.g., ensure adequate follow-up or document final assessments).
If applicable, mention that replacement participants will follow the same recruitment and eligibility procedures as the original participants.
8. CLINICAL INVESTIGATION INTERVENTION
The template demands you to describe:
Describe all treatments for each arm of this investigation. Methods, equipment and timing for assessing, recording and analysing variables.
The SIGNATURES2023 did not have arms, therefore we left this section empty.
8.1 Identity of the medical device under investigation
The template demands you to describe:
Describe all treatments for each arm of this investigation. Methods, equipment and timing for assessing, recording and analysing variables.
The SIGNATURES2023 did not have arms, therefore we left this section empty.
8.1.1 Experimental Intervention (medical device)
The template demands you to describe:
Intervention Details:
Describe the experimental intervention and any medical or surgical procedures involved.
Specify the route and place of implantation, if applicable.
Deviations from Commercial Product:
Note any deviations from the standard commercial product.
Device Usage:
For pre-market investigations, describe how the device is used or implanted.
Include necessary training and experience for proper use.
Proctoring:
Mention if proctoring is required during the intervention.
Supporting Materials:
Consider adding pictures or sketches to illustrate handling, application, or implantation processes.
Avoid repeating information from Chapter 3.2 and focus on details specific to the experimental intervention.
In the SIGNATURES2023 study we shortly answered following, not repeating the whole again:
Measurements with optimized pulse sequences as described in sections 3.2, 6.1 and for the evaluation 9.2.1.
8.1.2 Control Intervention (standard/routine/comparator)
Here the CIP template gives the following instructions as bullet list:
Comparator Details:
Describe the comparator(s), including routine (standard) medical devices (MDs), medicinal products, or other interventions.
Provide details such as name, material, model/type, software version, and accessories.
Include a picture of the MD, if applicable.
Usage and Application:
Specify the route and place of implantation for MD comparators.
Note any deviations from the commercial product.
Sham Interventions:
Describe procedures for sham interventions, if applicable.
Training and Experience:
Include details on the necessary training and experience for proper use of the comparator.
Consider using pictures or sketches to illustrate handling, application, or implantation processes.
Describe how the investigational medical device (MD) and comparator (if applicable) are labelled.
Ensure labels comply with Art. 6.10 ISO14155, indicating the device is for investigational use only, unless not required (e.g., based on the clinical development stage or investigation design).
Supply to Investigational Site:
Detail how the MD and comparator are provided to the investigational site.
Re-Supply Logistics:
If applicable, describe the logistics for re-supply of the MD.
Post-Market Investigations:
Note that labelling is not mandatory for post-market device investigations.
Deviations from Commercial Product:
Specify any deviations from the standard commercial product, if applicable.
The investigational medical device (MD) in this study is a combination of three components:
CE-Marked MR Scanner: A certified, CE-marked MR scanner, ensuring that all standard safety precautions and regulatory requirements remain in place.
Non-CE-Marked Pulse Sequences: Custom-written pulse sequences developed using the manufacturer’s dedicated software environment, which is also used internally by the manufacturer for similar purposes.
Non-CE-Marked Dual-Tuned Head Coil: A newly developed dual-tuned head coil specifically designed for the intended applications in this study.
All mandatory safety and performance tests for the non-CE-marked components have been completed. Swissmedic [or your local EU-CA]has thoroughly reviewed the application and approved the study, ensuring compliance with all regulatory and safety standards. This approach integrates innovation while maintaining the safety framework of the CE-marked scanner.
8.1.4 Storage Conditions
As a bullet list the CIP template requires following information:
Storage Conditions:
Describe how the investigational MD and comparator MD/medicinal products are stored (e.g., temperature range, light exposure, sterile environment).
Secure Storage:
Ensure MD supplies are kept in a secure, limited-access storage area under recommended conditions.
Standard Procedures:
For MDs already in use, mention that “supply,” “storage,” and “return or destruction” follow standard procedures, without requiring specific details in the CIP.
8.2 Discontinuation or modifications of the intervention
The CIP instructions state:
Describe criteria for discontinuing or modifying allocated interventions for a given subject (e.g., removal of the implanted MD in response to harms, subject request, or improving/worsening disease).
It is evident that the CIP template is far from optimal for MD studies focused on MR scanning, making it particularly challenging and cumbersome to complete. We have adapted the provided instructions into the following text:
If incidental findings are detected during the intervention (MR scan) for any subject, the procedure will be immediately discontinued and replaced with appropriate sequences to investigate the findings in greater detail. All subjects will be informed about any incidental findings after the examination. Compliance with our institution’s policy, which mandates informing subjects of such findings under all circumstances, is essential. Failure to adhere to this requirement would disqualify the subject from participation in the study, as noted in the exclusion criteria.
8.3 Compliance with clinical investigation intervention
The CIP template gives the following instruction:
Describe the procedures for monitoring subject compliance and the strategies to improve adherence to the intervention, and any procedures for monitoring adherence (e.g., return of unused MD, laboratory tests). Define non-compliance and how such subjects should be handled.
Translated to a typical MR-trial situation one could think to describe following aspects:
For an MR trial using custom-written sequences and a non-CE-marked RF coil, the instruction means you need to address the following:
Monitoring Subject Compliance:
Procedures for Compliance Monitoring:
Explain how you will ensure participants adhere to study protocols, such as attending scheduled MR scans and following pre-scan instructions (e.g., fasting, avoiding metal accessories).
Include any specific monitoring processes related to the investigational devices, such as ensuring the RF coil is used correctly and the custom pulse sequences are applied as intended.
Strategies to Improve Adherence:
Detail measures to support compliance, such as clear pre-study instructions, reminders (e.g., phone calls, emails), and pre-scan checklists for both participants and staff.
Adherence Monitoring Specific to MR Equipment:
Describe how the investigational devices will be accounted for during and after use. For example:
Ensuring proper use of the RF coil by trained personnel.
Regular checks of the pulse sequences to confirm correct application.
Include methods such as documenting the use of devices in a log or verifying protocol adherence through system logs or data reports.
Defining and Handling Non-Compliance:
Definition of Non-Compliance:
Define what constitutes non-compliance in the context of your MR trial. Examples might include:
Participants not attending scheduled scans.
Failure to follow safety protocols (e.g., wearing compatible clothing or reporting contraindications).
Improper use or misuse of the investigational devices by staff or participants.
Handling Non-Compliant Participants:
Outline steps to address non-compliance, such as:
Re-educating participants on study requirements.
Excluding participants from the study if non-compliance persists or compromises safety/data integrity.
Documenting incidents of non-compliance and their resolution.
We wrote for the SIGNATURES2023 trial the following text (which was accepted by the local CEC) and is very short (Remark: looking back, this text is way to short, but nevertheless accepted):
For methodology evaluations, the only non-compliance to be considered is the case that a subject does not lie still enough. This normally becomes evident during the scan from image or spectral artifacts or changes in achieved field homogeneity. The importance of lying still is reiterated through the intercom and the affected sequences are repeated. For severe restlessness, the scan is aborted and rescheduled with another subject.
8.4 Data Collection and Follow-up for withdrawn subjects
The template describes the following what kind of information is required here.
Data Collection for Withdrawn Subjects:
Record the reason(s) for withdrawal, if provided by the subject.
If withdrawal is due to safety or performance issues related to the medical device (MD), the Principal Investigator (PI) should seek the subject’s permission to monitor their condition outside the investigation.
Data Evaluation:
Evaluate data and material already collected according to Art. 3 Abs. b ClinO-MD.
Data Handling After Withdrawal:
Specify whether collected data will be:
Anonymized: If possible, anonymize the data after evaluation.
Coded (Not Anonymized): If anonymization is not possible, the data remains coded.
Biological Material Handling:
Specify whether biological material will be:
Anonymized: If possible, anonymize after evaluation.
Destroyed: Destroy biological material after evaluation if anonymization is not feasible.
The following line must be included according the instructions:
The medical follow-up of withdrawn subjects, or of subjects that drop out from the investigation prematurely is described in chapter 9.2.5 and chapter 9.2.6.
We entered this sentence without any change for the SIGNATURES2023 trial.
8.5 Clinical investigation specific preventive measures
The CIP template gives following instructions for the investigator:
Describe any specific preventive measures, including rescue medication for the subjects or treatments that are prohibited (restrictions). Their use should be recorded in the CRF. Describe their potential impact on the objectives of the investigation.
In the SIGNATURES2023 study it we did not adequately handle this section, but it was nevertheless accepted. A much better text would be the following for pure MR-study trials.
To ensure participant safety and compliance with regulatory requirements, specific preventive measures are implemented during the study:
Body Temperature Measurement:
Before entering the scanner, each participant’s body temperature is measured to confirm they are within the safe range for the procedure.
This step was mandated by Swissmedic [or your local EU-CA]to prevent potential risks associated with elevated body temperature during MR scanning.
Use of MRI Screening Form:
The MRI screening form includes targeted background questions (e.g., prior surgeries or medical implants) to verify participant eligibility and safety.
The accuracy of the form’s responses is confirmed during a personal interview with the participant.
Restrictions on Prohibited Treatments or Devices:
Any medical treatments, implants, or conditions that are contraindicated for MR scanning are recorded in the CRF.
These restrictions are carefully monitored to ensure they do not interfere with the study objectives.
8.6 Concomitant Interventions (treatments)
The CIP template gives following instructions on this section:
Describe any specific or relevant concomitant care and interventions that are permitted (additional treatments) during the investigation. Their use should be recorded in the CRF. Describe their potential impact on the objectives of the investigation.
The CIP template gives following instructions on this section:
Provide plans of accurate and adequate records maintenance from shipment to the sites until return or disposal including the quantities, the dates of receipt, use, and return, identification of each MD (batch number/serial number or unique code), the expiring date if applicable, the subject identification, the physical storage location, the date on which the MD was returned by the patient/explanted, if applicable, the date of return of unused, expired or malfunctioning MDs, if applicable.
The accountability includes the accountability of the comparator(s).
Accurate and comprehensive records will be maintained to ensure full accountability of the investigational medical devices (MDs), including the non-CE-marked RF coil and custom pulse sequences. The following measures will be implemented:
Pulse Sequence Accountability:
Records of pulse sequence programming, including all development stages, will be meticulously maintained in lab journals by each investigator.
Intermediate source code and executable code versions of all pulse sequences will be securely stored in a privately owned software versioning system (Git).
RF Coil Accountability:
The non-CE-marked RF coil will be tracked through a detailed log, documenting its batch number/serial number or unique identifier, receipt date, and physical storage location.
Usage during MR examinations will be recorded, including subject identification and the dates of use.
Examination Records:
Data from MR examinations will be extensively documented during scanning and during the evaluation phase. Relevant experimental scans will be performed multiple times and reviewed by the team to ensure accuracy and reliability of conclusions.
Device Return and Disposal:
If applicable, the RF coil’s return, malfunction, or disposal will be recorded, including the date of return or disposal of the device.
Comparator Accountability:
Although no comparator device is included in this study, any future use of comparator devices will follow the same rigorous accountability procedures.
8.8 Return, Analysis or Destruction of the Medical Device
The CIP template text gives following instructions:
Provide a statement if the MD under investigation is shipped back to the Sponsor disposed/destructed at the hospital at the end of the investigation. Add procedures for preparation and shipment of used MD at the end of the investigation.
For MD already in use at the hospital “return or disposed/destructed” are according to standard procedures and mentioning this in the CIP is enough (no details needed).
In case of device deficiencies, including malfunction, usability issues, or inadequacy in the information supplied by the manufacturer including labelling, the devices will be returned to the sponsor for analysis.
Add procedures for documentation by the centre (e.g. pictures that need to be taken in situ and of the explant), and for preparation and shipment of used devices and explants.
In an MR-study, where the subject of the study is the test of the medical device itself this section is most likely not relevant. In the SIGNATURES2023 study we therefore wrote:
Not applicable.
9. CLINICAL INVESTIGATION ASSESSMENTS
The CIP template gives the following instruction:
Describe the clinical procedures, diagnostic methods, collection, storage of samples taken, etc. relating to the clinical investigation and in particular highlighting any deviation from normal clinical practice (Annex XV, chapter 2, Art. 3.6.5 MDR)
No text added here in our CIP document of SIGNATURES2023.
9.1 Clinical investigation flow chart(s) / table of clinical investigation procedures and assessments
The CIP template gives the following instruction:
Provide a detailed graph, chart or table of flow of the investigation and for the subject (“assessment schedule”) with what is measured and how, grouped according to primary and/or secondary endpoints. Include the allowed time frames for each visit. The flow chart should comprise all investigation procedures during the whole course of the investigation, not only the assessed endpoints. It may be referred to the chapters “clinical investigation procedures” in case all these details are provided there. It is recommended that the flow chart is repeated here.
We wrote:
Please refer to the table under INVESTIGATION SCHEDULE above (see e.g. Table 1).
9.2 Assessments of outcomes
The CIP template gives the following instructions on what here written:
If not already described under chapter 5: Describe for each endpoint (if applicable) what variables will be assessed/observed and how it will be done (e.g., questionnaires, laboratory tests), including any related processes to promote data quality (e.g., duplicate measurements, training of assessors; equipment to be used and arrangements for maintenance and calibration). Provide the rationale or justification to use certain methods and not others etc. Define the time windows allowed.
9.2.1 Assessment of primary outcome
We wrote here the following (the SIGNATURES2023 has four phases):
Phases I-IV
MRSI Data Reconstruction — Reconstruction of the raw EPSI/MRSI data will preferably take place on the Mars server of the Terra system. Currently efforts are being made to get the reconstruction done on the Terra. Alternative the reconstruction of the data will be performed within the Midas software which based on IDL, of which our institute possesses two licences.
Spectral quality — The number of spectra collected per subject are in the order of several ten thousand. A first overall assessment of the data will be made manually by an expert. Quality filtering will be performed using either a deep learning (manuscript to be submitted) or machine learning approach45,46 . The deep learning part of this quality filtering is financially covered by the project. Expert decision on the iterative improvement of the spectra (failed or successful improvement). Quantitatively, the error of the spectral quantification will be either be assessed by the Cramer-Rao-Lower-Bounds (CRLB) or by gradient information provided by the tensor flow library, a measure that determines the precision of the estimated concentrations from the acquired spectra using a model of metabolite contributions in the tissue.
Quality filtering — Additionally to these the supervised quality evaluations, fully automated quality filtering will be applied using machine learning and deep learning technologies which are currently under development but will be available at the start of the data evaluation phase of the project.
Spectral Processing and Quantification — Spectral processing will be performed within spectrIm-QMRS a home build software package for MRS and large data size MRSI datasets. Quantification will be performed with either tdfdfit, or with a deep learning package which is currently under development.
Co-registration and statistics — Co-registration of 3D MRSI datasets will be performed using FSL to map metabolic data onto brain atlas. Z-score statistics and statistical analysis will be performed using R and RStudio.
General remarks — The non-quantitative output consists of the spectra obtained from the new methods that are compared to theoretically expected spectra. Quantitatively, detected metabolites will be assessed by standard model fitting tools developed earlier in this institution. Fitting precision is determined as CRLB, calculated in the same tool. Repeatability is determined as coefficient of variance (CV) for each evaluated metabolite as determined from immediately repeated scans. Intersubject variability is assessed by CV of determined metabolite content over measurements over a group of subjects (n=10). This measure includes the intra-subject repeatability variance, but is the standard way used in the literature for such MR evaluations. Repeated measures ANOVA can be used to separate the sources of variability. The same applies to apparent metabolite diffusion coefficients for some of the subprojects. For some subprojects, difference spectra are the prime output (if no exact model for fitting is available, e.g. exchanging protons that are turned better visible).
9.2.2 Assessment of secondary outcomes
The CIP template gives the following instructions on what here written:
If not already described under chapter 5.2: What will be assessed, when and how (e.g., The secondary outcome, change of diastolic and systolic blood pressure at the various time-points, will be measured as described for the primary endpoint.).
Here the following was written for the SIGNATURES2023 study:
Secondary outputs use the same modeling/processing tools as described 9.2.1.
9.2.3 Assessment of other outcomes of interest
The CIP template gives following instructions for this section:
If not already described under chapter 5.3: What will be assessed, when and how (e.g., demographic characteristics, physical examination, quality of life, biomarkers: describe sample kind, preparation, storage (in biobanks and the appropriate procedure with separate PIC) or destruction, shipment to other labs/ countries if applicable. In case of pharmacokinetic parameters: describe condition of subject (e.g., fasting, x hours after treatment with MD), time-points of sampling, size of sample taken, sample processing, storage, shipping, substances to be analysed, how their concentration is measured, validation of analytical system).
Here the following was written for the SIGNATURES2023 study:
Not applicable.
9.2.4 Assessment of safety outcomes
The CIP template gives following instructions for this section:
If not already described under Chapter 5.4: What will be assessed, when and how.
9.2.4.1 Adverse events
Recording of adverse event information, what information needs to be collected: time of onset, duration, resolution, action to be taken, assessment of intensity, relationship with the MD and with the procedures of the investigation, expectedness, seriousness. Define specific process to ask the subject at the visits about adverse events, collection of spontaneous reports.
Refer to chapter 10.1 for AE definition and reporting procedures to CA and CEC.
9.1.4.2 Laboratory parameters
Specify laboratory parameters to be assessed; define time-points of assessment; describe sampling if deviating from hospital routine; specify tests to be used (e.g., for pregnancy: blood, urine; urinalysis); describe analysis of samples: local or abroad, if abroad, describe procedure for shipment, storage until shipment; if not yet known, refer to instruction to be written for the investigation team and to be part of the investigation manual.
Define when abnormal laboratory parameters are considered as adverse events in chapter 10.3.1 for category C investigations and in chapter 10.4.1 for category A investigations. Refer to chapter 10 for reporting procedures to CA and CEC.
9.1.4.3 Vital signs
Describe how and when they will be assessed (e.g., heartbeat, blood pressure, body temperature, ECG) (e.g., in supine position after 5 minutes resting).
We (again!) filled out this issue in a wrong way, namely that we do not assess safety outcomes which is definitively the wrong answer (I noticed this while creating this blog post). But, again the local CEC did not notice this. A better, legal compliant answer would be (adapted to the MR-trial case):
Safety outcomes will be assessed throughout the study to ensure compliance with Swissmedic [or your local EU-CA]requirements and participant safety. Comprehensive safety evaluations have been conducted during the preclinical phase, and the results are documented in the submitted safety report. These evaluations form the basis for monitoring safety during the clinical investigation. What will be assessed
What will be assessed:
Device-Specific Safety:
The safety of the non-CE-marked RF coil and custom pulse sequences will be monitored, focusing on specific parameters such as Specific Absorption Rate (SAR), temperature increases, and any potential adverse device effects.
Participant Safety:
Participant-specific safety measures include screening for contraindications, monitoring during MR scanning, and assessing for any adverse events related to the investigational device.
When and How Safety Outcomes Will Be Assessed:
Pre-Scan Assessments:
Body temperature measurement and MR safety screening forms will be completed before each scan to confirm participant readiness and safety.
During the Scan:
Real-time monitoring of device performance and participant well-being will be conducted during scanning sessions.
Data logs from the MR scanner and associated devices will be reviewed to identify any irregularities.
Post-Scan Evaluations:
Participants will be monitored for adverse events following the MR scan, and any findings will be documented and reported as required.
9.2.5 Assessments in subjects who prematurely stop the clinical investigation
The CIP template gives following instructions for this section:
Describe follow-up procedures and assessments in subjects who withdrew/drop out from the investigation prematurely (e.g., recording of adverse events, physical examination, laboratory parameters, vital signs). The information provided here should not contradict the information provided under chapter 7.4. clinical investigation discontinuation criteria. Define follow-up period.
Indicate if and how the collected data of subjects withdrawing their consent during the course of the investigation is used and analysed. Indicate what happens to the data after the analysis. The details given here must match the information given in the patient information and consent form and in chapter 8.4 and 12.6.
Here the following was written for the SIGNATURES2023 study:
If a participant withdraws before entering the scanner or before any useful data has been acquired, both the participant and their corresponding data will be excluded from the study. However, if a participant withdraws after potentially useful data has been collected, the corresponding data will be retained and used in coded form.
9.2.6 Follow-up of the subjects after the regular termination of the clinical investigation
The CIP template gives following instructions for this section:
Describe the arrangements for taking care of the subjects after their participation in the clinical investigation has ended, where such additional care is necessary because of the subjects’ participation in the clinical investigation and where it differs from that normally expected for the medical condition in question.
Here the following was written for the SIGNATURES2023 study:
Neither for patients nor for healthy controls a follow up examination is planned.
9.3 Procedures at each visit
The CIP template gives following instructions for this section:
Describe the procedures at each visit according to investigation phase: e.g., screening, baseline, visits during intervention, close-out visit, follow-up visits. Include additional tasks as scheduling of next visit, time windows permitted, etc.
9.3.1 Recruitment/Information
In any Clinical Investigation Plan (CIP), the section on “Recruitment/Information” plays a critical role in demonstrating compliance with ethical and regulatory requirements. It outlines how potential participants are approached, informed, and ultimately recruited into the study, ensuring that all processes align with the principles of informed consent and respect for participants’ autonomy. This section is essential not only for meeting the expectations of ethics committees but also for safeguarding the rights and welfare of study subjects. By detailing these processes, researchers show their commitment to transparency, ethical rigor, and adherence to frameworks like ISO 14155 and national regulations, such as Switzerland’s ClinO-MD. Including a thorough “Recruitment/Information” section enhances the credibility of your application and minimizes risks of delays due to ethics committee feedback. For MR scientists navigating these submissions, this is a key step in building trust and meeting the stringent standards of clinical research governance.
The official CIP template informs the applicants the following way:
E.g. Screening visit, Day (e.g., -10 to 0): List all exams/tests and other actions to be performed.
The following section we wrote on this and could serve as a starting point for you:
Recruitment of participants will be conducted via flyers displayed on physical and digital blackboards (proposed flyer submitted for review). Interested individuals may reach out by telephone or email to request further information. A designated contact person for the MR aspect of the study will handle these inquiries. Recruitment of patients will be managed by clinical collaboration partners associated with the study, as detailed earlier in this proposal. Specific patient groups will be recruited through relevant specialists, including diabetes patients, high-grade stenosis patients, and individuals with Alzheimer’s disease or mild cognitive impairment.
At least two days prior to their examination, potential participants will be provided with study information over the phone, followed by an email containing the written information sheet, consent form, and the necessary MRI safety questionnaire. The names of potential participants will be recorded, but contact details will remain confidential, and any personal information will be securely discarded if they choose not to participate. Participants also have the option to inquire anonymously. For additional information, the principal investigator or a designated representative will follow up as needed.
9.3.2 MR examination day
The CIP templates informs the applicant in the following way:
E.g. Visit 1, Baseline (Day e.g., 1): List all exams/tests, actions to be performed according to flow chart (chapter 9.1) including also e.g., application of the MD, Scheduling of next visit
This section outlines the standardized procedures for conducting MR examinations and glucose supplementation in the study. Clear protocols ensure participant safety, compliance with regulatory standards, and consistency in data collection.
MR Examination: Participants arrive at the [your MR-scanner facility, location], where they are briefed again about the study and their participation. They provide informed consent and complete the MR safety form, with the MR safety questions reiterated orally. Participants then change into MR-safe clothing provided by the facility. The MR examination proceeds, with participants remaining in the scanner for the required duration. For healthy volunteers, this ranges from 1.5 to 2.5 hours. Timing details for patients are outlined in Tables 8–11 above.
Glucose Supplementation: Either α-D-glucose for 1H-MRSI or [6,6′-2H2]-glucose for 2H-MRSI is prepared at least two hours prior to the examination to allow the solutions to reach thermodynamic equilibrium between α- and β-glucose, minimizing the effects of mutarotation. This equilibrium ensures more stable and interpretable data during the study.
9.3.3 Split into subtitles by type of visit
The official CIP template instructs the following way:
E.g. Visit 2-5 (± indicate the window), if they are identical, otherwise describe each visit separately. Final visit, safety follow-up visit 7-9 (± indicate the window). Mention the hand-over of the implant card in case of implantable MD.
For the SIGNATURES2023 project we wrote, (since we only do an MR-scans):
Not applicable.
10. SAFETY
The general CIP instruction to this Chapter is:
Describe plans for collecting, documenting, assessing, reporting, and managing solicited and spontaneously reported adverse events, adverse device effects and other unintended effects of the interventions or conduct of the investigation.
10.1 Definition and Assessment of (Serious) Adverse Events and other safety related events
In any clinical investigation involving medical devices, robust systems for identifying, documenting, assessing, and managing adverse events and device deficiencies are critical. This ensures participant safety, aligns with ethical principles, and demonstrates compliance with regulatory standards like the MDR and ISO 14155. Adverse events, whether related to the device or not, must be systematically evaluated to mitigate risks and maintain the credibility of the study. This section establishes clear definitions and processes for handling safety-related events, underscoring the importance of transparency and accountability in clinical research. Such practices are fundamental for gaining approval and fostering trust with regulatory bodies and participants.
This section is already defined by the for the applicant by BASEC. There is nothing to write yourself here. Although the applicants must be aware of the defined notions. So in the SIGNATURES2023 application the following was written:
Any untoward medical occurrence, unintended disease or injury or any untoward clinical signs (including an abnormal laboratory finding) in subjects, users or other persons whether or not related to the MD.
Any adverse event that led to any of the following:
(a) death,
(b) serious deterioration in the health of the subject that resulted in any of the following:
(i) life-threatening illness or injury,
(ii) permanent impairment of a body structure or a body function,
(iii) hospitalisation or prolongation of patient hospitalisation,
(iv) medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function,
(v) chronic disease,
(c) foetal distress, foetal death or a congenital physical or mental impairment or birth defect.
Note: planned hospitalization for pre-existing condition, or a procedure required by the CIP, without a serious deterioration of the health status of the subject, is not considered an SAE
Inadequacy of a medical device related to its identity, quality, durability, reliability, safety or performance, of an investigational device, including malfunction, user errors and inadequate information supplied by the manufacturer.
Failure of an investigational device to perform in accordance with its intended purpose when used in accordance with the instructions for use or the CIP.
Any device deficiency that might have led to a serious adverse event if appropriate action had not been taken, intervention had not occurred, or circumstances had been less fortunate.
Serious adverse device effect (SADE) which by its nature, incidence, severity or outcome has not been identified in the current version of the risk analysis report.
A causal relationship towards the medical device or the procedure of the investigation should be rated by the Sponsor-Investigator as follows:
Not related: The relationship to the device or procedures can be excluded.
Possible: The relationship with the use of the investigational device is weak but cannot be ruled out completely. Alternative causes are also possible.
Probable: The relationship with the use of the investigational device seems relevant and/or the event cannot reasonably be explained by another cause.
Causal relationship: The serious event is associated with the investigational device or with procedures beyond reasonable doubt.
10.2 Adverse events categorization
In the context of an MR-MD trial categorized as type C, this section underscores the systematic approach to assessing adverse events while acknowledging the inherently low risk associated with non-CE-marked sequences and RF hardware. Despite these investigational components being very safe, applicants must remain aware of these classifications and processes to ensure compliance and uphold participant safety. Rigorous safety protocols further ensure that the risks remain manageable and well-monitored throughout the trial.
In the SIGNATURES2023 application, we took over the CIP-template text:
The adverse events are categorized by the Sponsor-Investigator using the following algorithm:
Does the AE meet the seriousness criteria?
No, it is not serious:
Is the relationship to the device or the procedure possible, probable or causal?
No: non-related AE
Yes: ADE
Yes, it is serious: SAE
Is the relationship to the device or the procedure possible, probable or causal?
No: non-related SAE
Yes: SADE
Is it anticipated (within expected type, severity and frequency of the complications)?
No: unanticipated SADE (USADE)
Yes: anticipated SADE (ASADE)
10.3 Documentation and reporting in Medical Device Category C clinical investigations
The instruction of the template is the following:
Important note concerning all following sections of this chapter: add, respectively adapt to other local requirements in case of international investigations.
We wrote the following section for the SIGNATURES2023 trial:
Device deficiencies and all adverse events (AE) including all serious adverse events (SAE) are collected, fully investigated and documented in the source document and appropriate CRF during the entire investigation period, i.e. from patient’s informed consent until the last CIP-specific procedure, including a safety follow-up period.
Documentation of AEs (including SAEs) by the PI includes diagnosis or symptoms, start and stop dates of event, event treatment, event resolution, assessment of seriousness and causal relationship to MD and/or investigation procedure (Art. 32 ClinO-MD, ISO14155).
Documentation of DDs by the PI includes description of event, start date, investigational device information, action taken with regard to the investigational device, and whether the DD led to an AE. The Sponsor shall review all DDs and determine and document in writing whether they could have led to a SAE (DD with SADE potential) (Art 32. ClinO-MD, ISO14155).
The Sponsor-Investigator provides the CA and the CEC with the documentation at their request (Art. 32 ClinO-MD).
Any AE and SAE are immediately reported to the Sponsor-Investigator by the local operator of the MR scanner.
10.3.1 Foreseeable adverse events and anticipated adverse device effects
We wrote the following section for the SIGNATURES2023 trial:
Foreseeable adverse events include those typically associated with MRI at any field strength. These encompass incidents such as accidents involving ferromagnetic objects being attracted to the magnet, as well as burns or tissue overheating due to excessive RF energy, particularly in cases where metal-containing materials (e.g., tattoo ink) interact with RF fields. However, the likelihood of such events occurring is extremely low due to the stringent screening protocols in place for participants entering the study and the magnet room. This triple-layered screening process includes: (1) screening at the time of study registration, (2) completion of a written MR safety questionnaire before entering the scan room, and (3) oral verification of critical safety questions, such as inquiries about prior surgeries. RF overload is further mitigated by the scanner’s built-in software and hardware safeguards, and the occurrence of such an event would require an unprecedented failure of multiple independent safety systems. Detailed preventive measures and evaluations can be found in the submitted Risk Analysis, Risk Management Plan, and Risk Management Report.
As with any MRI examination, a small subset of participants exposed to a strong and inhomogeneous magnetic field, such as the 7T system used in this study, may experience transient effects like nausea or dizziness. These effects typically resolve when participants remain still or are no longer exposed to the inhomogeneous field. If these effects fall within commonly reported ranges and resolve shortly after exposure, they will not be classified as adverse events.
Note that this section is essential for an MD MR-trial; please refer to the post of the Investigator Brochure to find details on the risk documentation that has to be provided.
10.3.2 Reporting of (Serious) Adverse Events, device deficiencies, and other safety related events
The CIP template is explicit on what is expected here:
All device deficiencies (DD), all serious adverse events (SAE) and choose the applicable all non-serious adverse events (AE)ornon-serious adverse events (AE)identified in this CIPas being critical to the evaluation of the results of the investigation(please phrase the compliance statement in the Synopsis accordingly) are collected, fully investigated and documented in the source document and appropriate CRF during the entire investigation period, i.e. from patient’s informed consent until the last CIP-specific procedure, including a safety follow-up period.
Documentation of AEs (including SAEs) by the PI includes diagnosis or symptoms, start and stop dates of event, event treatment, event resolution, assessment of seriousness and causal relationship to MD and/or investigation procedure (ISO14155 [please indicate version/year]).
Documentation of DDs by the PI includes description of event, start date, investigational device information, action taken with regard to the investigational device, and whether the DD led to an AE (ISO14155 [please indicate version/year]).
Specify here how the information on AEs is systematically collected (e.g., by clinical safety assessment and/or safety lab at the regular visits, as applicable and clinically justified in the context of the specific CIP). Also specify here the follow-up period, if applicable (also in case of premature withdrawal of the subject from the investigation). If no such safety follow-up is needed, please specify and justify.
In case that AEs identified as being critical to this evaluation and not all AEs shall be recorded as defined above, please include a list of the AEs evaluated as being critical and that shall be recorded. Please note that in this case full compliance with ISO 14155:2020 cannot be claimed.
Note that this section is relevant for an MR-MD-based trial. We identified for the SIGNATURES2023 trial the following related points:
Identification and handling of risks:
The following risk analysis document, risk management document, and the risk management report submitted to Swissmedic [or your local EU-CA]handle all identified risks of SIGNATURES2023:
Risk_Analysis_v2.pdf
Risk_Management_Plan_v2.pdf
Risk_Management_Report_v2.pdf
The content is not repeated here.
The instructions for this section are formulated by BASEC the following way:
Describe how, by whom and in what time frame the serious and other reportable AE (health hazards, laboratory abnormalities, pregnancies if applicable, etc.) are reported. Note: The Sponsor is responsible for the notifications to CA and to the CECs. The sponsor may delegate the task, but not the responsibility. Describe the reporting responsibilities of the PI to the Sponsor in case of a multicentre investigation, when the Sponsor and the PI are not the same person. Similarly, define the reporting roles and responsibilities to the manufacturer when the Sponsor and the PI are the same person. Describe if there are exceptions for the reporting.
Reporting to the Sponsor:
The following events are to be reported to the Sponsor by the PI (or authorized designee) within 24 hours and 3 days (give reporting deadlines as applicable. These depend of stage of development and severity of possible consequences. Refer to the European guidance document MDCG 2020-10/1 for details) after becoming aware of the event:
All SAEs Health hazards that require measures DDs with SAE potential Other AEs and DDs identified in this CIP as being critical to the evaluation of the results of the investigation
The Sponsor shall define the timelines for reporting of non-serious AEs and DDs to the Sponsor.
The sponsor shall review the investigator’s assessment of adverse events and determine and document in writing the seriousness and relationship to the investigational device and procedures required by the CIP (ISO 14155). The Sponsor shall evaluate AEs and SAEs with regard to causality and seriousness. Device deficiencies are also assessed regarding their potential to lead to an SAE (DD with SAE potential) (Art 32. ClinO-MD, ISO 14155).
Pregnancies
Note: Depending of the investigation, reporting of pregnancies may not be necessary.
If reporting is needed, include in the CIP how pregnancies will be reported (usually within 24 hours to the Sponsor), and how occurrence of pregnancy will be handled in the investigation (patient is withdrawn, outcome of the pregnancy should be followed-up, etc). If it is suspected that the MD may have interfered with the effectiveness of a contraceptive medication/device, specify how this should be reported. Details can depend on the type of investigation and intervention.
Reporting to the Competent Ethics Committee and to Swissmedic[or your local EU-CA]:
The following events are to be reported to the CEC and to the CA promptly (Art. 33 ClinO-MD):
any serious adverse event that has a causal relationship with the MD to be investigated, the comparator or the investigation procedure, or where such causal relationship is reasonably possible; any device deficiency that might have led to a SAE if appropriate action had not been taken, intervention had not occurred, or circumstances had been less fortunate; (DD with SADE potential); any new findings in relation to any event referred to in points (a) and (b).
In order to ensure prompt notification, the Sponsor may initially submit an incomplete notification.
In line with European guidance document MDCG 2020-10/1 Rev. 1, reportable SAE and DD must be sent to Swissmedic [or your local EU-CA]within 7 days, or 2 days for SAE requiring prompt action for the safety of other study subjects [or verify thesereporting timelinesor your local EU-CA].
If applicable: For conformity-related clinical trials in sub-categories C1 and C2 that are also being conducted abroad: The sponsor notifies the CEC and CA without delay of all events, device deficiencies and findings as specified above which arise from the conduct of the clinical trial abroad.
If safety and health hazards that require measures must be taken immediately during the conduct of the investigation, the Sponsor notifies the CEC and CA within 2 days of these measures and the circumstances which made them necessary (Art. 34 ClinO-MD).
If applicable: For clinical trials that are also being conducted or are also due to be conducted in EU or EEA states, The Sponsor notifies the CEC and CA within 2 days of all imposed or voluntary safety and protective measures that are being implemented in EU or EEA states and the circumstances that necessitated them (Art. 34 ClinO-MD).
Periodic safety reporting (Art. 35 ClinO-MD):
Once a year, the sponsor submits to the CEC and CA a list of all SAEs and DDs and provides it with a report on their severity, causal relationship with the device and/or the intervention and on the safety of the participants (outcome, event status). The sponsor informs the CEC and CA annually about the general progress and status of recruitment of the clinical investigation (also abroad). Any safety-relevant measures taken by the sponsor or imposed by ethics committees or authorities anywhere in the world as well as results from other clinical investigations with the investigational device (if applicable) shall be described. Based on the data presented in the report, the sponsor will draw his/her conclusions regarding the safety of the subjects and the continuation of the investigation. The safety report and the general progress report can be merged in one single report.
The cumulative list of reportable serious adverse events and device deficiencies (MDCG 2020-10/2 Rev. 1) per cut-off date is submitted in parallel.
We submitted the following text for SIGNATURES2023 trial:
Reporting to the Sponsor-Investigator
The following events are to be reported to the Sponsor-Investigator by the local investigator (i.e. authorized designee of PI) within 24 hours after becoming aware of the event:
All SAEs
Health hazards that require measures
Device deficiencies
The Sponsor-Investigator will evaluate SAEs with regard to causality and seriousness. Device deficiencies are also assessed regarding their potential to lead to an SAE (DD with SADE potential).
Pregnancies
Pregnant subjects are excluded from the study. A pregnancy test is conducted unless the patient is at least 12 months postmenopausal.
Reporting to the Competent Ethics Committee and to Swissmedic [or your local EU-CA] :
The following events are to be reported to the CEC and to the CA promptly (ClinO-MD):
any serious adverse event which has a causal relation with the MD, comparator or procedure/test method or where a causal relation appears to be possible (SADE);
any device deficiency which, in the absence of appropriate measures or intervention or in less favourable circumstances, could have led to serious adverse events (DD with SADE potential);
any new information relating to an event already notified under points (a) and (b).
In order to ensure prompt notification, the Sponsor may initially submit an incomplete notification.
If safety and health hazards that require measures must be taken immediately during the conduct of the investigation, the Sponsor notifies the CEC within 2 days of these measures and the circumstances which made them necessary (ClinO-MD).
Reporting to Swissmedic [or your local EU-CA]
The MDCG 2020-10/1 rev.1 guidance document outlines the following key reporting timelines for reporting to Swissmedic [or EMA or your local responsible administration]:
Immediate Reporting of Serious Adverse Events (SAEs):
Serious Adverse Events (SAEs): Must be reported to the competent authority (e.g., Swissmedic [or your local EU-CA]) as soon as possible but no later than within 2 days of the sponsor becoming aware of the event.
Device Deficiencies with SAE Potential: These must also be reported within 2 days if the deficiency could have led to a serious adverse event under different circumstances.
Annual Safety Report: (ASR)
An Annual Safety Report (ASR) will be submitted to Swissmedic [or your local EU-CA]and the responsible Ethics Committee(s) once a year from the date of approval of the clinical investigation. The ASR will include a comprehensive overview of the safety profile of the investigational device, incorporating the following elements:
ASR: Summary of Serious Adverse Events (SAEs) and Device Deficiencies
A detailed list of all Serious Adverse Events (SAEs) and device deficiencies that occurred during the reporting period, including the date of occurrence, a description of the event, and its outcome.
An analysis of these events to assess their impact on the safety of participants, including any trends or patterns observed and their implications for the continued conduct of the investigation.
ASR: Cumulative Data Review
A cumulative review of all SAEs and device deficiencies reported since the start of the clinical investigation, providing a broader context for understanding the overall safety profile of the device.
A discussion on whether the observed events align with the known safety profile of the device or suggest any new risks that need to be addressed.
ASR: Risk Assessment and Mitigation Strategies
An updated risk assessment based on the cumulative safety data, including any new risks identified during the reporting period.
A description of any changes made to the investigation to mitigate identified risks, such as amendments to the protocol, informed consent process, or investigator training.
ASR: Impact on the Clinical Investigation
An evaluation of how the safety data has impacted the progress and conduct of the clinical investigation, including any decisions made to continue, modify, or suspend the study.
Justification for the continuation of the study in light of the safety data, if applicable.
ASR: Safety Measures Implemented
A summary of any safety measures implemented during the reporting period due to urgent safety concerns, including the rationale for these measures and their effectiveness in mitigating risks.
Communication of Safety Information
Details on how safety information was communicated to investigators, participants, and other stakeholders, including any updates to the Investigator’s Brochure, informed consent documents, or participant information sheets.
ASR: Future Safety Monitoring Plans
A description of the safety monitoring plans for the upcoming year, including any changes to the frequency or scope of safety assessments based on the data reviewed.
End of Study Reporting
The final report must be submitted to the competent authority within 1 year of the end of the clinical trial.
If the clinical trial is terminated early, a final report must be submitted within 3 months.
Reporting of Safety Measures
Any safety and protective measures implemented during the clinical trial due to urgent safety reasons (imminent risk of death, serious injury, or serious illness) will be reported to the competent authority within 2 days. The reporting timeline for all other reportable events is 7 days.
An Annual Safety Report (ASR) is submitted by the Sponsor to the CEC and to the CA, yearly (ClinO-MD). The ASR contains a list of all SADEs and DDs and a report on their degree of seriousness, causal relationship with the MD and procedure and on subjects’ safety.
10.3.3 Follow-up of (Serious) Adverse Events
The instructions given in the CIP template are:
Describe how, by whom and in what time frame the serious and other reportable AE (health hazards, laboratory abnormalities, pregnancies if applicable, etc.) are reported. Note: The Sponsor is responsible for the notifications to CA and to the CECs. The sponsor may delegate the task, but not the responsibility. Describe the reporting responsibilities of the PI to the Sponsor in case of a multicentre investigation, when the Sponsor and the PI are not the same person. Similarly, define the reporting roles and responsibilities to the manufacturer when the Sponsor and the PI are the same person. Describe if there are exceptions for the reporting.
Participants with an ongoing (S)AE at the last scheduled study contact will be followed until resolution of the event, until a stabilized condition of the subject has been achieved, or until the subject is lost to follow-up. The time frame is described in section 10.3.2.
10.4 Documentation and reporting in Medical Device Category A clinical investigations
Since this blog describes type C MR-MD-trials:
Not applicable.
10.4.1 Foreseeable adverse events and anticipated adverse device effects
Since this blog describes type C MR-MD-trials:
Not applicable.
10.4.2 Reporting of Safety related events
Since this blog describes type C MR-MD-trials:
Not applicable.
10.5 Assessment, notification and reporting on the use of radiation sources
Since this blog describes type C MR-MD-trials:
Not applicable.
11. STATISTICAL METHODS
The instructions of the CIP template are following:
Describe the statistical considerations done for the investigation, with justification, including a power calculation for the sample size, the statistical methods to be employed, the level of significance that will be used, including timing of any planned interim analysis(ses).
Special reasoning and sample sizes may apply for early clinical investigations (e.g. feasibility studies [ISO14155]).
This section is highly dependent on the MD-MR-trial you intend to perform, and it is of no real use to write here what for the SIGNATURES2023 was defined.
11.1 Hypothesis
The instructions of the CIP template are following:
If a Null Hypothesis is tested, state explicitly both Null and Alternative Hypotheses in terms of the primary endpoint(s) and justify them in regard of the subject population and dose. The stated safety and benefit hypotheses have to be used in the determination of Sample Size. Relate these hypotheses to the investigation objectives.
If hypothesis testing is not used, then discuss how the approach used (e.g. Bayesian methods) will address the objectives.
Also this section is highly dependent on the MD-MR-trial you intend to perform, and it is of no real use to write here what for the SIGNATURES2023 was defined.
11.2 Determination of Sample Size
The instructions of the CIP template are following:
Provide the number of subjects planned to be enrolled. Reason for choice of sample size with justification, including a power calculation for the sample size. Provide the estimated number of subjects for each investigation site and investigation arm (if applicable) needed to achieve the safety and benefit objective, how it was determined, including clinical and statistical assumptions supporting any sample size calculations, the power of the investigation, the type I error (one- or two-sided) and the related risk, the clinical justification.
If “sex and gender” dimension is of primary interest, does the sample size estimation integrate this aspect? Are the statistical analyses appropriate?
Also this section is highly dependent on the MD-MR-trial you intend to perform, and it is of no real use to write here what for the SIGNATURES2023 was defined.
11.3 Statistical criteria of termination of the investigation
The instructions of the CIP template are following:
Describe the statistical criteria for the termination of the investigation (“discontinuation criteria”) or the stopping rules, for example in case of evidence of early benefits or harm for parts of investigation and for the entire investigation). If applicable, describe the ‘stop/go’ rules for temporarily discontinuing the investigation.
Also this section is highly dependent on the MD-MR-trial you intend to perform, and it is of no real use to write here what for the SIGNATURES2023 was defined.
We wrote here however:
Not applicable.
11.4 Planned Analyses
The instructions of the CIP template are following:
Make brief statements of the analyses that are planned, the methods and types and which variables and with what data sets and when (a detailed statistical analysis plan may be written as a separate document after finalisation of the CIP and may be referred to this document, e.g. statistical analysis plan), including timing of any planned interim analysis(ses).
Include a statement that analyses of “sex and gender” differences are planned. If such an analysis is not possible, please state the reasons.
Also this section is highly dependent on the MD-MR-trial you intend to perform, and it is of no real use to write here what for the SIGNATURES2023 was defined.
11.4.1 Datasets to be analysed, analysis populations
The instructions of the CIP template are following:
Describe the analysis populations, evaluation groups (i.e. the selection of subjects to be included in the analyses (e.g., all randomized subjects, all dosed subjects, all eligible subjects, evaluable subjects) and data sets to be used for analysis and methods for any additional analyses (e.g., subgroup and adjusted analyses). This applies to all endpoints / outcomes to be analysed.
Also this section is highly dependent on the MD-MR-trial you intend to perform, and it is of no real use to write here what for the SIGNATURES2023 was defined.
11.4.2 Primary Analysis
The instructions of the CIP template are following:
Describe the analysis populations, evaluation groups (i.e. the selection of subjects to be included in the analyses (e.g., all randomized subjects, all dosed subjects, all eligible subjects, evaluable subjects) and data sets to be used for analysis and methods for any additional analyses (e.g., subgroup and adjusted analyses). This applies to all endpoints / outcomes to be analysed.
Also this section is highly dependent on the MD-MR-trial you intend to perform, and it is of no real use to write here what for the SIGNATURES2023 was defined.
11.4.3 Secondary Analyses
The instructions of the CIP template are following:
Describe the intended secondary analysis that will be done, when and how and by whom it will be done. Indicate the pass and fail criteria to be applied to the results of the investigation.
Describe the intended subgroup analyses, if applicable, that will be done, when and how and by whom they will be done, add hypothesis related to each subgroup.
Also this section is highly dependent on the MD-MR-trial you intend to perform, and it is of no real use to write here what for the SIGNATURES2023 was defined.
11.4.4 Interim analyses
The instructions of the CIP template are following:
Describe the intended interim analysis that will be done, why, when and how and by whom it will be done, taking into consideration their purpose, frequency, timing, scope, statistical procedures, Data Monitoring Committee involvement, and stopping guidelines (refer to chapter 11.3). Explain the methods that will be used to adjust for interim analyses, or give a rationale for why adjustment is not necessary.
Also this section is highly dependent on the MD-MR-trial you intend to perform, and it is of no real use to write here what for the SIGNATURES2023 was defined.
11.4.5 Deviation(s) from the original statistical plan
The instructions of the CIP template are following:
Describe the procedures for reporting any deviation(s) from the original statistical plan (any deviation(s) from the original statistical plan should be described and justified in the CIP and/or in the final report, as appropriate).
Also this section is highly dependent on the MD-MR-trial you intend to perform, and it is of no real use to write here what for the SIGNATURES2023 was defined.
11.5 Handling of missing data and drop-outs
The instructions of the CIP template are following:
Describe how missing data will be handled (e.g. multiple imputation, last observation carried forward, complete case analysis, consider primary and secondary outcomes…).
Describe if dropouts are replaced. If sensitivity analyses are planned, specify them. All subjects shall be accounted for and documented, including those withdrawn from the investigation or lost to follow-up).
Also this section is highly dependent on the MD-MR-trial you intend to perform, and it is of no real use to write here what for the SIGNATURES2023 was defined.
12. QUALITY ASSURANCE AND CONTROL
The instructions of the CIP template are following:
Describe how quality is assured and controlled. The Sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs and Working Instructions, at all sites in case of multicentric investigations. Indicate the software used. The PI is responsible for proper training of all involved investigation personnel.
One could write something like this:
The study will be supervised by the sponsor-investigator, who will guarantee that all legal aspects of the study will be obeyed, and research is performed in accordance with state-of-the-art scientific methods. In at least monthly meetings with the sponsor-investigator, all investigators working on subprojects will report on study progress and any potential special circumstances concerning the ethics of the study. The sponsor-investigator will be responsible for proper training of all involved study personnel such as PhD students and technicians (see site delegation log form) and the training will be logged in the study training log form provided.
SOP will be used as are applied in regular patient MR-scans. The definitive choice of which software packages will be used will be decided on during the trial, since parts of these softwares will be developed during the project.
12.1 Data handling and record keeping / archiving
The instructions of the CIP template are following:
Describe how data are handled and that all investigation related documents are archived. A list of the essential clinical investigation documents which should be maintained in the investigation site and sponsor file is given in ISO14155 Annex E.
Note: In order that you can comply with all ISO14155 regulation, you should get a copy of ISO14155 (including Annex E) via your institute or the local CTU. It is quite expensive to purchase these documents.
Data Coding and Naming Convention — Healthy volunteer and patient data will be coded to clearly indicate the group to which each individual belongs (e.g., patient or volunteer). The key to the coded data will remain securely with the Principal Investigator (PI), who can retrieve the individual’s real identity if necessary.
Naming Convention for Participant Coding — Each participant’s identifier will include the following components:
PID: A 3-digit integer representing the participant ID.
Examination Number: A 1-digit counter indicating the number of times the same participant (with the same PID) has been examined (usually 1).
Age: The participant’s age in years at the time of the examination (3 digits).
Group: Either ‘v’ for volunteer or ‘p’ for patient.
Gender: ‘m’ for male or ‘f’ for female.
Nucleus of Interest: The main nucleus studied, either ‘1H’ (proton) or ‘2H’ (deuterium).
If both 1H and 2H nuclei are studied for a participant, the identifier will include the substring 1H_2H.
Examples:
001_2_031_v_f_1H A 31-year-old female volunteer examined for the second time with a focus on proton spectroscopy.
005_1_073_p_m_2H A 73-year-old male patient examined for the first time with a focus on deuterium spectroscopy.
This coding system ensures clarity, consistency, and secure handling of participant data while allowing flexibility for multi-nucleus studies.
12.1.1 Case Report Forms
The instructions of the CIP template are following:
Describe how the investigation data is recorded, e.g. with paper or electronic Case Report Forms (p-/e-CRF). A CRF is maintained for each enrolled subject. CRFs must be kept current to reflect subject status at each phase during the course of the investigation. Subjects must not be identified in the CRF by name or initials and birth date. Describe the coding used for the investigation, e.g. subject number in combination with year of birth (see the guidance document published on swissethics.ch “coding of trial subject accepted by swissethics and secure storage of subject identification list” https://swissethics.ch/assets/Themen/akzeptierte_verschluesselung_e.pdf)
If paper-CRFs are used, describe how data is entered into an electronic database for analysis (e.g., double data entry).
Note: The person(s) authorized by the PI to enter the data in the CRF must be listed on the delegation log.
For the SIGNATURES2023 study we improved our initial text, and you could use following text as a starting point for your trial:
For each enrolled trial participant, an electronic Case Report Form (eCRF) will be maintained. The eCRFs will be updated promptly to reflect the participant’s status during all phases of the trial. Participant coding is described in detail in Section 12.1 above. For MR examinations, the standard coding convention used is xw_DIN_yymmdd_wxyz, where yymmdd represents the date of the examination, and wxyz is a sequential number assigned for each day. This coding ensures unique identification of examinations while preserving participant confidentiality.
All study-related data will be collected and recorded in a coded format, and participant names will not be disclosed in the eCRF or any study documentation. Only authorized trial team members, as listed in the database access log, are permitted to enter data into the eCRF. The sponsor-investigator is responsible for ensuring that all personnel entering data are properly trained and instructed in the use of the eCRF system.
If it becomes necessary for the clinical partners to use a paper CRF due to an inability to directly complete the eCRF, the paper CRF will be filled out by the “klinische Zuweiser” and subsequently entered into the REDCap database by the Neuroradiology team. This ensures all data is accurately transferred into the electronic system. All procedures comply with guidance documents published by swissethics, including the accepted methods for subject coding and secure storage of the subject identification list (see: swissethics guidance).
12.1.2 Specification of source data and source documents
The instructions of the CIP template are following:
Source data should be available at the site to document the existence of the investigation subjects. Source data must include the original documents relating to the investigation, as well as the medical treatment and medical history of the subject. In case of electronic source data (e.g. from Apps or from automatic recording devices), describe how the data is handled, transferred, stored and accessed by the PI and authorised staff.
Describe what is considered the source documents in the investigation (specify what is the source document for each data collected in the CRF, e.g., demographic data, visit dates, participation in investigation and ICFs, randomisation codes, SAEs, SADEs, USADEs, and concomitant medication, results of relevant examinations. Identify data that are directly recorded in the CRF, which should also be considered being source data. Also describe where original source data are kept at the site. You can also refer to a separate document in the Appendices (‘source data description and source data location’).
For the SIGNATURES2023 study we improved our initial text, and you could use following text as a starting point for your trial:
We will use worksheets in paper form for ease of use in the DIN. This paper sheet contains only coded information (no explicit subject name). The data will be entered in the eCRF based on the worksheets.
The data will be entered into a Redcap database by the study coordinator or the sponsor-investigator, subsequently. The paper CRFs will be stored in the office of the sponsor-investigator.
Other source data are the DICOM images and spectra acquired at the MR scanners, which will be stored in non-coded form in the clinical PACS system (for potential use of general-purpose images that are recorded during the study session with standard CE-marked sequences in case of clinical need of the participants months or years after the study). The images acquired with the research sequences are labelled with sequence identifiers such that they can’t be confused with images from clinically used sequences. They will also be stored in coded form on the investigators’ research PACS systems. The encryption of the DICOM data for long time storage in the scientific PACS is by the use of an application which performs encryption of DICOM conform the Swiss Federal Human Research Act (HRA, RS 810.30) after data transfer. The data transfer is initiated immediately after data acquisition by the MR operator. The study coordinator verifies that the complete data is stored in the correct PACS systems, and is encrypted in the correct way, and maintains the key which enables back traceability of the data in case the name of the person in the study needs to be traced back.
Further, source data will include the original documents related to the study such as signed informed consent documents that will be stored in paper form and in electronically scanned form. Processed data is stored on hard drives with regular RAID configured back-ups.
12.1.3 Archiving of essential clinical investigation documents
The instructions of the CIP template are following:
All the documents of the investigation must be archived for a minimum of (time according to local legislation) years after regular or premature termination of the investigation.
Describe Sponsor (Art. 40 Abs 1 ClinO-MD) and PI (Art. 40 Abs 2 ClinO-MD) responsibilities. Specify location and length of storage. Archiving for 10 years, in the case of an implantable device 15 years in Switzerland (Art. 40 ClinO-MD).
For the SIGNATURES2023 study we improved our initial text, and you could use following text as a starting point for your trial:
All study-related data, both written and electronic—including MR data—will be securely retained for a minimum of 10 years following the completion or premature termination of the trial. The Sponsor-Investigator will implement measures to prevent accidental or premature destruction of these records.
Notes recorded in lab books during the examinations will be preserved as original documents and securely stored on the premises of the PI’s institution, within locked cupboards located in locked offices. Similarly, all software and data evaluations will be stored on hard drives under the same secure conditions and backed up in the institutional archiving system to ensure long-term accessibility and safety.
12.2 Data management
The general instructions on data management are described as follows in the CIP template:
Describe plans for data entry, coding, security, and storage, including any related processes to promote data quality (e.g., double data entry; range checks for data values). In case electronic data capture systems are used, this chapter shall include a description of procedures for verification, validation and securing the database.
If data will not be anonymised after the statistical analysis, describe in which form they will be stored (e.g. coded). If the data is anonymised, describe how this is done
Reference to where details of data management procedures can be found, if not in the CIP.
12.2.1 Data Management System
The instructions of the CIP template are following:
Describe what system (including cloud services and software) is being used and who is responsible and how it is tested before the investigation begins (may include a description of where the system is hosted).
For the SIGNATURES2023 study we wrote the following which you could use following text as a starting point for your trial:
The CRFs in this trial are implemented electronically using a dedicated electronic data capturing (EDC) system (REDCap, https://www.project-redcap.org/). The EDC system is activated for the trial only after successfully passing a formal test procedure. All data entered in the CRFs are stored on a Linux server in a dedicated mySQL database. Responsibility for hosting the EDC system and the database will be located in {you institute}.
12.2.2 Data security, access, and back-up
The instructions of the CIP template are following:
Describe who has access to data, how, where and when – and which backup systems are in place (if applicable).
For the SIGNATURES2023 study we wrote the following which you could use following text as a starting point for your trial:
The server hosting the EDC system and the database is kept in a locked server-room. Only the system administrators have direct access to the server and back-ups. A role concept with personal passwords (site investigator, statistician, monitor, administrator etc.) regulates permission for each user to use the system and database as he/she requires.
All data entered into the CRFs are transferred to the database using Transport Layer Security (TLS) encryption. Each data point has attributes attached to it identifying the user who entered it with the exact time and date. Retrospective alterations of data in the database are recorded in an audit table. Time, table, data field and altered value, and the person are recorded (audit trail).
A multi-level back-up system is implemented. Back-ups of the whole system including the database are run internally several times per day and on external tapes once a day. The back-ups are stored in a secure place in a different building.
12.2.3 Analysis and archiving
The instructions of the CIP template are following:
Describe how data are extracted and where they are stored, database status recording, duration and place of storage.
For the SIGNATURES2023 study we wrote the following which you could use following text as a starting point for your trial:
At ongoing and final analyses, data files will be extracted from the database into statistical packages to be analyzed where needed. After database lock, the status of the database is recorded in special archive tables.
The sponsor will keep the Trial Master File, the extracted data, the meta data, and interim/final reports for at least 10 years.
12.2.4 Electronic and central data validation
The instructions of the CIP template are following:
Describe how data are validated.
For the SIGNATURES2023 study we wrote the following which you could use following text as a starting point for your trial:
The data will be reviewed by the EDC system to ensure completeness and plausibility. Additionally, regular internal central data reviews will be conducted to verify the completeness of collected data and the accuracy of the primary outcome measures.
Prior to database lock, the principal investigator will validate the data by providing their signature, confirming its accuracy and integrity.
12.3 Monitoring
The instructions for this sections of BASEC are detailed and as follows:
Describe the regular monitoring visits at the PI’s site prior to the start and during the course of the investigation organised by the Sponsor. Give a detailed description of what, which data and documents will be monitored and to which extent (these points are given here as examples only: subject enrolment logs, informed consents and informed consent process, source data verification, inclusion and exclusion criteria, subjects’ visit schedule, safety, processing of subjects’ data, preservation of subjects confidentiality, reporting to CEC and RA and approvals, provisions of records and data retention, etc…). Indicate which organisation or person does the monitoring; specify monitor qualification and training. Describe procedure to review the monitoring visit reports, follow-up on monitoring findings and corrective actions.
Alternatively the extent and nature of monitoring activities and all the details described in the above paragraph, based on the objective and design of the investigation, can be written in a Monitoring Plan. The Monitoring Plan must be annexed to the CIP (Annex XV, Chapter 2, Art. 3.6.6. MDR).
Provide a statement that the source data/documents are accessible to monitors and questions are answered during monitoring by the PI and the site staff.
We had a short text here, but for this blog we made a more complete text of the duties of the “monitor”. For your trial you could get inspired by the following text:
Monitoring is an integral part of the quality control activities implemented for this study to ensure compliance with the Clinical Investigation Plan (CIP), Good Clinical Practice (GCP), and applicable regulatory requirements. {Professor Dr. X or your local CTU}, a long-standing expert in device-related MR research, including MR research at ultra-high field (UHF), has been designated as the study monitor for the SIGNATURES2023 investigation.
Regular monitoring visits will be conducted at the PI’s site before the study begins and throughout its duration. These visits will include a thorough review of study-related processes, data, and documentation. The following aspects will be monitored:
Subject enrolment logs: Verification of participant eligibility based on inclusion and exclusion criteria.
Informed consent and informed consent process: Confirmation that informed consent has been properly obtained and documented for all participants.
Source data verification (SDV): Cross-checking source data with eCRFs to ensure data accuracy and consistency.
Visit schedules: Compliance with scheduled participant visits and data collection timelines.
Safety monitoring: Review of adverse events (AEs), serious adverse events (SAEs), and adverse device effects (ADEs), including their documentation and reporting.
Processing of participant data: Verification that participant data is handled securely and confidentially, in compliance with applicable regulations.
Reporting to Competent Ethics Committee (CEC) and Regulatory Authority (RA): Review of submissions, approvals, and any required updates or amendments.
Data preservation and retention: Confirmation that records and data are stored securely and in compliance with the retention requirements.
The monitor will have access to all relevant study documentation, participant records, facilities, and other resources as necessary to perform their duties. The Principal Investigator (PI) or their designee will provide full support during these visits, including addressing any questions or concerns raised by the monitor.
{Professor Dr. X or your local CTU} has the necessary qualifications and extensive experience in the field, ensuring high-quality oversight of the study. The monitor will document each visit in a monitoring report, detailing observations, findings, and any identified issues. These reports will be reviewed promptly by the PI and Sponsor-Investigator. Any findings requiring corrective action will be addressed without delay, with follow-up visits as necessary to verify implementation.
To ensure compliance and transparency, all source data and documentation will remain accessible to the monitor, and all involved parties are committed to maintaining strict confidentiality of participant data.
12.4 Audits and Inspections
The instructions for this sections of BASEC are detailed and as follows:
Describe the frequency and procedures for auditing the investigation, if any, and whether the process will be independent from the PI and the Sponsor. Provide a statement that the documentation of the investigation and the source data/documents are accessible to auditors/inspectors (also CEC and CA) and questions are answered during inspections. All involved parties must keep the subject data strictly confidential.
We had a short text here, but for this blog we made a more complete text of the duties of the “monitor”. For your trial you could get inspired by the following text:
Audits and inspections for the SIGNATURES2023 study will be conducted by Professor Dr. X [or CTU] at three key points: the beginning of the study, midway through the investigation, and at its conclusion. Professor Dr. X, a recognized expert in MR research across low, medium, and ultra-high field strengths, has been appointed to oversee these activities. While the Clinical Trial Unit (CTU) was approached to perform auditing for this medical device study, the PI was informed that the local CTU lacks the requisite expertise in this area. Consequently, Professor X.Y ., an expert in the field of MRI was selected to fulfill this role.
The Competent Authorities (CA) and Competent Ethics Committees (CEC) may also conduct independent inspections of the study at any time. In the event of such an inspection, the sponsor-investigator will grant inspectors full access to all study documentation, participant records, facilities, and other resources relevant to the investigation. Throughout the inspection process, the sponsor-investigator will actively support inspectors by addressing any queries and providing additional information as required.
All study-related documentation and source data will be readily accessible to auditors and inspectors, ensuring transparency and compliance. All involved parties are committed to maintaining strict confidentiality of participant data in accordance with applicable laws and ethical standards.
12.5 Confidentiality, Data Protection
The instructions for this sections of BASEC are detailed and as follows:
Data protection; should include the statement that direct access to source documents will be permitted for purposes of monitoring (chapter 12.3), audits and inspections (chapter 12.4) and should declare who will have access to the documents of the investiation, dataset, randomization code, etc. during and after the investigation (refer to chapter 13 for publication and dissemination of the results of the investigation).
We had a short text here, but for this blog we made a more complete text of the duties of the “monitor”. For your trial you could get inspired by the following text:
The generation, transmission, storage, and analysis of health-related personal data (if collected) in this project will strictly adhere to current Swiss legal requirements for data protection and comply with ClinO-MD Art. 3. All health-related personal data captured during this study will be treated as strictly confidential, and disclosure to third parties is prohibited. Participant confidentiality will be safeguarded through coding measures to prevent identification.
Access to project data will be restricted to authorized personnel only. Data will be handled with the utmost discretion to ensure privacy and security. Direct access to source documents, datasets, randomization codes, and other study-related records at the study site will be permitted exclusively for the purposes of monitoring (see Chapter 12.3), audits, or inspections (see Chapter 12.4). This includes access by the Competent Authorities (CA) and Competent Ethics Committees (CEC) to all information necessary for them to fulfill their oversight responsibilities.
Following the conclusion of the investigation, access to data will remain restricted to the sponsor-investigator and authorized individuals, as detailed in Chapter 13 regarding the publication and dissemination of study results. Strict measures will be in place to ensure the confidentiality of participant data during and after the study.
12.6 Storage of biological material and related health data
The instructions for this sections of BASEC are detailed and as follows:
In the event the data of the investigation is stored in a data-registry: add here that the coded data of the subjects who consented for the further use of their data (independently of the investigation specific consent) will be stored in a registry for an undetermined length of time, and the data could be re-used for other research projects (provided previous approval by the CEC).
If applicable, describe for how long and where the samples and personal data are stored, or state that samples are destroyed and data anonymised after the end of the storage period. The information provided here must match the information given in chapters 8.4 and 9.2.5.
In the event of Biobank or registry storage, confirm that coded samples and/or data are only stored if the subjects consent for further use has been obtained. This consent is given (or withheld) independently of the participation in the investigation (Art. 17. ClinO).
In SIGNATURES2023 this was not relevant (yet):
Not applicable.
13. PUBLICATION AND DISSEMINATION POLICY
The instructions in the CIP of BASEC are quit lengthy:
Give the publication policy of the results of the investigation, if not addressed in a separate agreement, according to Art. 42 ClinO-MD.
Describe plans to communicate the results of the investigation to the subjects, healthcare professionals, the public, and other relevant groups (e.g., via a summary in lay language, publication, reporting in results databases, or other data sharing arrangements); anticipate for authorship eligibility guidelines and any intended use of professional writers and, if any plans for granting public access to the full CIP, subject-level dataset, and statistical code, including who will have ultimate authority over any of the activities. Mention the protection of trade secrets, if applicable.
Confirm that if “sex and gender” effects are observed, they will be published in the final study report. If an analysis is performed but no “sex and gender” effects are observed, this should also be published in the final study report.
The Sponsor will enter and publish a summary of the results of the clinical investigation in a public recognized register (as specified in Art. 64 Abs. 1 lit a or b ClinO) (complete the paragraph as appropriate):
a) immediately after submitting the final report (for completed clinical trials with devices that already bear a conformity marking and were used in accordance with the instructions, or in the event of an early termination or interruption of a clinical trial: in accordance with Article 37)
or b) at the latest before the device is placed on the market or one year after submitting the final report if the device has not been placed on the market by this point in time. (for all other completed clinical trials, in accordance with Article 37).
The Sponsor also ensures that a lay summary of the results is entered in BASEC within the period specified in the paragraph above. The entry is made at least in the national languages of Switzerland in which the study participants were recruited.
If publication of the results is not possible within the specified period for scientific reasons, the sponsor will explain this in the application documents and indicate when publication will take place. Adapt this paragraph accordingly.
The investigator will provide each participant with the lay summary of the results of the clinical investigation at the end of the study, directly. The investigator should ensure that participants are adequately informed about this in the patient information document and also that they are informed where the lay summary of the results of the clinical investigation will be published online.
We had a very short section here in our accepted CIP. Here is the improved section to get inspired for your CIP:
The findings of this trial will be disseminated through peer-reviewed articles published in reputable scientific journals. The publication policy adheres to the requirements of Art. 42 ClinO-MD and follows authorship eligibility guidelines, ensuring appropriate credit is given to all contributors. Professional writers will not be employed for the dissemination of results unless explicitly mentioned in advance.
Reporting and Public Access The Sponsor will ensure that a summary of the results is entered into a publicly recognized clinical trial register, such as ClinicalTrials.gov, in compliance with Art. 64 Abs. 1 lit a or b ClinO-MD. Specifically:
For completed clinical investigations involving devices that already bear a conformity marking and were used in accordance with their instructions for use, or in the event of early termination or interruption, the summary will be submitted immediately after the final report, as per Article 37.
For all other completed clinical investigations, the summary will be submitted no later than one year after the final report or before the device is placed on the market, whichever occurs first.
The Sponsor will also ensure that a lay summary of the results, written in a language understandable to the general public, is entered into BASEC. This summary will be available in the national languages of Switzerland used for participant recruitment. If the publication cannot occur within the specified timeframe due to scientific reasons, the Sponsor will provide an explanation to the regulatory authorities, along with a revised timeline.
Communication with Study Participants and Relevant Groups Study participants will be provided with the lay summary of results directly at the end of the study. This commitment will be clearly communicated to participants in the patient information document, which will also detail where the lay summary will be published online. Healthcare professionals and other relevant groups will be informed through targeted dissemination strategies, such as presentations at scientific conferences, symposia, and professional meetings.
Data Transparency and Trade Secrets The Sponsor is committed to data transparency while ensuring the protection of trade secrets, where applicable. The full CIP, subject-level dataset, and statistical code may be made available upon request to qualified researchers following the conclusion of the investigation. Access to these materials will be governed by strict confidentiality agreements and ethical considerations, with ultimate authority resting with the Sponsor-Investigator.
Sex and Gender Analysis If sex and gender effects are observed during the investigation, they will be explicitly addressed and published in the final study report. If no such effects are observed, this outcome will also be documented and included in the report.
Regulatory and Funder Obligations In addition to public dissemination, the Sponsor-Investigator will fulfill all reporting obligations to Swissmedic [or your local EU-CA], the Competent Ethics Committees (CEC), and the Swiss National Science Foundation (SNSF) as the funding body. This includes the timely submission of required reports, summaries, and updates as per the applicable regulations and funding requirements.
14. FUNDING AND SUPPORT
14.1 Funding
The instructions in the CIP of BASEC for this section are:
Provide brief statement of sources and types of financial support for the investigation. If applicable, reference to other places or contracts/documents where this information is captured.
This is highly project specific. List here your public and/or private funding.
14.2 Other Support
The instructions in the CIP of BASEC for this section are:
Provide brief statement of any other type of support received to conduct the investigation (MD, comparator, investigation material, software’s, …). If applicable, reference to other places or contracts/documents where this information is captured.
We had a very short section here in our accepted CIP. Here is the improved section to get inspired for your CIP:
The TIC supports this investigation by providing free scan time for portions of the methodological development phase, enabling the refinement and optimization of the MR protocols. {Your scanner manufacturer} contributes to the study under the framework of an established master collaboration contract, providing original source code and access to the pulse sequence programming tools to facilitate the development of new MR sequences essential for the study. Further details regarding these contributions are outlined in the master collaboration contract and associated technical documentation.
15. INSURANCE
The CIP instruction of BASEC on this is following:
Give proof of insurance cover or indemnification of subjects in case of injury, pursuant to Art. 3 ClinO-MD. E.g., “Insurance is provided by the Sponsor and fulfils the legal provision of art. 3 ClinO-MD. A copy of the insurance certificate is filed in Investigator’s file and in the Sponsor’s file.”
Note: Category A1 performance studies are exempt from liability coverage requirements (ClinO Art. 12). Categories A2 and C performance studies need to document the guarantee of liability (insurance certificate or equivalent guarantee) (ClinO Art. 13).
The insurance must cover damage occurring up to 20 years after the end of the clinical investigation.
The policy value shall be set in accordance with ClinO Annex 2.
It can be referred here to another place where the document is found, e.g., chapter 17 or elsewhere.
Here is the some text to get inspired for your CIP (normally your research institute must have a specific for your project insurance; verify this with your institute before starting measurements):
Appropriate insurance coverage will be provided by the Sponsor. A copy of the certificate is filed in the trial master file, and is uploaded to BASEC.
16. REFERENCES
Maintain the given CIP defined References in your document:
Humanforschungsgesetz, HFG Bundesgesetz über die Forschung am Menschen (Bundesgesetz über die Forschung am Menschen, HFG) vom 30. September 2011/ Loi fédérale relative à la recherche sur l’être humain (loi relative à la recherche sur l’être humain, LRH) du 30 septembre 2011 / Legge federale concernente la ricerca sull’essere umano (Legge sulla ricerca umana, LRUm) del 30 settembre 2011)
Verordnung über klinische Versuche mit Medizinprodukten (KlinV-Mep) vom 1. Juli 2020 / Ordonnance sur les essais cliniques de dispositifs médicaux (OClin-Dim) du 1er juillet 2020 /. Ordinanza sulle sperimentazioni cliniche con dispositivi medici (OSRUm-Dmed) del 1 luglio 2020
Verordnung über klinische Versuche mit Ausnahme klinischer Versuche mit Medizinprodukten (Verordnung über klinische Versuche, KlinV) vom 20. September 2013 / Ordonnance sur les essais cliniques hors essais cliniques de dispositifs médicaux (Ordonnance sur les essais cliniques, OClin) du 20 septembre 2013. Ordinanza sulle sperimentazioni cliniche ad eccezione delle sperimentazioni cliniche con dispositivi medici
(Ordinanza sulle sperimentazioni cliniche, OSRUm) del 20 settembre 2013
Medizinprodukteverordnung (MepV) vom 17. Oktober 2001 / Ordonnance sur les dispositifs médicaux (ODim) du 17 octobre 2001 / Ordinanza relativa ai dispositivi medici (ODmed) del 17 ottobre 2001
Medical Device Regulation (EU) 2017/745 of 5 April 2017 (MDR)
MDCG 2024-3 Guidance on content of the Clinical Investigation Plan for clinical investigations of medical devices
Strahlenschutzverordnung (StSV) vom 26. April 2017 / Ordonnance sur la radioprotection (ORaP) du 26 avril 2017 / Ordinanza sulla radioprotezione (ORaP) del 26 aprile 2017.
International Conference on Harmonization (ICH) Guideline for Good Clinical Practice E6(R2), (www.ich.org).
16. B REFERENCES SPECIFIC TO PROPOSAL
This was a SIGNATURES2023 specific reference list. This was more time efficient with the reference manager Mendeley we used.
References
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Schöll M, Lockhart SN, Schonhaut DR, et al. PET Imaging of Tau Deposition in the Aging Human Brain. Neuron. 2016;89(5):971-982. doi:10.1016/J.NEURON.2016.01.028
Coleman R, Hoffman J, Hanson M, Sostman H, Schold S. Clinical application of PET for the evaluation of brain tumors. J Nucl Med. 1991;32(4):616-622. Accessed August 16, 2021. https://europepmc.org/article/med/2013802
Andronesi OC, Kim GS, Gerstner E, et al. Detection of 2-Hydroxyglutarate in IDH-Mutated Glioma Patients by In Vivo Spectral-Editing and 2D Correlation Magnetic Resonance Spectroscopy. Sci Transl Med. 2012;4(116). doi:10.1126/SCITRANSLMED.3002693
Tate AR, Underwood J, Acosta DM, et al. Development of a decision support system for diagnosis and grading of brain tumours using in vivo magnetic resonance single voxel spectra. NMR Biomed. 2006;19(4):411-434. doi:10.1002/NBM.1016
Wang H, Tan L, Wang HF, et al. Magnetic Resonance Spectroscopy in Alzheimer’s Disease: Systematic Review and Meta-Analysis. Journal of Alzheimer’s Disease. 2015;46(4):1049-1070. doi:10.3233/JAD-143225
Stefano N de, Filippi M. MR Spectroscopy in Multiple Sclerosis. Journal of Neuroimaging. 2007;17(SUPPL. 1):31S-35S. doi:10.1111/J.1552-6569.2007.00134.X
Kruse B, Hanefeld F, Christen HJ, et al. Alterations of brain metabolites in metachromatic leukodystrophy as detected by localized proton magnetic resonance spectroscopy in vivo. Journal of Neurology 1993 241:2. 1993;241(2):68-74. doi:10.1007/BF00869766
Lu M, Zhu X, Zhang Y, Mateescu G, Chen W. Quantitative assessment of brain glucose metabolic rates using in vivo deuterium magnetic resonance spectroscopy. J Cereb Blood Flow Metab. 2017;37(11):3518-3530. doi:10.1177/0271678X17706444
Feyter HM de, Behar KL, Corbin ZA, et al. Deuterium metabolic imaging (DMI) for MRI-based 3D mapping of metabolism in vivo. Sci Adv. 2018;4(8):eaat7314. doi:10.1126/SCIADV.AAT7314
Straathof M, Meerwaldt AE, de Feyter HM, de Graaf RA, Dijkhuizen RM. Deuterium Metabolic Imaging of the Healthy and Diseased Brain. Neuroscience. Published online January 22, 2021. doi:10.1016/J.NEUROSCIENCE.2021.01.023
Mahar R, Zeng H, Giacalone A, Ragavan M, Mareci TH, Merritt ME. Deuterated water imaging of the rat brain following metabolism of [2H7]glucose. Magn Reson Med. 2021;85(6):3049-3059. doi:10.1002/MRM.28700
Serés Roig E, de Feyter HM, Nixon TW, et al. Deuterium metabolic imaging of the human brain in vivo at 7 T. Magn Reson Med. 2023;89(1):29-39. doi:10.1002/MRM.29439
Min Nam K, Gursan A, Bhogal A, et al. Deuterium Echo-Planar Spectroscopic Imaging (DEPSI) to Dynamically Monitor Deuterated Glucose in the Liver at 7T. In: 2021 ISMRM & SMRT Annual Meeting & Exhibition . ; 2021. Accessed September 10, 2021. https://cds.ismrm.org/protected/21MPresentations/abstracts/0231.html
Weng G, Radojewski P, Sheriff S, et al. SLOW: A novel spectral editing method for whole-brain MRSI at ultra high magnetic field. Magn Reson Med. Published online March 28, 2022. doi:10.1002/MRM.29220
Kaiser LG, Hirokazu K, Fukunaga M, Matson GB. Detection of glucose in the human brain with 1H MRS at 7 Tesla. Magn Reson Med. 2016;76(6):1653-1660. doi:10.1002/MRM.26456
Koepsell H. Glucose transporters in brain in health and disease. Pflugers Archiv. 2020;472(9):1299. doi:10.1007/S00424-020-02441-X
Vaishnavi SN, Vlassenko AG, Rundle MM, Snyder AZ, Mintun MA, Raichle ME. Regional aerobic glycolysis in the human brain. Proceedings of the National Academy of Sciences. 2010;107(41):17757-17762. doi:10.1073/PNAS.1010459107
Sonntag KC, Ryu WI, Amirault KM, et al. Late-onset Alzheimer’s disease is associated with inherent changes in bioenergetics profiles. Scientific Reports 2017 7:1. 2017;7(1):1-13. doi:10.1038/s41598-017-14420-x
Mosconi L. Glucose metabolism in normal aging and Alzheimer’s disease: methodological and physiological considerations for PET studies. Clinical and Translational Imaging 2013 1:4. 2013;1(4):217-233. doi:10.1007/S40336-013-0026-Y
Ding F, Yao J, Zhao L, Mao Z, Chen S, Brinton RD. Ovariectomy Induces a Shift in Fuel Availability and Metabolism in the Hippocampus of the Female Transgenic Model of Familial Alzheimer’s. PLoS One. 2013;8(3):e59825. doi:10.1371/JOURNAL.PONE.0059825
Kara F, Belloy ME, Voncken R, et al. Long-term ovarian hormone deprivation alters functional connectivity, brain neurochemical profile and white matter integrity in the Tg2576 amyloid mouse model of Alzheimer’s disease. Neurobiol Aging. 2021;102:139-150. doi:10.1016/J.NEUROBIOLAGING.2021.02.011
Dastur DK, Dastur DK. Cerebral Blood Flow and Metabolism in Normal Human Aging, Pathological Aging, and Senile Dementia. Journal of Cerebral Blood Flow and Metabolism. 1985;5:1-9.
Raichle ME, Posner JB, Plum F. Cerebral blood flow during and after hyperventilation. Arch Neurol. 1970;23(5):394-403. doi:10.1001/ARCHNEUR.1970.00480290014002
Boyle PJ, Scott JC, Krentz AJ, Nagy RJ, Comstock E, Hoffman C. Diminished brain glucose metabolism is a significant determinant for falling rates of systemic glucose utilization during sleep in normal humans. J Clin Invest. 1994;93(2):529-535. doi:10.1172/JCI117003
Goyal MS, Hawrylycz M, Miller JA, Snyder AZ, Raichle ME. Aerobic Glycolysis in the Human Brain Is Associated with Development and Neotenous Gene Expression. Cell Metab. 2014;19(1):49-57. doi:10.1016/J.CMET.2013.11.020
Vlassenko AG, Vaishnavi SN, Couture L, et al. Spatial correlation between brain aerobic glycolysis and amyloid-β (Aβ) deposition. Proceedings of the National Academy of Sciences. 2010;107(41):17763-17767. doi:10.1073/PNAS.1010461107
Phelps ME, Barrio JR. Correlation of brain amyloid with “aerobic glycolysis”: A question of assumptions? Proceedings of the National Academy of Sciences. 2010;107(41):17459-17460. doi:10.1073/PNAS.1012684107
Goyal MS, Vlassenko AG, Blazey TM, et al. Loss of Brain Aerobic Glycolysis in Normal Human Aging. Cell Metab. 2017;26(2):353-360.e3. doi:10.1016/J.CMET.2017.07.010
Mosconi L, Pupi A, de Leon MJ. Brain Glucose Hypometabolism and Oxidative Stress in Preclinical Alzheimer’s Disease. Ann N Y Acad Sci. 2008;1147(1):180-195. doi:10.1196/ANNALS.1427.007
Gruetter R, Ugurbil K, Seaquist ER. Steady-State Cerebral Glucose Concentrations and Transport in the Human Brain. J Neurochem. 1998;70(1):397-408. doi:10.1046/J.1471-4159.1998.70010397.X
Choi IY, Lee SP, Kim SG, Gruetter R. In vivo measurements of brain glucose transport using the reversible Michaelis-Menten model and simultaneous measurements of cerebral blood flow changes during hypoglycemia. J Cereb Blood Flow Metab. 2001;21(6):653-663. doi:10.1097/00004647-200106000-00003
Ishibashi K, Kawasaki K, Ishiwata K, Ishii K. Reduced uptake of 18F-FDG and 15O-H2O in Alzheimer’s disease-related regions after glucose loading. Journal of Cerebral Blood Flow and Metabolism. 2015;35(8):1380-1385. doi:10.1038/JCBFM.2015.127/ASSET/IMAGES/LARGE/10.1038_JCBFM.2015.127-FIG2.JPEG
Kao HL, Lin MS, Wu WC, et al. Improvement of Cerebral Glucose Metabolism in Symptomatic Patients With Carotid Artery Stenosis After Stenting. Clin Nucl Med. 2015;40(9):701-707. doi:10.1097/RLU.0000000000000880
Klijn CJM, Kappelle LJ, Tulleken CAF, van Gijn J. Symptomatic Carotid Artery Occlusion. Stroke. 1997;28(10):2084-2093. doi:10.1161/01.STR.28.10.2084
Bakker FC, Klijn CJM, Jennekens-Schinkel A, Kappelle LJ. Cognitive disorders in patients with occlusive disease of the carotid artery: A systematic review of the literature. J Neurol. 2000;247(9):669-676. doi:10.1007/S004150070108/METRICS
van der Grond J, Balm R, Kappelle LJ, Eikelboom BC, Mali WPTM. Cerebral Metabolism of Patients With Stenosis or Occlusion of the Internal Carotid Artery. Stroke. 1995;26(5):822-828. doi:10.1161/01.STR.26.5.822
Guedj E, Varrone A, Boellaard R, et al. EANM procedure guidelines for brain PET imaging using [18F]FDG, version 3. Eur J Nucl Med Mol Imaging. 2022;49(2):632-651. doi:10.1007/S00259-021-05603-W
Caminiti SP, Sala A, Presotto L, et al. Validation of FDG-PET datasets of normal controls for the extraction of SPM-based brain metabolism maps. Eur J Nucl Med Mol Imaging. 2021;48(8):2486-2499. doi:10.1007/S00259-020-05175-1/METRICS
Nugent S, Croteau E, Potvin O, et al. Selection of the optimal intensity normalization region for FDG-PET studies of normal aging and Alzheimer’s disease. Scientific Reports 2020 10:1. 2020;10(1):1-8. doi:10.1038/s41598-020-65957-3
Heyman A, Fillenbaum GG, Mir-ra SS. Consortium to Establish a Registry for Alzheimer’s Disease (CERAD): Clinical, neuropsychological, and neuropathological components. Aging Clin Exp Res. 1990;2(4):415-424. doi:10.1007/BF03323962
Petersen RC, Caracciolo B, Brayne C, Gauthier S, Jelic V, Fratiglioni L. Mild cognitive impairment: a concept in evolution. J Intern Med. 2014;275(3):214-228. doi:10.1111/JOIM.12190
Poppe C, Elger BS, Wangmo T, Trachsel M. Evaluation of decision-making capacity in patients with dementia: Challenges and recommendations from a secondary analysis of qualitative interviews. BMC Med Ethics. 2020;21(1):1-8. doi:10.1186/S12910-020-00498-Y/TABLES/3
Barros NP de, McKinley R, Wiest R, Slotboom J. Improving labeling efficiency in automatic quality control of MRSI data. Magn Reson Med. 2017;78(6):2399-2405. doi:10.1002/MRM.26618
Pedrosa de Barros N, Slotboom J. Quality management in in vivo proton MRS. Anal Biochem. 2017;529:98-116. doi:10.1016/J.AB.2017.01.017
Chong DGQ, Kreis R, Bolliger CS, Boesch C, Slotboom J. Two-dimensional linear-combination model fitting of magnetic resonance spectra to define the macromolecule baseline using FiTAID, a Fitting Tool for Arrays of Interrelated Datasets. Magnetic Resonance Materials in Physics, Biology and Medicine. 2011;24(3):147-164. doi:10.1007/S10334-011-0246-Y/METRICS
Döring A, Adalid V, Boesch C, Kreis R. Diffusion-weighted magnetic resonance spectroscopy boosted by simultaneously acquired water reference signals. Magn Reson Med. 2018;80(6):2326-2338. doi:10.1002/MRM.27222
Hoefemann M, Bolliger CS, Chong DGQ, van der Veen JW, Kreis R. Parameterization of metabolite and macromolecule contributions in interrelated MR spectra of human brain using multidimensional modeling. NMR Biomed. 2020;33(9). doi:10.1002/NBM.4328
17. APPENDICES
The BASIC CIP template clearly indicates the required documents in this section:
NOTE: Further relevant information can be found in the ISO14155, Annex A Clinical Investigation Plan (CIP)
Documents that do frequently change during the course of the investigation can be mentioned as ‘documents provided separately’ and listed here.
The section headings can be renamed accordingly.
Investigator’s Brochure
General Insurance Conditions, insurance certificate
List of norms
List of investigational sites / PIs (List of countries or centres where data will be collected)
The files of the following [your scanner manufacturer] scanner related annexes are found in the following subdirectory of the eDoc file format of Swissmedic [or EMA or your local responsible administration]:
File obtained by Cambridge Isotope related the deuterated glucose can be found in the following sub-directory of this application of the eDoc file format of Swissmedic [or EMA or your local responsible administration]:
17.4 Quality standards of the dual tuned head coil
Files obtained by [your RF-coil manufacturer] on the dual tuned head coil can be found in the following sub-directory of this application of the eDoc file format of Swissmedic [or EMA or your local responsible administration]:
Since the BASEC website does not allow the upload of multiple CRFs, all CRF forms belonging to this study can be found in the following zip-document:
All-CRFs-SIGNATURES2023-V2.zip
This uploaded zip-file contains the following documents:
CRF_MRSI_V1_All_groups_SIGNATURES2023.pdf
CRF-DeviceDeficiencyForm_v1_SIGNATURES2023.pdf
CRF-MCI-AD-SIGNATURES2023-V1.pdf
CRF_HGCS_SIGNATURES2023_V1.pdf
CRF_SAE_Form_SIGNATURES2023_v1.pdf
The moment these BASEC and Swissmedic [or EMA or your local responsible administration] applications are approved, these CRF forms will be turned into a Recap relational database which is available at [your local CTU or equivalent].
17.5 Risk analysis SIGNARURES2023 related documents
The required risk analysis document, risk management plan document, risk report document and are concatenated in following file:
Risk_Analysis_Plan_Report_BASEC_v2.zip
This file is a concatenation of the following 3 files of the Swissmedic / [or EMA or your local responsible administration]proposal:
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