Lead EC: General and main site’s documents

Essential BASEC Documents for Ultra-High Field MR Projects

Discover the key documents required for submitting an in vivo MR project to BASEC/your local EU-CA/[your local EU-CA/ethics committee], focusing on investigations using non-CE-marked RF coils and pulse sequences, not necessarily, at ultra-high field strengths.

In the Table below you find all the documents uploaded to BASEC / [or local responsible EU-CA]  for obtaining an ethics approval for my SIGNATURES2023 project that has the following characteristics. It includes:

• Ultra High Field MR and MRSI
• MR and MRSI measurements
• MR-measurements on healthy subjects
• MR-measurements on 4 different patient groups
• MR-pulse sequence development (i.e. non-CE-marked pulse sequences)
  • the use of  externally developed [your scanner manufacturer] C2P sequences
  • the use of PulseSeq sequences
  • the use of in house developed [your scanner manufacturer pulse sequence environment] C2P sequences based sequences
• The use of a dual tuned head coil
• In vivo metabolic response measurements after deuterated or normal alpha-D-glucose  supplementation in healthy and patients.

Table 1: Overview of files uploaded to BASEC

Category/Type	Filename	Date of Document	Version
Cover Letter	accompanying-letter-local_ec.pdf	11.10.2024	NA
Investigator’s Brochure (IB)	investigator-brochure-clean.pdf	11.10.2024	V5.0-clean
Investigator’s Brochure (IB)	investigator-brochure-clean.pdf	11.10.2024	V5.0-diff
General Safety & Performance Requirements	[your-scanner_manufacturer]_conformance-documentation.zip	18.03.2024	V2.0
General Safety & Performance Requirements	glucose-for-supplementation-applicable-standards.zip	18.03.2024	V2.0
General Safety & Performance Requirements	RF-coil-documents-provided-by-Coilmanufacurer.zip	11.10.2024	V5.0
General Safety & Performance Requirements	risk-analysis-plan-and-report.zip	18.03.2024	V2.0
Clinical Investigation Plan (CIP)	CIP-plan-clean.pdf	11.10.2024	5.0-clean
Clinical Investigation Plan (CIP)	CIP-plan-diff.pdf	11.10.2024	5.0-diff
Case Report Forms (CRFs)	All-CRFs-clean.zip	11.10.2024	V5.0-clean
Case Report Forms (CRFs)	All-CRFs-diff.zip	11.10.2024	V5.0-diff
CV of Principal Investigator	CV-Principle-Investigator.pdf	18.03.2024	NA
Sponsor Evidence of Qualification	Advanced-GCP-course-certificate-PI.pdf	18.03.2024	NA
Staff List involved in trial	List-of-trial-involved-staff.pdf	13.03.2024	NA
GCP Training Certificates (basic, advanced)	Basic-GCP-course-certificate.pdf	31.01.2023	NA
Sponsor Relation Statement with Manufacturer	Statement regarding Relationship between Sponsor and Manufacturer.pdf	13.03.2024	NA
Contract Sponsor or PI with RF-coil manufacturer	Coil-Manufacturer-PI-Research-Contract.pdf	16.05.2024	NA
Statement of Conformity MR-scanner manufacturer	Scanner-Manufacturer-Conformity-Statement.pdf (sequences)	12.03.2024	V2.0
Statement of Conformity Sequence Creator (PI)	Manufacturer-Conformity-Statement.pdf (sequences)	12.03.2024	V2.0
Statement of Conformity of PI on overall system	risk-analysis-plan-report-basec-v2.zip	18.03.2024	V2.0
Proof of insurance of clinical trial	police-probandenver…ersicherung-01.pdf	31.01.2023	NA
Flyer to recruit healthy volunteers	Flyer-gesunde-probanden-clean.pdf	03.06.2024	V4.0-clean
Flyer to recruit healthy volunteers	Flyer-gesunde-proba…es2023-v4-diff.pdf	03.06.2024	V4.0-diff
Participant Info & Consent (ICF)	ICF-and-study-information-clean.pdf	03.06.2024	V4.0
Participant Info & Consent (ICF)	ICF-and-study-information-diff.pdf	03.06.2024	V4.0-diff
List of relevant-documents	List-of-relevant-documents-clean.pdf	21.05.2024	V1
List of relevant-documents	List-of-relevant-documents-clean.pdf	21.05.2024	V1
Risk analysis related documents	risk-related-docs-v2-signatures2023.zip	13.03.2024	V2
Monitoring Plan	Monitoring-Plan-KlinO-MD-clean.pdf	06.09.2024	V3-clean
Monitoring Plan	Monitoring-Plan-KlinO-MD-plan-v3-diff.pdf	06.09.2024	V3-diff
Correspondence other official bodies (e.g other Legal Services and/or Unitectra etc.)	Mail-trafic-Unitectra-PI.pdf	23.10.2024	NA
Cover letter simultaneous Swissmedic submission	Accompanying-letter-Swissmedic.pdf	24.10.2024	NA

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Accompanying Letters in Combined local Ethics Committee and Swissmedic / [local EU-CA/ethics committee] Proposals

Accompanying letters for combined submissions to the local ethics committee (EC, commonly referred to as “Kantonale Ethik Komission” in Switzerland) [or local responsible EU-CA]  and [Swissmedic / local EU-CA/ethics committee] play a pivotal role in facilitating approval processes for clinical trials. These letters serve as a structured and formal response to feedback or critiques received during prior submission rounds. They reflect the sponsor’s commitment to addressing all concerns in a systematic and transparent manner.

Key Elements

1. Response to Criticism: The letter systematically addresses all points of criticism or clarification raised in earlier reviews, ensuring that responses are comprehensive and well-documented. This structured approach is crucial for advancing the review process efficiently.
2. Structure and Alignment: Each critique is addressed in alignment with the original feedback structure, often citing specific sections or documentation. Cross-references to updated protocols, consent forms, or data collection frameworks help clarify responses.
3. Clear Reference to Regulatory Standards: References to applicable regulatory frameworks, such as ISO 14155 for clinical investigations or specific clauses of the ClinO-MD (Ordinance on Clinical Trials with Medical Devices) / EU-MDR, underline adherence to required standards​​.
4. Evidence of Revision: The letter highlights substantial changes or corrections made to documentation. For instance, discrepancies in inclusion/exclusion criteria or technical clarifications, such as those related to MR-pulse sequence safety under IEC 60601-2-33, are explained and justified​​.
5. Transparency and Forward-Looking Statements: When certain points remain unresolved, the letter may request further guidance or propose additional measures for risk mitigation. For instance, where SAR (Specific Absorption Rate) compliance under prolonged MR-use is questioned, references to computational modeling or experimental data are typically included.

References to Requirements

• In addressing documentation requirements, reference should be made to ClinO-MD Articles 31-34, which outline the necessary reporting and safety measures, as well as Article 40, which specifies long-term data retention obligations. Compliance with these requirements ensures that all adverse events, safety interventions, and critical trial endpoints are properly recorded and reported.
• ISO 14155 Standard: Ensures the robustness of the clinical investigation protocol​.
• IEC 60601-2-33: Pertinent for safety evaluations involving medical imaging equipment such as MR systems​.

Best Practices

• Be Comprehensive: Address every point raised, no matter how minor it may seem. Leaving gaps can lead to further delays.
• Use Structured Formats: Numbered lists and subheadings make it easier for reviewers to follow your responses.
• Reference Source Documents: Always back up claims with direct references to updated sections of the submission, including annexed documents.

Accompanying letters are not mere formalities; they are strategic documents that showcase the sponsor’s dedication to ethical and regulatory compliance. Ensuring that these letters are well-crafted and comprehensive significantly increases the likelihood of moving forward smoothly in the clinical trial approval process.

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The Investigator’s Brochure (IB) for Combined local Ethics Committee and Swissmedic  [or local responsible EU-CA] Proposals

When I started working on clinical investigations requiring submissions to both local ethics committees and Swissmedic, I was clueless about the Investigator’s Brochure (IB) — a critical document. Neither Swissmedic nor other official sources were willing to provide useful guidance; their official stance seemed to be: “We are not an information service for scientists preparing applications.” Later, I learned through insider discussions that this lack of assistance is a deliberate policy. In this post, I’ll share what I’ve learned to help others navigate the complexities of the IB and ensure their efforts are structured and efficient.

What Is the Investigator’s Brochure?

The Investigator’s Brochure (IB) is a key document in clinical trial submissions. It provides a comprehensive summary of the investigational product(s), detailing their scientific, preclinical, and clinical properties. Its primary purpose is to support ethical and regulatory assessments by presenting the rationale, safety, and potential efficacy of the investigational device or drug.

Major Aspects to Address in the IB

Based on my own experience and a review of structured guidance (though neither Swissmedic nor local ethics committee or local CTU), the IB should systematically address the following key elements:

• General Overview and Device Description
  • Define the investigational device, including hardware and software components.
  • Clearly distinguish between CE-marked and non-CE-marked components, especially if custom-developed items (e.g., software for pulse sequences) are included​.
    • Example: In the SIGNATURES2023 project, the MRI system, head coil, and pulse sequences are all categorized and described in detail​.
•  Preclinical Testing
  • Highlight testing results for safety and performance, including physical and biological tests.
  • If your device includes new hardware (e.g., an RF coil) or modified software, include thermal risk analyses, peripheral nerve stimulation (PNS) evaluations, and electromagnetic compatibility results​​.
• Clinical Investigation Plan
  • Provide a high-level overview of the clinical investigation: its scope, objectives, and phases.
  • Discuss the target patient population, inclusion/exclusion criteria, and ethical considerations​.
    • Example: The SIGNATURES2023 project outlines a four-phase study from preclinical proof of safety to pilot patient tests.
• Risk Management
  • Detail your risk identification and mitigation strategies, addressing risks specific to the investigational device.
  • For MRI-related studies, this might include risks from high-field magnetic strength, specific absorption rates (SAR), and compatibility with patient implants​.
• Monitoring and Data Management
  • Explain how the study will be monitored, including compliance with good clinical practices (GCP).
  • Describe plans for data retention and reporting, ensuring adherence to Swiss and EU standards for clinical trials.​
• Device Classification and Regulatory Context
  • Define the risk classification of your device under EU MDR (e.g., Class IIa for SIGNATURES2023).
  • Discuss the historical use of similar devices and previous investigations to establish a safety profile​.
• Annexes and Supplementary Data
  • Provide supporting documents, such as:
    • User manuals.
    • Safety and risk management documentation.
    • Test reports (e.g., thermal safety and RF safety tests).
    • Relevant standards and certificates (e.g., ISO 13485 compliance for hardware manufacturers)​.
    • Lessons Learned
    • NOTE: Swissmedic and  [or local responsible EU-CA] are organisations that verify your application: Accept that Swissmedic/EMA regard themselves as a regulatory authority, not an advisory service. Expect no help in structuring your investigators brochure IB (at least I did not get it from Swissmedic).
• Learn from Examples
  •  Studying IBs from previous investigations (where available) is invaluable. They provide practical insights into structure and content.
• Think Structurally
  • Every section should systematically address the regulatory requirements. Don’t leave room for reviewers to ask obvious questions.
• Highlight Safety and Compliance
  • The IB is your chance to demonstrate that your investigational device is safe and that your trial is ethically sound.

Conclusion

The Investigator’s Brochure is not just a regulatory requirement; it’s the backbone of a well-prepared submission to your local ethics committee and Swissmedic/ local EU-CA/ethics committee. By addressing safety, clinical relevance, and compliance in a structured way, you can pave the path for approval. Read my blog post, where I’ll dive deeper into specific sections of the IB, such as preclinical testing and device interaction summaries.

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General Safety & Performance Requirements

Risk Related Documents in SIGNATURES2023

Effective risk management is a cornerstone of ethical and regulatory compliance in clinical investigations involving medical devices, particularly in studies like SIGNATURES2023 that incorporate non-CE-marked components. To address safety concerns and meet Swissmedic and local Ethics Committee ( local EC) requirements, three key documents were developed:

1. Risk Analysis
   This document systematically identifies and evaluates potential risks associated with the investigational device, including the non-CE-marked dual-tuned RF coil and research pulse sequences. It categorizes risks based on severity and likelihood, providing a clear framework for prioritizing risk mitigation strategies.
2. Risk Management Plan
   The plan outlines the structured approach for managing identified risks throughout the project. It specifies roles and responsibilities, mitigation actions, and periodic review processes, ensuring that all risks are effectively addressed and that residual risks are kept within acceptable limits.
3. Risk Management Report
   This report consolidates the outcomes of the risk management process, documenting how risks were mitigated and verifying the effectiveness of these measures. It concludes with a benefit-risk analysis that justifies the study’s safety and ethical integrity.

These documents collectively demonstrate a rigorous approach to risk management, reinforcing the safety of participants and compliance with ISO 14971 and relevant regulatory standards. Researchers preparing similar proposals should emphasize the integration of these components to ensure approval from both Swissmedic and local local EU-CA/ethics committee.

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Clinical Investigation Plan (CIP)

The Clinical Investigation Plan (CIP) is the cornerstone document for any ethics committee submission in an MR research project. It outlines the study’s objectives, methodology, and procedures, ensuring compliance with ethical and regulatory standards. For MR scientists, the CIP serves as both a roadmap for conducting the investigation and a critical means of communicating the study’s scientific validity and participant safety measures to the ethics committee. A well-structured CIP is essential to gaining approval and should detail aspects such as participant recruitment, risk management, data protection, and monitoring plans.

For a step-by-step guide on crafting an effective CIP, including practical advice tailored to MR research, visit this blog post. It covers all the details you’ll need to ensure your CIP is both comprehensive and submission-ready.

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Case Report Forms (CRFs)

Case Report Forms (CRFs) are standardized documents used to systematically collect and record data during clinical investigations, ensuring consistency, accuracy, and completeness in documenting research outcomes. They are critical for capturing patient demographics, medical history, investigational procedures, adverse events, and study outcomes in alignment with the study protocol. CRFs are required by regulatory bodies, including Swissmedic and the local ethics committee (local EC), both of which review these forms as part of their assessment of clinical investigations. Typically, CRFs are initially created in text format to outline the necessary data fields, and they can subsequently be converted into electronic databases, such as RedCap, to facilitate secure data entry, management, and analysis. Their use is also mandated by international standards such as ISO 14155 and regulatory frameworks like the EU Medical Device Regulation (MDR) and FDA’s 21 CFR Part 11, ensuring compliance with Good Clinical Practice (GCP). This process enhances the transparency, reliability, and regulatory acceptance of the collected data while supporting patient safety and the ethical integrity of clinical trials​​​.

Please refer to a post on CRFs related to a CRFs in MR-trials using non CE-marked pulse sequence and RF-coil components.

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Principal Investigator CV

The Principal Investigator (PI) CV is a pivotal element in a ClinO-MD application, as it demonstrates the PI’s qualifications, expertise, and suitability to lead the clinical investigation. This document will be closely scrutinized by both Swissmedic and the local ethics committee. A well-prepared CV not only ensures compliance but also strengthens the overall application by showcasing the PI’s ability to uphold ethical standards, manage risks, and ensure participant safety.

Key Requirements for a PI CV

1. Personal Information:
   • Full name, contact information, and institutional affiliation.
   • Professional title and current position.
2. Educational Background:
   • Degrees (e.g., MD, PhD, MSc), with fields of study and awarding institutions.
   • Include post-graduate training or specialized courses relevant to the clinical investigation, such as medical device technology or imaging methods.
3. Certifications and Training:
   • Good Clinical Practice (GCP) certification (mandatory for clinical investigations).
   • Training in ISO 14155: Clinical investigation of medical devices for human subjects.
   • Human Research Act (HRA) compliance training in Switzerland.
   • Relevant courses or certifications in ethical research, patient safety, or device-specific methods.
4. Professional Experience:
   • Highlight clinical research experience, particularly with medical devices or similar investigational setups.
   • Specific mention of experience with investigational devices (e.g., studies involving MR imaging, RF coils, or software elements in medical devices).
   • Management of past or ongoing studies regulated by Swissmedic, EU MDR, FDA, or equivalent bodies.
   • Mention leadership roles in research teams or multi-center studies.
5. Publications and Presentations:
   • List peer-reviewed publications, particularly those related to the investigational device or relevant medical fields.
   • Include presentations or posters at international conferences (e.g., ISMRM or ESMRMB for MR-related studies).
6. Professional Memberships:
   • Membership in relevant organizations such as ISMRM, ESMRMB, or local Swiss societies for medical imaging and medical device development and research like IES, SSBE or equivalent.
   • Membership in ethical review or regulatory committees (if applicable).
7. Study-Specific Skills and Competencies:
   • Directly relate your expertise to the study’s focus (e.g., knowledge of MR imaging, pulse sequence development, patient monitoring, or safety protocols).
   • Mention familiarity with regulatory requirements like the ClinO-MD, ISO 14155, and Swissmedic directives.
   • Evidence of robust knowledge of risk management and adverse event reporting processes.
8. Languages:
   • Proficiency in languages relevant to the study (e.g., German for participant interaction in Swiss studies).
   • Fluency in English for regulatory and academic communication.
9. Continuing Education:
   • Highlight recent participation in workshops, conferences, or online courses relevant to medical device research.

Advice for Structuring your CV

• Keep the CV professional and concise (2–4 pages), while ensuring all required details are covered.
• Use bullet points to make the document easy to read and navigate.
• Focus on achievements and experience that are directly relevant to the study and regulatory requirements.
• Use consistent formatting for sections and headings for clarity.

Additional Points to Highlight

• Demonstrate a strong track record of ensuring patient safety and ethical research conduct.
• Include examples of (prior) handling complex investigational setups, such as experimental devices or software integration.
• Provide details of experience with ethics committee submissions and Swissmedic/ [or local responsible EU-CA]  applications.
• Mention contributions to the development or validation of investigational medical devices.
• Showcase leadership in managing multidisciplinary teams, particularly in clinical trials.

Swissmedic/ [or local responsible EU-CA] and local ethics committee value experience that assures compliance with ethical and regulatory frameworks while safeguarding participant welfare. Highlighting relevant qualifications and tailoring the CV to the study’s unique aspects, such as investigational MR scans or software, can significantly enhance its impact and facilitate a smooth approval process.

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Sponsor Evidence of Qualification

The Sponsor Evidence of Qualification is a critical document required for a ClinO-MD application (and most probably also for a MD  [or local responsible EU-CA] MDR-application), as it demonstrates the sponsor’s ability to oversee the clinical investigation effectively and ensure compliance with Good Clinical Practice (GCP) and other regulatory standards. In the context of an MR-trial in Switzerland or the EU, this document must include proof of the sponsor’s knowledge, resources, and systems to manage the study responsibly.

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Key Requirements for Sponsor Evidence of Qualification

1. GCP Certification:
   • Proof of completion of a Basic GCP course (e.g., certified by TransCelerate).
   • Proof of completion of an Advanced GCP course, focusing on clinical investigations involving medical devices or specific study components like MR imaging.
   • Certificates should clearly indicate the sponsor’s representatives who attended the training and the date of completion.
2. ISO 14155 Training:
   • Evidence of training in the ISO 14155 standard for the clinical investigation of medical devices.
3. HRA and ClinO-MD Knowledge:
   • Documentation of training or seminars on the Swiss Human Research Act (HRA) and Clinical Trials Ordinance with Medical Devices (ClinO-MD).
   • If the trial involves multi-national coordination, proof of familiarity with the EU Medical Device Regulation (MDR) 2017/745 is advantageous.
4. Experience Documentation:
   • List of past clinical investigations sponsored, particularly focusing on medical devices or MR-related trials.
   • Demonstration of familiarity with risk management, adverse event reporting, and safety monitoring.
5. Quality Management System (QMS) Evidence:
   • Evidence of an operational QMS compliant with ISO 13485 or similar standards.
   • Standard Operating Procedures (SOPs) for clinical trials, including patient safety monitoring, data handling, and regulatory compliance.
6. Financial Resources:
   • Proof of funding or financial solvency to support the clinical trial’s duration, including resource allocation for unexpected events or delays.
7. Insurance Coverage:
   • Documentation of liability insurance covering potential risks to participants during the clinical trial.
8. Key Team Members:
   • CVs of key team members involved in managing the trial, including the study director, safety monitoring personnel, and data management staff.
   • Specific focus on their experience in clinical trials, medical device investigations, and regulatory compliance.

Additional Documents Relevant to ClinO-MD MR Trials

• Technical Expertise Evidence:
  • Documentation of experience with investigational MR scanners, RF coils, and software (e.g., experimental pulse sequences).
  • Certification of competency in MR-specific safety standards, such as IEC 60601-2-33 or NEMA MS 8 (useful for description of SAR).
• Collaboration Agreements:
  • Contracts or agreements with the clinical sites, confirming their participation and readiness to adhere to the trial protocol.
• Ethical Compliance:
  • Copies of approvals from local and national ethics committees.
  • Previous correspondence with Swissmedic or other regulatory bodies, showing compliance history.
• Clinical Monitoring Plans:
  • A detailed plan outlining how the sponsor will monitor the trial, including on-site visits, data verification, and adverse event tracking.
• Device-Specific Training:
  • Evidence that investigators and technicians have been trained on the investigational MR system and associated protocols.
• Safety and Risk Management Plans:
  • Comprehensive plans for managing risks associated with MR scanning, including specific absorption rate (SAR) monitoring and emergency procedures.
• Data Protection Compliance:
  • Proof of adherence to GDPR (EU) and Swiss data protection laws for handling participant data.

Advantages of Including Additional Documentation

Including supplementary documents, such as recent audits or certifications of compliance, enhances the credibility of the sponsor and reassures Swissmedic/EMA and your local ethics committee of their capability to manage the trial safely and ethically. Tailoring the evidence of qualification to reflect specific expertise in MR-related clinical investigations will strengthen the application and demonstrate readiness for regulatory scrutiny.

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Staff List involved in trial

The Staff List Involved in the Trial is a mandatory submission for the local ethics committee (local EC) and is often required for Swissmedic/ [or local responsible EU-CA]  as part of a ClinO-MD application. This document provides transparency regarding the qualifications, roles, and responsibilities of all personnel involved in the clinical investigation, ensuring that the study is conducted safely, ethically, and in compliance with regulatory standards.

Purpose and Importance of the Staff List

1. Transparency:
   • Provides a clear overview of the team managing the study, allowing the local EC and Swissmedic to assess whether the personnel possess the necessary qualifications and experience.
   • Ensures accountability by identifying who is responsible for key tasks, such as patient safety, data collection, device handling, and regulatory compliance.
2. Competence Assessment:
   • Demonstrates that the study team includes individuals with the requisite expertise, particularly in areas such as Good Clinical Practice (GCP), device-specific safety (e.g., MR-related protocols), and clinical trial management.
   • Reassures regulators that the team can handle potential risks, including managing adverse events and ensuring the proper use of investigational devices.
3. Regulatory Compliance:
   • Ensures alignment with ISO 14155, which requires that all personnel involved in clinical investigations are qualified for their assigned tasks.
   • Supports adherence to Swissmedic and local EC requirements for ensuring patient safety, ethical conduct, and data integrity.

Key Components of a Staff List

1. Personnel Details:
   • Full names and titles of all staff involved in the study.
   • Contact information for key personnel, such as the Principal Investigator (PI) and study coordinator.
2. Roles and Responsibilities:
   • Clearly define each individual’s role, such as:
     • Principal Investigator (overall study oversight).
     • Sub-Investigators (specialized tasks, e.g., MR safety supervision).
     • Study Coordinator (day-to-day management and communication).
     • Imaging Technicians (MR protocol execution, patient positioning).
     • Data Managers (handling and storage of clinical and imaging data).
     • Research Nurses (participant care and monitoring).
3. Qualifications and Experience:
   • Include a brief description of each individual’s qualifications (e.g., medical degrees, certifications in MR safety, GCP training).
   • Highlight relevant experience, particularly in clinical investigations and device-specific studies.
4. Training Records:
   • Document staff completion of mandatory training, such as:
     • GCP and advanced GCP certifications.
     • MR-specific safety training (e.g., SAR monitoring, handling high-field MR scanners).
     • Protocol-specific training provided by the sponsor or device manufacturer.
5. Contingency and Oversight:
   • Identify backup personnel for critical roles to ensure continuity of the trial in case of staff unavailability.
   • Clearly define oversight mechanisms (e.g., PI reviews all safety reports, or periodic audits by the study coordinator).

How to Motivate Choices for the Staff List

1. Expertise Alignment:
   • Justify the selection of staff based on their specific skills and expertise required for the study (e.g., an MR physicist for high-field imaging studies or a neurologist for Alzheimer’s disease trials).
2. Training and Certification:
   • Emphasize compliance with regulatory training requirements, such as GCP and device-specific certifications, to demonstrate readiness and adherence to standards.
3. Experience with Similar Studies:
   • Highlight prior involvement of staff in comparable clinical investigations to build confidence in the team’s capability to handle complex protocols and investigational devices.
4. Diversity of Roles:
   • Explain how the team structure ensures comprehensive coverage of all study aspects, from patient care to data management.

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GCP Training Certificates (basic, advanced)

GCP Training Certificates (Basic, Advanced) are a key requirement for the Principal Investigator (PI) of an MR-related study in Switzerland, as mandated by the ClinO-MD. These certificates serve as proof that the PI possesses the foundational knowledge and advanced understanding of Good Clinical Practice (GCP), ensuring adherence to ethical, scientific, and regulatory standards throughout the clinical investigation. The basic GCP training covers the principles of conducting trials in compliance with ISO 14155, focusing on patient safety, data integrity, and compliance with applicable regulations. Advanced GCP training delves deeper into specialized topics such as managing complex studies, device-specific considerations, and regulatory nuances relevant to medical devices. While it is obligatory for the PI to hold these certifications, it is highly recommended for other key study personnel, such as sub-investigators and study coordinators, to obtain GCP training as well. This not only strengthens the study’s overall compliance but also demonstrates a robust commitment to quality and ethical standards, which can be advantageous during Swissmedic/ [or local responsible EU-CA]and local ethics committee reviews.

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Statement of Relation Sponsor and Manufacturer

The Manufacturer Statement is a critical document in the context of medical device (MD) trials, particularly in investigator-initiated studies where investigational devices, such as custom-developed MRI pulse sequences, are used. In many MR studies initiated by MR scientists, the manufacturer and the Principal Investigator (PI) are often the same individual. This dual role requires a clear declaration of compliance with regulatory and safety standards, as outlined by frameworks such as the EU Medical Device Regulation (MDR, 2017/745).

Key Components of the Manufacturer Statement

1. Dual Role of Manufacturer and PI:
   • Acknowledge the dual role where the PI is also the manufacturer of the investigational device, ensuring both technical and clinical accountability.
   • Emphasize how this alignment facilitates direct oversight of the device’s compliance with applicable standards and trial protocols.
2. Compliance with Standards:
   • Declare adherence to general safety and performance requirements, such as those in Annex I of the MDR, ISO 14155 (clinical investigation guidelines), and IEC 60601-2-33 (safety standards for MR equipment).
   • Confirm that, apart from the investigational aspects under study, all other safety and performance measures are in place to protect participant health.
3. Documentation and Accessibility:
   • Confirm the maintenance and accessibility of technical documentation (e.g., design, validation, and risk management records) for Swissmedic or other relevant authorities for at least 10 years post-trial (15 years for implantable devices).
   • Highlight the PI’s responsibility to make this documentation available during regulatory inspections.

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Contract with RF-coil manufacturer

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Research Agreement with Scanner Manufacturer

A Research Agreement with the Scanner Manufacturer is a cornerstone document for clinical investigations involving MRI systems, particularly when experimental protocols, pulse sequences, or non-standard equipment are used. For ethics committee (local EC) and Swissmedic / local EU-CA/ethics committee applications, this agreement demonstrates a structured and transparent collaboration, ensuring regulatory compliance and robust research practices. It also reflects the manufacturer’s confidence in the research institution and its team, reinforcing the credibility of the proposed study.

Key Aspects of a Research Agreement

Perhaps not all issues may apply to your planned trial or your case, but one could think of the following aspects for your research agreement with you MR-scanner manufacturer:

1. Purpose and Scope:
   • Clearly define the investigational nature of the collaboration, such as testing custom pulse sequences, integrating experimental software, or using non-CE-marked components under controlled conditions.
   • Emphasize that investigational applications are used solely within the trial’s ethical and regulatory framework.
2. Manufacturer Confidence:
   • A research agreement with a reputable scanner manufacturer, such as [your scanner manufacturer] signals trust in the institution’s capabilities. Manufacturers do not support collaborations with teams they perceive as unqualified or likely to jeopardize the reputation of their product(s).
   • This endorsement indirectly assures Swissmedic / [or local responsible EU-CA]  and your local EC that the study aligns with high safety and competency standards.
3. Transparency and Regulatory Compliance:
   • Outline the roles and responsibilities of both parties, ensuring complete transparency in the investigational setup.
   • Demonstrate adherence to ISO 14155 (clinical investigation of medical devices), IEC 60601-2-33 (MRI safety), and local regulations such as ClinO-MD, Swiss medical device law, or EMA guidelines.
   • Highlight risk management practices and the use of safety protocols to protect participants and ensure proper handling of investigational components.
4. Provision and Use of Equipment:
   • List any equipment, software, or technical support provided by the manufacturer, specifying whether items are CE-marked.
   • For non-CE-marked components, include commitments to preclinical safety testing and clear statements on investigational use only, as per regulatory requirements.
5. Ethical and Legal Safeguards:
   • Address confidentiality, data protection (e.g., GDPR, Swiss data laws), and IP rights, ensuring ethical and legal compliance.
   • Confirm that investigational work respects the manufacturer’s proprietary rights while safeguarding the trial’s transparency.
6. Termination and Amendments:
   • Define the process for modifying or terminating the agreement, ensuring both parties can adapt to unforeseen ethical or technical challenges.

Advantages for local EC and Swissmedic / local EU-CA/ethics committee Applications

• Enhanced Credibility: A research agreement with a reputable manufacturer shows that the manufacturer has vetted the research team, which strengthens the application by reflecting trust in the team’s qualifications and the study’s safety.
• Transparency: Clearly outlined roles, responsibilities, and safety measures demonstrate a high level of openness, which both local EC and regulatory bodies prioritize.
• Professional Oversight: The manufacturer’s involvement indicates additional oversight, which reduces the risk of errors or non-compliance during the trial.

If setup appropriately, this agreement is not just a formality—it is a testament to the preparedness and professionalism of the research team, offering assurance to regulatory bodies and ethics committees that the study is safe, ethical, and scientifically sound. A well-crafted agreement can significantly improve the chances of approval by showcasing this alignment.

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Statement of Conformity for Pulse Sequence Creation

My SIGNATURES2023 application included a Statement of Conformity for Pulse Sequence Creation confirms that user-developed pulse sequences created in the [your scanner manufacturer] [your scanner manufacturer pulse sequence] development environment maintain the safety standards of CE-marked systems when executed on [your scanner manufacturer] MRI hardware. If you work with a different brand of scanner, ask your provider to provide you with such a document.

According to this document, sequences generated using [your scanner manufacturer pulse sequence environment] software adhere to the limits established by the IEC 60601-2-33 standard, particularly concerning Specific Absorption Rate (SAR) monitoring and peripheral nerve stimulation (PNS). These safeguards remain active as long as the standard CE-marked hardware and software are used, and the developer follows the guidelines outlined in the [your scanner manufacturer pulse sequence environment] User Guide and Operator Manual.

Key Points from the Document

1. Safety Assurance:
   • The MR system ensures compliance with SAR and PNS limits for all sequences, including custom-developed ones, as defined by IEC 60601-2-33.
   • Additional hardware and software components in the system prevent these limits from being exceeded.
2. CE-Mark Retention:
   • The use of custom sequences does not alter the CE-marked status of the MR system, provided that regular, unmodified product hardware and software are used.
3. Responsibilities:
   • [Your scanner manufacturer] ensures patient safety regarding RF absorption and magnetic field switching as long as the conditions of the system’s CE-marked configuration are met.
   • The responsibility for the clinical applicability, image labeling, and testing of custom sequences (e.g., phantom testing, unit testing) lies with the user.
4. Regulatory and Legal Compliance:
   • Developers are responsible for complying with local laws and regulations, including registering a clinical trial if necessary.

This statement is critical for Swissmedic/EMA and local EC applications, as it demonstrates that investigational sequences developed within the manufacturer’s framework comply with the same safety standards as the system’s CE-marked sequences. It also clarifies the division of responsibility, emphasizing the developer’s role in ensuring the suitability and regulatory compliance of custom sequences.

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Statement of Conformity by your MR-scanner Manufacturer

The Statement of Conformity for the MR-Scanner is a critical document that demonstrates the compliance of the specified MRI system with essential safety, performance, and regulatory standards. This document should be requested from the manufacturer of the scanner and is a key component of applications to regulatory bodies such as Swissmedic/ local EU-CA/ethics committee and local ethics committees (local EC).

The document typically includes the following elements:

• Device Information: The type of MRI scanner (e.g., [your scanner type]) and its specific product identification number.
• Manufacturer Details: The name and address of the manufacturer (e.g., [your scanner manufacturer]).
• Declaration of Compliance: A statement certifying that the device complies with international and regional standards for medical electrical equipment, including but not limited to:
  • IEC 60601-1: General requirements for basic safety and essential performance.
  • IEC 60601-2-33: Particular requirements for the basic safety and essential performance of magnetic resonance equipment for medical diagnosis.
  • ISO 14971: Application of risk management to medical devices.
  • ISO 13485: Quality management systems for regulatory purposes.
  • Other standards relevant to electromagnetic compatibility (e.g., IEC 60601-1-2), usability (e.g., IEC 60601-1-6), and software lifecycle processes (e.g., IEC 62304), depending on the scanner’s configuration.

The Statement of Conformity assures that the scanner adheres to the latest regulatory and technical requirements for safety, performance, and usability. It is an essential component of any research or clinical trial application involving MRI technology, confirming that the scanner operates within defined safety parameters and supports ethical use in investigational contexts. Always ensure that this document is updated to reflect the latest certification and standards compliance for the specific scanner model.

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Statement of Conformity by PI on the Overall Scanner System

The Statement of Conformity of the Principal Investigator (PI) is a crucial document for medical device trials involving combinations of CE-marked and non-CE-marked MR-scanner components. In the SIGNATURES2023 study, the investigational system comprises two non-CE-marked parts (the dual-tuned head coil and custom-developed pulse sequences) and two CE-marked parts (the scanner hardware and operating system). While the CE-marked components meet predefined safety and performance standards individually, the integration of these four components creates an overall non-CE-marked system, requiring the PI to formally declare the safety and compliance of the entire setup for investigational use.

This statement is required because:

1. Comprehensive Responsibility: The PI is responsible for ensuring the safety, ethical compliance, and functionality of the integrated system as described in the Investigator’s Brochure (IB), which provides detailed technical and operational documentation.
2. Regulatory and Ethical Safeguards: By issuing the statement, the PI demonstrates that the combined system has been evaluated for potential risks, and that appropriate mitigations are in place to protect study participants.
3. Transparency for Oversight: The statement assures regulatory bodies (e.g., Swissmedic) and local ethics committees that the PI acknowledges and has addressed the unique challenges posed by the integration of CE-marked and non-CE-marked components.

This declaration is critical to establish the system’s investigational status, provide accountability for its safe use, and ensure compliance with relevant standards such as ISO 14155 and ClinO-MD. It aligns with the overarching goal of safeguarding participant welfare while supporting robust clinical investigation practices.

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Proof of insurance of clinical trial

The Proof of Insurance for a Clinical Trial is a critical requirement to ensure financial coverage for potential risks or harm that participants may experience during a clinical investigation. This obligation is rooted in ISO 14155, which governs clinical investigations of medical devices for human subjects, as well as local regulatory frameworks such as the Swiss ClinO-MD and broader EU Medical Device Regulation (MDR 2017/745). These standards and regulations emphasize the sponsor’s responsibility to safeguard participants by ensuring liability coverage through appropriate insurance.

Regulatory Basis

1. ISO 14155:
   • Section 5.3 of ISO 14155 explicitly requires sponsors to have financial arrangements in place to cover the costs of medical treatment or compensation in case of trial-related injuries or harm.
   • This ensures participant protection and ethical compliance.
2. Swiss ClinO-MD:
   • Mandates sponsors to provide evidence of appropriate liability insurance or financial guarantees to cover damages arising from the clinical trial.
3. EU MDR 2017/745:
   • Annex XV requires sponsors of clinical investigations to ensure adequate insurance coverage for participant protection.

Types of Insurance

• Institutional Insurance:
  • Larger academic institutions often have umbrella insurance policies that cover clinical trials conducted under their auspices. These policies typically include liability coverage for trial-related risks.
• Third-Party Insurer:
  • For independent or smaller sponsors, contacting an insurance provider familiar with clinical trials is necessary to obtain specific coverage. These policies are tailored to the trial’s scope, risk level, and participant demographics.

What to Include in the Insurance Documentation

1. Policy Information:
   • Name and details of the insurer.
   • Policy number and effective dates.
2. Coverage Scope:
   • Coverage for trial-related injuries or adverse events.
   • Details on geographical scope (e.g., Switzerland, EU).
3. Participant Inclusion:
   • Confirmation that all participants in the trial are covered.
4. Policy Limits:
   • Description of financial limits and terms of the coverage.

Compliance and Submission

The ethics committee (EC) requires the proof of insurance to verify that participants are protected against unforeseen risks. Swissmedic/EMA [or local responsible EU-CA]may also review this documentation as part of the approval process for clinical investigations. Sponsors should ensure the policy aligns with ISO 14155 and ClinO-MD/MDR requirements to avoid delays in trial authorization.

Securing this insurance demonstrates the sponsor’s commitment to participant safety, ethical standards, and regulatory compliance.

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Participant Information and Consent (ICF)

Introduction

The Informed Consent Form (ICF) is a cornerstone document for any clinical study involving human participants and is required for ethical approval by Swissmedic, the European Medicines Agency (EMA), and the local ethics committees (ECs). The content of the ICF depends heavily on the specifics of the trial, including the study design, participant groups, and investigational procedures. In the SIGNATURES2023 study, for example, four different ICFs were prepared to address the unique requirements of three patient groups and one healthy volunteer group. This demonstrates how tailored the ICF must be to adequately inform participants of their role, rights, and the risks and benefits involved in the study. Be aware that these document are for sure critically revised your local EC but might also be reviewed by Swissmedic or [or local responsible EU-CA] .

Legal Background

The requirement for an ICF is rooted in several legal and ethical frameworks:

1. Swiss Human Research Act (HRA) and Ordinance on Clinical Trials with Medical Devices (ClinO-MD):
   • Mandates that participants receive comprehensive information about the study to make an informed decision.
2. ISO 14155:
   • Requires adherence to Good Clinical Practice (GCP), which includes obtaining written informed consent before any study-related procedures.
3. EU General Data Protection Regulation (GDPR):
   • Emphasizes transparency regarding the use of participant data, ensuring they are informed about how their data will be stored, analyzed, and protected.
4. Helsinki Declaration:
   • Establishes the ethical principles for medical research involving human subjects, including the obligation to obtain informed consent.

General Advice for MR Researchers Preparing an ICF

Recruitment and Informed consent procedure template

From the uploaded ICF for healthy volunteers in the SIGNATURES2023 study, the following general guidance can be extracted for other MR researchers:

1. Structure the ICF Clearly:
   • Use sections to organize the information, such as:
     • Overview of the study.
     • Detailed study procedures.
     • Risks and benefits.
     • Data protection and insurance coverage.
     • Consent statements.
   • This ensures participants can easily navigate and understand the document.
2. Tailor the ICF to the Study:
   • Customize the content for different participant groups, addressing specific risks and procedures relevant to each group (e.g., healthy volunteers versus patients).
3. Describe Risks and Benefits Transparently:
   • Clearly explain risks, including those specific to MR procedures (e.g., SAR exposure, peripheral nerve stimulation) and investigational devices (e.g., non-CE-marked components).
   • Highlight the absence of direct benefits for healthy volunteers while emphasizing the potential contribution to future diagnostics.
4. Include Practical Details:
   • Outline what participants will need to do, such as duration in the MR scanner, intake of substances (e.g., deuterated glucose), and specific tasks during imaging.
5. Data Protection and Confidentiality:
   • Provide detailed information on how personal data and imaging results will be handled, ensuring compliance with GDPR and local data protection laws.
6. Participant Rights:
   • Emphasize voluntariness and the ability to withdraw at any time without affecting ongoing medical care.
7. Legal and Ethical Oversight:
   • Mention that the study has been reviewed and approved by Swissmedic and the relevant ethics committees, providing assurance of adherence to regulatory and ethical standards.

By tailoring the ICF to the specifics of the study and adhering to the legal and ethical requirements, MR researchers can ensure that participants are fully informed and that the study receives the necessary ethical and regulatory approvals.

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List of relevant-documents

Risk analysis related documents

Three SIGNATURES2023 specific risk documents for the overall MR-scanner system have been submitted also to Swissmedic as well as the local EC:

• Risk analysis
• Risk report
• Risk management plan

These documents for the combined Swissmedic/ [or local responsible EU-CA] local EC were shortly characterized above and on the three links above point to specific posts with detailed information on how to write such documents.

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Monitoring Plan

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Flyer to recruit healthy volunteers

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Correspondence other official bodies (e.g other Legal Services and/or Unitectra etc.)

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Cover letter Swissmedic simultaneous submission

When submitting proposals to Swissmedic or  the [or local responsible EU-CA], and your local local ethics committees (local ECs), it is essential to include tailored cover letters for each body. Since submissions to these entities in Switzerland must occur on the same day, any change requests from one body often need to be addressed and updated in the corresponding submission to the other. To streamline communication and ensure alignment, it is advisable to attach the cover letter sent to Swissmedic when submitting to the ECs, and vice versa. This cross-referencing of cover letters demonstrates transparency, maintains consistency in the application process, and assures both bodies that their feedback will be integrated appropriately across all regulatory documents.

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Finally

At the Ethics Commission they sat,
Sticklers with rules to combat.
With laws they’d obsess,
But science? No guess—
Their logic as flat as a mat.