ATTORNEY-CLIENT PRIVILEGED AND CONFIDENTIAL — ATTORNEY WORK PRODUCT
MEMORANDUM
FROM: Amy Whitfield, Lead Associate, Healthcare & Life Sciences Practice Group, Calderwood & Harkness LLP
TO: Dr. Niamh Tierney, Vice President of Regulatory Affairs, Solstice Biomedical Devices Ltd. Marcus Hale, Vice President of U.S. Operations, Solstice Biomedical Inc.
CC: Miriam Calloway, Responsible Partner, Calderwood & Harkness LLP Dr. Sandra Ellison, Managing Director, Pinnacle Regulatory Consulting Group LLC
DATE: May 19, 2025
RE: IRB Submission Strategy for Protocol SBD-LUM-CL-001 ("LUMINA-US") — Clearwater Institutional Review Board LLC
ENGAGEMENT REF. NO.: 1037-00002
This memorandum is prepared by Calderwood & Harkness LLP for the exclusive use of Solstice Biomedical Devices Ltd. and Solstice Biomedical Inc. in connection with the above-referenced engagement. This document constitutes attorney work product and is protected by the attorney-client privilege. It should not be disclosed to any third party, including to Clearwater Institutional Review Board LLC, the U.S. Food and Drug Administration, or any clinical study site, without the prior written consent of Calderwood & Harkness LLP.
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I. Purpose and Scope of This Memorandum
The purpose of this memorandum is to outline the submission requirements, document preparation timeline, and ongoing compliance obligations associated with obtaining initial Institutional Review Board ("IRB") approval from Clearwater Institutional Review Board LLC ("Clearwater IRB") for the clinical study designated as Protocol SBD-LUM-CL-001, titled "LUMINA-US" (the "Study"). This memorandum is intended to serve as a comprehensive reference for the Solstice team, coordinating counsel, and regulatory consultants as the parties prepare for the initial IRB submission, and it identifies the critical-path activities that must be completed to support a target study commencement date of September 15, 2025.
Solstice Biomedical Inc. (Delaware File No. 7834291) (the "Sponsor" or "Solstice U.S."), the wholly owned U.S. subsidiary of Solstice Biomedical Devices Ltd. (Ireland, Companies Registration Office No. 648231) ("Solstice Ireland" or "Solstice Parent"), plans to conduct a prospective, single-arm, multicenter clinical study evaluating the safety and performance of the Solstice Lumina™ Continuous Glucose Monitoring System (the "Lumina CGM System" or the "Device") at six (6) U.S. clinical sites. The Study will enroll approximately 350 adult subjects—175 with Type 1 diabetes mellitus and 175 with Type 2 diabetes mellitus—and will evaluate sensor accuracy as the primary endpoint, measured by mean absolute relative difference ("MARD"), with a target of ≤ 9.0%.
The target date for enrollment of the first subject is September 15, 2025. To achieve this milestone, IRB approval must be obtained no later than September 1, 2025, allowing a two-week buffer for the completion of site initiation visits at all six clinical sites. The timeline is demanding, and the successful execution of the IRB submission strategy described herein is essential to maintaining the broader regulatory pathway, including the planned Pre-Submission ("Pre-Sub") meeting with the U.S. Food and Drug Administration ("FDA") on August 14, 2025, the downstream 510(k) submission targeted for April 30, 2026, and the anticipated FDA clearance in the third quarter of 2026.
This memorandum addresses the procedural pathway for Clearwater IRB review and identifies the regulatory framework governing IRB oversight, with particular attention to the requirements of 21 C.F.R. Part 50 (Protection of Human Subjects — Informed Consent), 21 C.F.R. Part 56 (Institutional Review Boards), and 21 C.F.R. Part 812 (Investigational Device Exemptions). It also addresses the interaction between the IRB review process and the parallel FDA Pre-Sub process, the insurance coverage considerations that Solstice must resolve before submission, and the coordination of responsibilities among Calderwood & Harkness LLP ("C&H" or "Calderwood & Harkness"), Pinnacle Regulatory Consulting Group LLC ("Pinnacle Regulatory"), and Veltrano Clinical Research Organization Inc. ("Veltrano CRO").
As a coordination note, Veltrano Clinical Research Organization Inc. (500 North Capitol Street, Suite 700, Indianapolis, IN 46204; Key Contact: Dr. Lisa Fontaine, Vice President of Clinical Operations) will serve as the contract research organization for the Study and will assist with site-level coordination, investigator document collection, site feasibility assessments, recruitment material development, and site initiation visits. However, the IRB submission itself is to be initiated by Solstice Biomedical Inc. as the study sponsor, and Solstice will be identified as the responsible party in all submissions to Clearwater IRB.
This memorandum should be read in conjunction with the following companion documents prepared or in preparation by Calderwood & Harkness in connection with this engagement:
• IDE Exemption Analysis Memorandum (1037-00002-002), addressing the non-significant risk ("NSR") determination and IDE exemption analysis under 21 C.F.R. § 812.2(c)(3);
• Informed Consent Form Review and Markup (1037-00002-003), containing Calderwood & Harkness's legal review and line-by-line markup of the draft informed consent form; and
• Pre-Submission Meeting Strategy Memorandum (1037-00002-004), addressing the strategy for the August 14, 2025 Pre-Sub meeting with CDRH.
II. Overview of Clearwater Institutional Review Board LLC
A. IRB Identification and Registration
The IRB selected to serve as the reviewing body for the LUMINA-US Study is Clearwater Institutional Review Board LLC, a limited liability company organized under the laws of the State of Florida. The relevant identifying information for Clearwater IRB is as follows:
• Full Legal Name: Clearwater Institutional Review Board LLC
• Entity Type: Limited Liability Company, organized under Florida law
• Principal Office Address: 3200 Bayshore Boulevard, Tampa, FL 33629
• IRB Registration Number: IRB-2019-04821, registered with the Office for Human Research Protections ("OHRP"), U.S. Department of Health and Human Services
• Federal Wide Assurance (FWA): To be confirmed by Solstice during the submission preparation phase; Solstice should request Clearwater IRB's current FWA number and verify its status on the OHRP website prior to submission
Clearwater IRB is a commercial, independent IRB—also commonly referred to as a "central" IRB—that provides review services to sponsors, contract research organizations, and clinical study sites across the United States. As a commercial IRB, Clearwater IRB is not affiliated with any single academic institution or healthcare system, which positions it to serve as the IRB of record for all six U.S. clinical study sites under the LUMINA-US protocol pursuant to a single-IRB review model.
The single-IRB model is consistent with the 2018 revisions to the Federal Policy for the Protection of Human Subjects (the "Common Rule"), codified at 45 C.F.R. Part 46, which generally require the use of a single IRB of record for cooperative research conducted at multiple domestic sites. Although the Common Rule revisions apply most directly to federally funded research, FDA has also endorsed the use of central IRB review for FDA-regulated clinical investigations, and this approach is well-established for multicenter device studies. By designating Clearwater IRB as the single IRB of record, Solstice will benefit from a unified review process, a single set of approval conditions, and a single point of contact for continuing review, amendments, and safety reporting across all six study sites.
B. Selection Rationale
The decision to engage Clearwater IRB as the reviewing IRB for the LUMINA-US Study reflects several strategic and operational considerations:
1. Streamlined Multi-Site Review. The central IRB approach eliminates the need to submit separate IRB applications to institutional IRBs at each of the six clinical sites, which would introduce variability in review timelines, consent form language, and approval conditions. Under the single-IRB model, Clearwater IRB will conduct a single protocol review and approve a single informed consent form template for use at all sites, with site-specific customization limited to local contact information and, where applicable, local regulatory requirements.
2. Timeline Efficiency. The use of a central IRB significantly reduces the overall timeline for obtaining IRB approval across all sites. Rather than managing six parallel IRB review processes—each with its own submission requirements, meeting schedules, and review timelines—Solstice will manage a single submission and a single review cycle, which is essential given the compressed timeline between the planned IRB submission date (July 21, 2025) and the target study start date (September 15, 2025).
3. Medical Device Study Experience. Clearwater IRB has substantial experience reviewing clinical studies involving medical devices, including studies of continuous glucose monitoring systems and other diagnostic devices classified as non-significant risk under 21 C.F.R. § 812.2(c)(3). This experience is particularly important in the context of the NSR determination, as Clearwater IRB's familiarity with the applicable regulatory framework will facilitate its independent assessment of the risk classification.
4. Uniform Consent and Protocol Review. The use of a central IRB ensures that all subjects enrolled at all six sites will receive the same IRB-approved informed consent form, with consistent risk disclosures, compensation terms, and procedural descriptions. This uniformity supports both regulatory compliance and the integrity of the clinical data generated by the Study.
5. Efficient Ongoing Oversight. During the course of the Study, Clearwater IRB will serve as the single point of contact for all continuing review, protocol amendment, adverse event reporting, and deviation reporting obligations, reducing the administrative burden on both the Sponsor and the clinical sites.
Calderwood & Harkness notes that each of the six clinical sites will need to enter into a reliance agreement or authorization agreement with Clearwater IRB, pursuant to which the site agrees to rely on Clearwater IRB's review and approval in lieu of review by the site's own local IRB (if any). Veltrano CRO should coordinate the execution of these reliance agreements as part of the site initiation process. Any site-specific requirements or conditions imposed by individual sites (e.g., institutional sign-off requirements) should be identified during the site feasibility assessment process and communicated to Calderwood & Harkness and Solstice promptly.
III. Regulatory Framework for IRB Review
A. Applicable Regulations
The IRB review of the LUMINA-US Study is governed by a set of interrelated federal regulations administered by the FDA. The following regulatory provisions are directly applicable:
21 C.F.R. Part 56 — Institutional Review Boards. Part 56 establishes the requirements for the composition, functions, operations, and review standards of IRBs that review clinical investigations regulated by the FDA. Part 56 applies to all clinical investigations conducted under the authority of sections 505(i) and 520(g) of the Federal Food, Drug, and Cosmetic Act, as well as clinical investigations that support applications for marketing authorization, including 510(k) submissions. Key provisions include the requirements for initial and continuing review of research (§ 56.109), criteria for IRB approval of research (§ 56.111), and record-keeping requirements (§ 56.115). Clearwater IRB, as a registered IRB, is subject to the requirements of Part 56 and is subject to FDA inspection to verify compliance with these requirements.
21 C.F.R. Part 50 — Protection of Human Subjects. Part 50 establishes the requirements for informed consent in FDA-regulated clinical investigations. Section 50.25 specifies the basic elements of informed consent that must be provided to each prospective study subject, including a description of the study procedures, reasonably foreseeable risks and discomforts, potential benefits, alternatives to participation, confidentiality protections, and the right to withdraw without penalty. Section 50.27 requires that informed consent be documented using a written consent form approved by the IRB. Part 50 also contains additional protections for specific vulnerable populations, including children (Subpart D), although these protections are not directly implicated by the LUMINA-US Study, which enrolls only adults aged 18 and older.
21 C.F.R. Part 812 — Investigational Device Exemptions. Part 812 provides the regulatory framework for clinical investigations of medical devices. Under Part 812, a sponsor seeking to conduct a clinical investigation of a device must obtain an approved Investigational Device Exemption ("IDE") from FDA before commencing the study, unless the study qualifies for an exemption from the IDE requirements. As discussed in greater detail in the companion IDE Exemption Analysis Memorandum, the LUMINA-US Study is anticipated to qualify for exemption from the IDE requirements under 21 C.F.R. § 812.2(c)(3) as a non-significant risk investigation of a diagnostic device. However, even IDE-exempt studies must comply with certain provisions of Part 812, including the requirements for informed consent (§ 812.2(b)(1)(i)), IRB review and approval (§ 812.2(b)(1)(ii)), monitoring (§ 812.2(b)(1)(iii)), recordkeeping and reporting (§§ 812.140, 812.150), and prohibition of promotion (§ 812.7).
In addition to the FDA regulations, the following regulatory and guidance documents are relevant to the IRB submission:
• 45 C.F.R. Part 46 — Protection of Human Subjects (the "Common Rule"), as revised in 2018, which applies primarily to federally funded research but informs the standards applied by many IRBs, including commercial IRBs, in their review of all human subjects research.
• FDA Guidance: "Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors" (updated periodically), which provides guidance on various aspects of IRB review, informed consent, and the conduct of FDA-regulated clinical investigations.
• FDA Guidance: "Use of a Single IRB for Cooperative Research" (issued in conjunction with the 2018 Common Rule revisions), supporting the use of a single IRB of record for multicenter studies.
B. IRB's Role in NSR Determination
The role of the IRB in the non-significant risk determination process is of central importance to the regulatory pathway for the LUMINA-US Study. Under 21 C.F.R. § 812.2(b), a clinical investigation of a device that an IRB determines to present a non-significant risk does not require an approved IDE from FDA. Instead, the investigation is subject to an abbreviated set of regulatory requirements, and the IRB's concurrence with the sponsor's NSR determination effectively serves as the authorization to proceed with the study.
The process works as follows:
1. Sponsor's Initial Determination. The sponsor (Solstice Biomedical Inc.) makes an initial determination that the clinical investigation presents no significant risk to study subjects. The sponsor must document this determination in writing, along with the supporting rationale, and must submit the determination to the IRB as part of the initial review package.
2. IRB's Independent Assessment. The IRB must make its own independent assessment of whether the investigation presents a significant risk or a non-significant risk. The IRB is not bound by the sponsor's determination and must evaluate the risk based on the information presented in the protocol, investigator's brochure, and other submission documents. In making this assessment, the IRB considers the definition of "significant risk device" set forth in 21 C.F.R. § 812.3(m), which includes devices that are intended as an implant, are purported or represented to be for a use in supporting or sustaining human life, are for a use of substantial importance in diagnosing, curing, mitigating, or treating disease or otherwise preventing impairment of human health, or otherwise present a potential for serious risk to the health, safety, or welfare of a subject.
3. Concurrence or Disagreement. If the IRB concurs with the sponsor's NSR determination, the investigation may proceed under the abbreviated IDE requirements. If the IRB determines that the investigation presents a significant risk, the sponsor must obtain an approved IDE from FDA before the study may commence. A disagreement on the NSR determination would materially affect the regulatory timeline for the LUMINA-US Study and would likely require postponement of the study start date pending IDE application and FDA review.
For the LUMINA-US Study, the Sponsor's NSR determination is based on the following considerations: (a) the Lumina CGM System is a diagnostic device with a non-therapeutic intended use (glucose monitoring); (b) the study design involves comparison of the investigational CGM readings against reference blood glucose measurements obtained through standard laboratory methods, which is a standard, well-established methodology for CGM accuracy studies; (c) the sensor component (Lumina C14) is a subcutaneously inserted electrochemical biosensor with a 14-day wear period, which, while technically "implantable" in the colloquial sense, is consistent in its risk profile with other CGM sensors that FDA and IRBs have historically treated as non-significant risk devices; and (d) there is substantial precedent for NSR determinations in CGM clinical studies. The full analysis supporting the NSR determination is set forth in the companion IDE Exemption Analysis Memorandum. Calderwood & Harkness will prepare the written NSR determination document for inclusion in the IRB submission package.
Clearwater IRB's concurrence with the NSR determination is a prerequisite to the commencement of the Study. If Clearwater IRB has questions or concerns about the NSR classification, Solstice should be prepared to provide supplemental information and, if necessary, to engage in dialogue with the IRB's reviewing board members to address their concerns.
C. IRB Review Standards
Under 21 C.F.R. § 56.111, the IRB must determine that the following criteria are satisfied before approving the LUMINA-US Study:
1. Risks to subjects are minimized. The IRB must find that the study procedures are designed to minimize risks to subjects, and that procedures already being performed on subjects for diagnostic or treatment purposes are used whenever appropriate. For the LUMINA-US Study, this analysis will focus on the risks associated with subcutaneous sensor insertion and 14-day continuous wear, as well as any risks associated with the study-specific blood glucose sampling procedures used to obtain reference measurements.
2. Risks are reasonable in relation to anticipated benefits. The IRB must determine that the risks to subjects are reasonable in relation to the anticipated benefits to the subjects and the importance of the knowledge that may reasonably be expected to result from the investigation. Because the LUMINA-US Study is a diagnostic accuracy study and is not designed to provide a direct therapeutic benefit to study subjects, the anticipated benefits will be framed primarily in terms of the contribution to the knowledge base supporting the development of a more accurate and reliable CGM system for patients with diabetes.
3. Selection of subjects is equitable. The IRB must assess the inclusion and exclusion criteria, recruitment procedures, and overall study design to ensure that the selection of subjects is equitable, taking into account the purposes of the research and the setting in which it will be conducted. The IRB should give particular attention to whether the study population (adults with Type 1 or Type 2 diabetes) is appropriately defined and whether any populations are unfairly excluded from or targeted for participation.
4. Informed consent is obtained and documented. The IRB must review the informed consent form to verify that it contains all of the elements required by 21 C.F.R. § 50.25 and that the consent process is adequate to ensure that subjects are making a truly voluntary and informed decision to participate.
5. Data monitoring provisions are adequate. The IRB must determine that the study includes adequate provisions for monitoring the data collected to ensure the safety of subjects. This analysis will focus on the Data Safety Monitoring Plan, including the adverse event reporting procedures, stopping rules, and the role of the medical monitor or Data Safety Monitoring Board.
6. Privacy and confidentiality are protected. The IRB must find that the study includes adequate provisions for protecting the privacy of subjects and maintaining the confidentiality of data. This includes an assessment of the data management procedures, the use of study identifiers, and the security measures applied to electronic data systems.
7. Additional safeguards for vulnerable populations. Where a study involves subjects who are likely to be vulnerable to coercion or undue influence—such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons—the IRB must determine that additional safeguards are included in the study to protect the rights and welfare of these subjects. The LUMINA-US Study enrolls only adults aged 18 and older and does not specifically target any vulnerable populations, but the IRB may nonetheless consider whether any aspects of the study design or recruitment process raise concerns regarding vulnerability.
The IRB's review will encompass the entirety of the submission package described in Section IV below, and the IRB may request additional information or documentation as part of its review. Calderwood & Harkness recommends that the submission package be prepared with these review criteria in mind, and that each document in the package clearly addresses the applicable criteria.
IV. Required Submission Documents
This section identifies the documents that must be assembled and included in the IRB submission package to Clearwater IRB. The submission package should be comprehensive, well-organized, and responsive to Clearwater IRB's submission requirements as set forth in its standard operating procedures and new study application form. Each document is described below, along with the responsible party for its preparation and any specific considerations relevant to the LUMINA-US Study.
A. Core Protocol Documents
1. Clinical Investigation Protocol
The cornerstone of the IRB submission is the Clinical Investigation Protocol, designated as Protocol SBD-LUM-CL-001, titled "LUMINA-US." The protocol must be presented in its final, approved version as of the date of IRB submission. The protocol must include, at a minimum, the following elements:
• Study Title: "A Prospective, Single-Arm, Multicenter Clinical Study to Evaluate the Safety and Performance of the Solstice Lumina™ Continuous Glucose Monitoring System in Adults with Type 1 and Type 2 Diabetes Mellitus" (Protocol SBD-LUM-CL-001, "LUMINA-US").
• Sponsor Identification: Solstice Biomedical Inc., 8400 Greensboro Drive, Suite 1100, McLean, VA 22102 (Delaware File No. 7834291).
• Contract Research Organization Identification: Veltrano Clinical Research Organization Inc., 500 North Capitol Street, Suite 700, Indianapolis, IN 46204 (Key Contact: Dr. Lisa Fontaine, Vice President of Clinical Operations).
• Study Design: Prospective, single-arm, multicenter clinical investigation.
• Subject Population: Approximately 350 subjects, comprising 175 subjects with Type 1 diabetes mellitus and 175 subjects with Type 2 diabetes mellitus. All subjects must be aged 18 years or older. Specific inclusion and exclusion criteria must be set forth in detail in the protocol.
• Number and Identification of Clinical Study Sites: Six (6) U.S. clinical sites. The specific site names, addresses, and principal investigators should be identified in the protocol or in a protocol appendix.
• Primary Endpoint: Sensor accuracy, measured by mean absolute relative difference ("MARD") against venous blood glucose reference measurements. The target performance criterion is a MARD of ≤ 9.0%.
• Secondary Endpoints: (a) Safety, as assessed by the incidence, severity, and relatedness of adverse events, including device-related adverse events and serious adverse events; (b) consensus error grid results, with a target of ≥ 99% of paired glucose readings falling within Zones A and B of the Clarke Error Grid; and (c) user labeling comprehension, assessed through validated questionnaires evaluating subjects' understanding of the device labeling and instructions for use.
• Device Description: A summary description of the Lumina CGM System, including the Lumina C14 sensor (a fourth-generation enzymatic electrochemical biosensor with a PtIr-4G platinum-iridium electrode coating, communicating via Bluetooth Low Energy 5.2) and the Lumina R7 reader/transmitter (an arm-worn wearable device that receives sensor data and transmits it to the Lumina Mobile App on iOS and Android platforms).
• Sensor Wear Duration: 14 days (336 hours) per sensor application.
• Measurement Range: 40–400 mg/dL.
• Study Duration: Approximately six (6) months in total, comprising approximately 14 weeks of subject enrollment, a 14-day sensor wear period for each subject, and approximately 8 weeks of data analysis following the last subject's last visit.
• Data Monitoring and Safety Reporting Procedures: A description of the safety monitoring structure, adverse event definitions and grading scales, timelines for reporting serious adverse events to the IRB and FDA, and stopping rules for the Study.
• Statistical Analysis Plan: A summary of the planned statistical methodology for analyzing the primary and secondary endpoints, including the sample size justification and the planned interim analyses (if any).
• Risk-Benefit Assessment: A comprehensive assessment of the risks and benefits of the Study, supporting both the IRB's review under 21 C.F.R. § 56.111 and the Sponsor's NSR determination.
The protocol must be internally consistent, clearly written, and responsive to the IRB's review criteria. Calderwood & Harkness will review the protocol's legal provisions, including the sections addressing informed consent procedures, subject compensation, confidentiality, and FDA inspection rights, and will provide comments to Solstice and Pinnacle Regulatory prior to finalization. The target date for protocol finalization is June 30, 2025.
2. Protocol Synopsis/Summary
In addition to the full protocol, the IRB submission should include a concise Protocol Synopsis or Protocol Summary, typically two to four pages in length, designed to provide IRB reviewers with a high-level overview of the Study before they review the full protocol. The synopsis should highlight the following:
• Study objectives (primary and secondary)
• Study design and methodology
• Subject population and enrollment targets
• Primary and secondary endpoints
• Device description and intended use
• Duration of subject participation
• Risk assessment and risk mitigation measures
• NSR determination summary
The Protocol Synopsis is particularly important because IRB board members may review it in advance of the full board meeting to familiarize themselves with the Study, and it may be the basis for the initial presentation of the Study at the board meeting. The synopsis should be prepared by Pinnacle Regulatory in coordination with Solstice.
B. Informed Consent Form (ICF)
The draft Informed Consent Form ("ICF") is a critical component of the IRB submission and will be subject to detailed review by Clearwater IRB. The ICF must be adapted for U.S. requirements under 21 C.F.R. Part 50 and must contain all of the elements specified in 21 C.F.R. § 50.25, including the following:
• Study Purpose and Procedures: A clear description of the purpose of the Study and the procedures to be followed, including subcutaneous sensor insertion using the provided applicator, 14-day continuous sensor wear, use of the Lumina R7 reader and/or the Lumina Mobile App to obtain glucose readings, and in-clinic visits for reference blood glucose sampling.
• Risks: A description of reasonably foreseeable risks and discomforts associated with participation, including risks specific to the Lumina C14 implantable sensor (e.g., insertion site pain, bleeding, bruising, infection, skin irritation, allergic reaction to adhesive or sensor materials) and risks associated with the Lumina R7 reader (e.g., skin irritation from prolonged wear, inaccurate glucose readings that could lead to inappropriate clinical decisions if the subject relies on CGM readings for diabetes management decisions during the study).
• Potential Benefits: A description of any benefits to the subject or to others that may reasonably be expected from participation. Because the LUMINA-US Study is a diagnostic accuracy study, the direct benefits to subjects are limited, and the ICF should clearly state that participation may not provide any direct medical benefit.
• Alternatives to Participation: A description of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject.
• Confidentiality Protections: A statement describing the extent to which the confidentiality of records identifying the subject will be maintained, including a description of the study's data management procedures, the use of coded identifiers, and the circumstances under which the subject's identity may be disclosed (e.g., FDA inspection, IRB audit).
• Subject Compensation: A description of the compensation to be provided to subjects for their participation, including the amount, schedule, and method of payment.
• Voluntary Participation and Right to Withdraw: A statement that participation is voluntary, that the subject may refuse to participate or may withdraw at any time without penalty or loss of benefits to which the subject is otherwise entitled, and that the subject's decision to participate or not will not affect the subject's medical care.
• FDA Inspection Rights: A statement that the FDA may inspect the records of the investigation, including the subject's medical records, and that by consenting to participate, the subject authorizes such inspection.
• Contact Information: The name and contact information for the principal investigator at the subject's study site, a contact for questions about the subject's rights as a research participant (including the Clearwater IRB contact information), and a contact for reporting study-related injuries or concerns.
Calderwood & Harkness is concurrently preparing a detailed legal review and line-by-line markup of the draft ICF (see companion document 1037-00002-003, "Informed Consent Form Review and Markup"). The markup will address compliance with 21 C.F.R. Part 50, consistency with the study protocol, appropriateness of the risk disclosures, and any recommended revisions to the language or structure of the consent form. The draft ICF must be finalized and approved by Clearwater IRB before any subject is enrolled in the Study.
The ICF should be written in clear, non-technical language at a reading level appropriate for the anticipated study population (generally, a sixth- to eighth-grade reading level). Solstice should also consider whether translated versions of the ICF will be needed at any of the six clinical sites to accommodate non-English-speaking subjects, and should discuss this with Veltrano CRO during the site feasibility assessment process.
C. Investigator's Brochure (IB)
The Investigator's Brochure ("IB") is a comprehensive document that compiles all available nonclinical and clinical data on the Lumina CGM System and provides investigators with the information necessary to understand the device, its intended use, and the known and anticipated risks associated with its use in the clinical study setting. Although the IB is more commonly associated with drug studies under ICH E6(R2) Good Clinical Practice guidelines, it is also standard practice—and often required by IRBs—for medical device clinical studies, particularly for investigational devices that have not yet received FDA marketing clearance.
The IB for the Lumina CGM System must include the following:
• Device Description: A detailed technical description of the Lumina CGM System, including the Lumina C14 sensor (fourth-generation enzymatic electrochemical biosensor with PtIr-4G platinum-iridium electrode coating, Bluetooth Low Energy 5.2 communication protocol, 14-day wear duration, 40–400 mg/dL measurement range) and the Lumina R7 reader/transmitter (arm-worn wearable device with integrated NFC and BLE connectivity, rechargeable battery, and compatibility with the Lumina Mobile App on iOS and Android platforms).
• Preclinical Data: Summaries of bench testing, analytical performance studies, electrical safety testing, electromagnetic compatibility testing, and software verification and validation testing performed on the Lumina CGM System.
• Biocompatibility Data: Summaries of biocompatibility testing conducted in accordance with ISO 10993 (Biological Evaluation of Medical Devices), including cytotoxicity, sensitization, irritation, systemic toxicity, and implantation testing for the Lumina C14 sensor, which is a body-contacting device with subcutaneous tissue contact for up to 14 days.
• EU Clinical Experience: A summary of the clinical data supporting the CE marking of the Lumina CGM System under the European Union Medical Device Regulation (EU MDR, Regulation (EU) 2017/745). The Lumina CGM System has been CE-marked since September 2024, pursuant to EU MDR Certificate No. MCA-2024-07319, issued by Meridian Conformity Assessment GmbH (Notified Body No. 0483). The IB should summarize the clinical evidence evaluated by the notified body, including any clinical investigations conducted in the European Union, and should provide a summary of post-market surveillance data, including complaint data and vigilance reports, accumulated since the CE marking was obtained.
• Known and Anticipated Risks: A comprehensive listing of known and anticipated risks associated with the use of the Lumina CGM System, categorized by severity and probability, including risks associated with sensor insertion, sensor wear, sensor failure, inaccurate glucose readings, reader malfunction, and software errors.
• Prior Regulatory History: A summary of the Sponsor's prior regulatory interactions with FDA, including the prior 510(k) clearance for the GlucoStrip RX-200 point-of-care blood glucose monitoring system (510(k) No. K192847, cleared November 14, 2019). While the GlucoStrip RX-200 is a different device than the Lumina CGM System, the prior clearance demonstrates the Sponsor's experience with FDA-regulated glucose monitoring devices and may be relevant to the IRB's assessment of the Sponsor's qualifications and regulatory track record.
Pinnacle Regulatory Consulting Group LLC is responsible for drafting the IB. Dr. Sandra Ellison (Managing Director) and Thomas Greenbaum are the lead personnel assigned to this task. The target completion date for the IB is July 7, 2025, which is the deadline for all core submission documents to be finalized in advance of the July 14, 2025 package assembly date. Calderwood & Harkness notes that the timely completion of the IB depends on the availability of the final biocompatibility testing data from Solstice's ISO 10993 testing program; Solstice should confirm the expected delivery date for this data with its testing laboratory and communicate any delays to Pinnacle Regulatory immediately.
D. Sponsor's NSR Determination and Supporting Rationale
As discussed in Section III.B above, the IRB submission package must include a written determination by Solstice Biomedical Inc. that the LUMINA-US Study qualifies as a non-significant risk investigation under 21 C.F.R. § 812.2(c)(3). This document is essential because it forms the basis for the IRB's independent assessment of the risk classification and, if the IRB concurs, allows the Study to proceed without a full IDE application to FDA.
The NSR Determination document should include:
• A statement of the Sponsor's determination that the Study is a non-significant risk investigation.
• A reference to the applicable regulatory provision (21 C.F.R. § 812.2(c)(3), exempting investigations of diagnostic devices from the IDE requirements if certain conditions are met, including compliance with the requirements of 21 C.F.R. § 812.2(b)).
• A detailed rationale supporting the NSR determination, including:
• The diagnostic (non-therapeutic) intended use of the Lumina CGM System;
• The study's use of a standard, well-established comparator methodology (venous blood glucose reference measurements) that does not itself present significant risk;
• The characteristics of the Lumina C14 sensor, which, although subcutaneously inserted, is a minimally invasive, short-term implant (14-day wear period) with a well-characterized risk profile consistent with other commercially available CGM sensors;
• Precedent NSR determinations by IRBs for similar CGM clinical studies, including studies of other continuous glucose monitoring systems that have been reviewed and approved by IRBs as non-significant risk investigations; and
• A risk analysis demonstrating that the Study does not present a potential for serious risk to the health, safety, or welfare of subjects within the meaning of 21 C.F.R. § 812.3(m).
The full analysis supporting the NSR determination is set forth in the companion IDE Exemption Analysis Memorandum (1037-00002-002). Calderwood & Harkness will prepare the formal NSR Determination document for Solstice's review and signature, and this document will be included in the IRB submission package.
It is essential that the IRB review and concur with this determination. If the IRB disagrees with the NSR classification and determines that the Study presents a significant risk, Solstice would be required to submit a full IDE application to FDA under 21 C.F.R. Part 812, which would add several months to the regulatory timeline and would almost certainly prevent the Study from commencing on September 15, 2025.
E. Investigator Qualifications and Site Information
The IRB submission must include documentation demonstrating the qualifications of the principal investigators and the adequacy of the clinical study sites. Specifically, the following documents should be collected from each of the six U.S. clinical sites:
• Curricula Vitae: Current curricula vitae for all principal investigators, including documentation of their medical training, board certifications, clinical research experience, and relevant publications. The CVs should be updated to reflect current appointments and should be signed and dated by the investigator.
• Medical Licenses: Copies of current, valid medical licenses for each principal investigator, demonstrating that the investigator is licensed to practice medicine in the state where the clinical site is located.
• FDA Form 1572 (Statement of Investigator): Although FDA Form 1572 is technically required for clinical investigations of drugs under 21 C.F.R. Part 312 and is not strictly required for device studies conducted under an NSR/IDE-exempt pathway, it is common practice—and often required by commercial IRBs—to collect a Form 1572 or equivalent statement from each principal investigator for device studies as well. The Form 1572 serves as the investigator's commitment to comply with applicable FDA regulations, the study protocol, and the terms of IRB approval. Clearwater IRB may require completion of Form 1572 or an equivalent investigator agreement form; Solstice and Veltrano CRO should confirm Clearwater IRB's specific requirements and prepare the appropriate documentation for each site.
• Financial Disclosure Forms: Completed financial disclosure forms for each principal investigator and sub-investigator, in accordance with 21 C.F.R. Part 54 (Financial Disclosure by Clinical Investigators). Part 54 requires disclosure of any financial interests that could affect the reliability of the clinical data, including equity interests in the sponsor, significant payments from the sponsor, proprietary interests in the device under investigation, and significant equity interests in a publicly traded sponsor. These disclosures must be collected before the investigator begins participation in the Study and must be updated during the course of the Study if the investigator's financial circumstances change.
• Facility Descriptions: Descriptions of the clinical facilities at each of the six study sites, including the availability of clinical space for sensor insertion and removal, laboratory capabilities for blood glucose reference measurements, emergency medical equipment and procedures, and proximity to hospital facilities (if the site is not located within a hospital).
• Investigator Training Documentation: Documentation confirming that each principal investigator and study staff member has completed training on the Lumina CGM System (including the Lumina C14 sensor insertion procedure, Lumina R7 reader operation, and the Lumina Mobile App), the study protocol (Protocol SBD-LUM-CL-001), and Good Clinical Practice ("GCP") requirements. GCP training may be documented through certificates of completion from recognized GCP training programs (e.g., CITI Program, ACRP, or equivalent).
Veltrano CRO (Dr. Lisa Fontaine) is responsible for coordinating the collection of investigator qualifications and site information from all six clinical sites. The target date for completion of this document collection is July 7, 2025. Calderwood & Harkness emphasizes that this is a frequently underestimated task in terms of time and effort, particularly when multiple sites are involved, and recommends that Veltrano CRO begin outreach to the clinical sites immediately to ensure that all documents are collected, reviewed for completeness, and formatted for inclusion in the IRB submission package by the target date.
F. Recruitment Materials
All materials intended to be used for subject recruitment must be submitted to Clearwater IRB for review and approval before use. The following recruitment materials should be prepared and included in the submission package:
• Subject Recruitment Advertisements: Draft advertisements in print, digital, and social media formats, designed to inform potential study subjects about the Study and invite them to participate. The advertisements must be truthful, non-misleading, and consistent with the information in the IRB-approved informed consent form.
• Recruitment Flyers: Draft flyers for display at clinical sites and related healthcare facilities, providing a brief description of the Study, the eligibility criteria, and contact information for interested potential subjects.
• Pre-Screening Scripts: Written scripts for use by study staff when conducting pre-screening interviews with potential subjects by telephone or through online questionnaires. The scripts should include standard language for explaining the Study, assessing preliminary eligibility, and scheduling screening visits.
• Online Screening Questionnaires: Draft online questionnaires (if applicable) for use in pre-screening potential subjects through the Study's website or other digital platforms.
All recruitment materials must be reviewed and approved by Clearwater IRB before they are used to recruit subjects. Under 21 C.F.R. Part 50 and applicable IRB guidance, recruitment materials are considered an extension of the informed consent process and must not be coercive, must not overstate the benefits of participation, and must accurately represent the Study. Calderwood & Harkness recommends that the recruitment materials be reviewed by counsel prior to submission to the IRB to ensure compliance with these requirements.
Veltrano CRO is responsible for preparing the recruitment materials in collaboration with Solstice's marketing team. The target date for finalization of all recruitment materials is July 14, 2025.
G. Subject-Facing Materials
In addition to the ICF and recruitment materials, the IRB submission should include all materials that will be provided to study subjects during the course of the Study, including:
• Subject Diary/Log Templates: Templates for use by subjects in recording their glucose readings, device experiences, symptoms, and any device-related issues during the 14-day sensor wear period. The diary should be designed to be user-friendly and should include clear instructions for completion.
• Patient Information Sheets: Supplementary information sheets providing additional detail about the Study, the Lumina CGM System, the sensor insertion and removal process, and what to expect during the 14-day wear period. These materials are intended to supplement the ICF and to serve as a reference for subjects during their participation.
• Instructions for Use (IFU): The instructions for use of the Lumina R7 reader and the Lumina Mobile App (iOS and Android versions) as they will be provided to study subjects. The IRB will review these materials to ensure that they are clear, accurate, and consistent with the study protocol and the ICF.
These materials should be prepared by Solstice in coordination with Veltrano CRO and should be submitted to Clearwater IRB as part of the initial submission package. Any revisions to these materials after initial IRB approval must be submitted as amendments.
H. Data Safety Monitoring Plan (DSMP)
The Data Safety Monitoring Plan ("DSMP") is a required component of the IRB submission and must describe the procedures and structures in place for monitoring subject safety during the conduct of the Study. The DSMP should address the following:
• Safety Monitoring Structure: A description of the safety monitoring structure for the Study, including whether a formal Data Safety Monitoring Board ("DSMB") will be convened or whether safety monitoring will be conducted by the Sponsor's designated medical monitor. For a non-significant risk device study of this nature, a formal DSMB is not always required, but the IRB may inquire about the rationale for the chosen monitoring approach.
• Adverse Event Reporting Procedures: A detailed description of the procedures for identifying, documenting, evaluating, and reporting adverse events, including the definitions of adverse events, serious adverse events, and device-related adverse events. The DSMP should specify the timelines for reporting serious adverse events to the IRB, FDA, and Sponsor, including the specific Clearwater IRB reporting timelines discussed in Section VII.C below.
• Stopping Rules and Early Termination Criteria: A description of the pre-specified criteria for pausing enrollment, suspending the Study at one or more sites, or terminating the Study early based on safety signals. The stopping rules should be clearly defined and should specify the decision-making authority and process for implementing a study pause or termination.
• Periodic Safety Reviews: A description of the schedule for periodic safety reviews, including the frequency of safety data review and the process for communicating safety findings to the IRB and investigators.
The DSMP should be prepared by Solstice (in collaboration with its medical monitor) and reviewed by Pinnacle Regulatory and Calderwood & Harkness for consistency with the study protocol and applicable regulatory requirements.
I. Insurance and Indemnification Documentation
The IRB submission must include evidence of adequate insurance coverage for the clinical investigation. Clearwater IRB, like most commercial IRBs, typically requires confirmation that the Sponsor has product liability and clinical trial insurance in place to cover potential claims arising from the conduct of the Study and the use of the investigational device.
The current insurance coverage information is as follows:
• Insurer: Atlas Underwriting Partners Ltd., 25 Fenchurch Avenue, London EC3M 5AD, United Kingdom
• Policy Number: AUP-PL-2024-00893
• Coverage Type: Product Liability and Clinical Trial Insurance
• Coverage Limits: $25,000,000 per occurrence / $50,000,000 aggregate
• Policy Period: October 1, 2024 through September 30, 2025
Important Note Regarding Coverage Gap: The Atlas policy expires on September 30, 2025, which is only fifteen (15) days after the target study commencement date of September 15, 2025. The LUMINA-US Study is not expected to complete until approximately March 15, 2026. This means that the current policy would provide coverage for only the first two weeks of the Study, leaving the remainder of the study duration—including the period of active sensor wear by enrolled subjects and the subsequent data analysis period—without insurance coverage. This is discussed in greater detail in Section VIII below. Solstice must confirm renewal or extension of the Atlas policy to cover the full study duration through at least March 15, 2026 (the target study completion date) and, preferably, through a tail period extending at least 12 months beyond the last subject's last visit to cover any latent claims.
In addition to the insurance documentation, the IRB submission should include the subject injury compensation and indemnification provisions as set forth in the study protocol. These provisions should describe the Sponsor's commitments regarding the treatment of study-related injuries, including who will bear the costs of treatment for injuries directly resulting from participation in the Study.
J. Additional Regulatory Documents
The following additional documents should be included in the IRB submission package, as applicable:
• Listing of Applicable FDA Guidance Documents: A list of the FDA guidance documents referenced in the protocol and relied upon in the design of the Study, including, without limitation, the FDA guidance titled "Integrated Continuous Glucose Monitoring Systems" (September 2023), which provides recommendations on clinical study design, performance testing, and labeling for iCGM systems.
• Summary of EU MDR CE Certification Status: A summary document describing the current EU MDR CE certification status of the Lumina CGM System, including the certificate number (MCA-2024-07319), the issuing notified body (Meridian Conformity Assessment GmbH, NB 0483), and a brief description of the EU commercial experience to date. This information may also be included in the Investigator's Brochure, but a standalone summary may be useful for the IRB reviewers.
• Device Labeling (Draft): Draft labeling for the Lumina CGM System as applicable to the clinical investigation, including the draft prescribing information, patient labeling, and any other labeling materials that will be used in connection with the Study. The IRB may review the draft labeling to assess the adequacy of the risk disclosures and instructions for use.
V. Submission Timeline and Key Deadlines
A. Reverse-Engineered Timeline from September 15, 2025 Study Start
The following timeline has been reverse-engineered from the target date for first subject enrollment (September 15, 2025) and takes into account the expected duration of the Clearwater IRB review process, the document preparation timelines, and the parallel FDA Pre-Sub process. This timeline assumes that the IRB review will proceed without material delays and that no significant protocol revisions will be required as a result of the FDA Pre-Sub meeting. Contingency scenarios are discussed in Section V.B below.
This timeline is aggressive but achievable if all parties execute their assigned responsibilities on schedule. The most significant risks to the timeline are discussed below.
B. Pre-Sub Meeting Timing Considerations
The Pre-Submission meeting with FDA (CDRH, Office of Health Technology 2, Division of Chemistry and Toxicology Devices) is targeted for August 14, 2025. This creates an inherent tension in the timeline because the Pre-Sub meeting will occur after the IRB submission (July 21, 2025) but before the anticipated IRB approval date (September 1, 2025). In other words, Solstice will be submitting the protocol to the IRB for review before receiving FDA's feedback on the clinical study design, endpoints, and other protocol elements.
This timing sequence is not unusual in the medical device industry, where sponsors frequently initiate IRB review in parallel with FDA interactions to avoid unnecessary delays. However, it does create a risk that FDA feedback at the Pre-Sub meeting could necessitate material changes to the protocol, which would in turn require a protocol amendment to be submitted to Clearwater IRB.
Strategy Recommendation: Calderwood & Harkness recommends the following approach:
1. Submit the IRB package based on the protocol as finalized as of late June/early July 2025. The protocol should be prepared with due consideration of FDA's published guidance documents (including the September 2023 iCGM guidance) and any informal feedback received from FDA during the Pre-Sub meeting request process. By aligning the protocol with FDA's known expectations, Solstice can minimize the likelihood of material protocol changes resulting from the Pre-Sub meeting.
2. If the FDA Pre-Sub meeting on August 14, 2025 results in material changes to the clinical study design or endpoints, Solstice should promptly prepare and submit a protocol amendment to Clearwater IRB for review before study commencement. Because the Pre-Sub meeting is scheduled approximately two and a half weeks before the target IRB approval date, there may be sufficient time for the IRB to review a limited protocol amendment in conjunction with its initial review, depending on the nature and extent of the required changes.
3. Contingency planning is essential. If FDA feedback at the Pre-Sub meeting necessitates significant protocol revisions—such as a change to the primary endpoint, the addition of a comparator arm, or a material change to the subject population—the September 15, 2025 study start date may need to be delayed to allow adequate time for protocol revision, IRB review of the amended protocol, and site initiation. This risk should be clearly communicated to Solstice management, including to Dr. Niamh Tierney and Marcus Hale, so that contingency plans can be developed in advance.
4. Prepare a contingency protocol amendment plan in advance of the August 14, 2025 Pre-Sub meeting, so that if material changes are required, the amendment can be prepared, reviewed, and submitted to the IRB with minimal delay. Calderwood & Harkness (Amy Whitfield and Kevin Morrissey) will prepare this contingency plan by August 15, 2025, following the Pre-Sub meeting.
C. Coordination with Veltrano CRO
Effective coordination with Veltrano CRO is essential to the successful execution of the IRB submission timeline. The following coordination tasks are critical:
• Investigator Document Collection: Dr. Lisa Fontaine (Vice President of Clinical Operations, Veltrano CRO) is responsible for coordinating the collection of investigator curricula vitae, medical licenses, financial disclosure forms, and Form 1572 equivalents (or Clearwater IRB's equivalent investigator agreement forms) from all six clinical sites. The target completion date for this task is July 7, 2025. Given the challenges inherent in collecting documents from multiple investigators across multiple sites—including the need to follow up on missing or incomplete documents, verify the currency of medical licenses, and ensure that financial disclosures are complete and accurate—Veltrano CRO should begin outreach to the clinical sites no later than May 26, 2025.
• Site Feasibility Assessments: Veltrano CRO is responsible for completing site feasibility assessments at all six clinical sites and confirming site readiness before the IRB submission is filed. Site feasibility assessments should evaluate each site's ability to comply with the study protocol, including the availability of clinical space, laboratory capabilities, trained staff, and institutional support for the Study. Any site-specific issues identified during the feasibility assessment—such as the need for local institutional review or sign-off, requirements for reliance agreements with Clearwater IRB, or limitations on subject recruitment—should be communicated to Solstice and Calderwood & Harkness promptly.
• Recruitment Material Preparation: Veltrano CRO is responsible for preparing the recruitment materials (advertisements, flyers, pre-screening scripts, and online questionnaires) in collaboration with Solstice's marketing team. These materials must be finalized by July 14, 2025 for inclusion in the IRB submission package.
VI. Clearwater IRB Submission Procedures
A. Submission Mechanics
Clearwater IRB accepts submissions through its online electronic portal system. The submission must be made electronically and must include the following components:
1. Completed New Study Application Form. Clearwater IRB provides a standardized new study application form that must be completed by the Sponsor. The application form typically requests identifying information about the Sponsor, the study protocol, the principal investigators, the clinical sites, the device under investigation, and the proposed subject population. The application form may also include specific questions about the risk classification (significant risk vs. non-significant risk), the type of review requested (full board vs. expedited), and the Sponsor's assessment of the study's risk-benefit profile. Solstice should obtain the most current version of Clearwater IRB's new study application form and review it in advance to ensure that all required fields can be completed by the submission date.