CIP330 BIMO Flashcards

Question

What indication is under investigation?

Answer 1

To demonstrate the performance of the DS5 in subjects 2-80 years of age for 7 days.

Answer 2

To demonstrate the accuracy of the DS5 in subjects 2-80 years of age for 7 days.

Answer 3

No During a challenge: -DKA -Severe hypo with seizures -Severe hypo requiring glucagon -Site would notify us within 24 hours -We would notify the FDA within 72 hours. Safety rep would notify the medical advisor and CSM of the event as soon as possible. CSM would notify regulatory for reporting to the FDA within 72 hours.

Answer 4

They may return at a later date to complete the visit. Examples: IV occlusion, primary and back-up YSI machines fail, or primary sensor dislodges and FST can’t be completed (replace all sensors and complete any FSTs not completed).

Answer 5

Depends on the age group. They either wear 2 or 3 sensors in the arm and/or buttock. 18-80: arm/arm 14-17: arm/arm/butt or butt/butt/arm 7-13: arm/arm/butt or butt/butt/arm 2-6: arm/butt (parent can choose the area for sensor placement)

Answer 6

100 adults (18-80) and 100 peds (2-17). 230 completed (would need to look at the data for adults and peds).

Answer 7

Sensor values compared to YSI values.

Answer 8

All AEs Skin assessments

Answer 9

No. The Marketing Survey was completed on paper by the subject at the exit visit and transcribed into the CRF by the site. It was not an endpoint (used for marketing purposes).

Answer 10

The monitoring plan only required that the first two subjects at each site for each age group cohort were 100% source verified. After, only certain CRFs and fields with those CRFs were selected for SDV as deemed critical to the study. Critical point in time (e.g., consent or exit) Safety (e.g., AE or SKA) Assess the first two subjects to determine if any changes are needed to CRFs/fields selected before going into the subset.

Answer 11

7 day training period and 7 days study period. Could go up to ~90 days for repeat of in-office procedures (primary sensor falls off, IV occlusions, primary and back-up YSI machine fail). Training Phase (V1-V3): completed in 30 days. Study Phase: completed in 60 days.

Answer 12

Fingersticks using the study meter. These are entered into the Activity Log CRF but are not used for analysis. No situation for both machines failed.

Answer 13

It’s defined in the protocol.

Answer 14

The subject and site call Tech Support (used for device deficiency reporting and troubleshooting). They communicate the calls to the site and study team.

Answer 15

Yes. TS Management per the training plan, but it was rolled out to others in Cornerstone per Aurelio.

Answer 16

It’s based on role for the sponsor and delegated tasks at the site per the training plan. Training can be pushed out in Cornerstone LMS for our sponsor. Most site training was completed at the SIV, however, it could be through read & acknowledge or trained by site staff already trained. Site knew what training was required because the SIV agenda stated what tasks required what training.

Answer 17

3 ways to check site training: (1) Prior to granting EDC access. (2) Site activation checklist for any new person. (3) IMV. The monitor also reviews the DoA for newly delegated staff. 2 ways to check on the sponsor end: (1) Prior to granting EDC access. (2) Annual TMF review.

Answer 18

Sponsor requested 4-7x/day. Also, one should be taken upon arrival for the FST and at the end of each FST. Per the data management plan: - BGs in EDC are review by monitoring. - Study meter data uploaded into CareLink that isn’t entered into the Activity Log is reviewed by Biostats (data files are sent to them by bioinformatics).

Answer 19

It was an exit survey completed by the subject on paper and transcribed into the CRF by site. Narratives gathered did not provide the basis for an AE but could lead to a discussion that result in identification of an adverse event. -> this was determined by safety as noted in the safety plan. Did every subject complete one?

Answer 20

The status would be not recovered/not resolved. It’s the investigator’s responsibility to let the subject know if any further treatment is needed outside of the study.

Answer 21

One for kidney stones. Hospitalization and surgical intervention (stent). Bode. The subject completed the study.

Answer 22

It’s a PC-based program used to time sync the sensor and download the sensor data.

Answer 23

It’s the communicator between the DS5 and the Synergy Download Utility Software. Works via Bluetooth.

Answer 24

It’s a web-based system allowing the site staff to upload the study BG meter data. No review was required by site in CareLink. The sensor upload was at the end of the sensor wear so it was retrospectively analyzed and compared to the sensor data. There was nothing they could have done with the data.

Answer 25

The DS5 (all components, used an unused had to be returned). The study meter (contour NextLink): only unused had to be returned to sponsor. Why did we allow the subjects to keep the meter? Because it was commercial.

Answer 26

No, the subject cannot see the sensor data. As instructed at visit 2, the subject should continue on their current diabetes regimen. The subject can use the study BG meter to manage their diabetes (commercially available).

Answer 27

Two siblings living in the same house used the other’s study meter. The site color coded these going forward; subjects were instructed to complete the study on the switched meters. Notes on the deviation CRF and device identification. One subject used their personal BG meter, which happened to be the same model as the study meter.

Answer 28

At Visit 2. If a sensor is replaced at home, the site will sync it at the next office visit (no time requirement). The study meter time is synced with the laptop time. Subjects are instructed not to change the time on the study meter.

Answer 29

Sensor insertion Sensor removal Training on the meter and SMBG testing (4-7x) Continue your current diabetes regimen to manage your diabetes. *Training materials include IFUs and other subject materials.

Answer 30

Observation only: eat and take their insulin per their usual diabetes management. Challenges: investigator will provide recommendations the night before and during the FST in regard to food intake, medication management, and glucose target.

Answer 31

The site will resort to SMBG/fingersticks. Those values are entered into the Activity Log CRF but are not used for analysis.

Answer 32

We agree on the selection criteria. I present a list of nominees along with the selection criteria to stakeholders. We conduct an SQV at the nominated sites. I present the SQV report to stakeholders, and we agree to select. The selection letter is sent to sites.

Answer 33

We nominated 15 sites and SQV’d 13 sites. All 15 were based on experience in other studies. The 13 sites had the ability to enroll peds, adults, or both in the timeframe needed.

Answer 34

During the training phase, if a sensor falls off early, subjects continue with the remaining sensors. If all fall off prior to 7 days, then it’s per the PI’s discretion if the subject moves on to the study phase. During the study phase, if the primary sensor is removed, then all sensors are replaced and the 7 days start over; subject will complete any FSTs not completed. If it’s a secondary sensor, then the subject will continue without replacing.

Answer 35

There’s medical oversight. A physician, or mid-level provider such as an NP or PA who has managed patients with diabetes must be present during the entire challenge. A nurse, physician, or mid-level provider such as an NP or PA who has managed patients with diabetes must be present during the FST.

Answer 36

BG meter is uploaded into CareLink Personal. Site creates an account for each subject. Ketone meter is entered into the activity log CRF. The DS5 is downloaded using the Synergy Download Utility Software (via the blue Bluetooth adapter) and uploaded into Box. The YSI data are uploaded into Box and batch loaded into the CRF. Hematocrit and A1C: results are in the ACM portal and entered into the CRF by the site.

Answer 37

It’s a cloud-based, file sharing tool using to exchange documents with the site.

Answer 38

The AE CRF. If the AE CRF is unavailable, then they can e-mail our safety team.

Answer 39

Per protocol, we desire all AEs in a timely manner. If it’s an SAE, SADE, UADE, Severe Hypo, or DKA, then we desire these within 24-hours of the site’s awareness. UADE must be reported to sponsor and the IRB within 10 working days. Sponsor will notify the investigators and the IRB of any event that results in a safety report per FDA regulations.

Answer 40

If they are minor, per protocol, these are only documented on the Activity Log CRF. If the are more serious, per the protocol, these are documented on the activity Log CRF and AE CRF.

Answer 41

They specify data that are manually reviewed. Could result in manual queries. *Don’t share if able: Includes roles, what data, and frequency of review.

Answer 42

The data are query-free, CRFs that require verification are verified, and CRFs that require approval are approved. All AEs have been entered and adjudicated by the CEC as needed.

Answer 43

Describes how the data are collected, processed, and stored.

Answer 44

Oracle Clinical

Answer 45

Subject is 14-80. Subject has an insulin carb ratio and insulin sensitivity factor. Ketone level is

Answer 46

We have a Product Shipping Release Authorization from our Regulatory team. FDA approval letter IDE approval letter Approved CIP and ICF Site CTA Radio frequency approval (per the PSRA)

Answer 47

We had two APRs (summer 2021 and summer of 2022). We had the final CSR in 2023. We closed out with the IRB in March 2021, prior to the first APR but still sent it to the sites and IRB in Sep 2021. We did not send the second APR. We sent the final CSR to the IRB and sites in May 2023. We didn’t submit the second APR because sites and the study were closed with the IRB. Why were they closed if China and the study were open? We wanted to ensure “prompt reporting to the IRB of changes in a research activity."

Answer 48

The IRB initially required two parent signatures on the assent. We appealed and the IRB agreed that only one parent signature was needed for 7-13 y.o. subject since they were not undergoing challenges and two parent signatures were needed for 14-AOM due to the challenges. No assent for 2-6.

Answer 49

Anticipated Adverse Device Effects = 5 - Stinging upon sensor insertion (1) - Pain at the sensor site (3) - Bruising at the sensor site (1) All recovered/resolved. None were serious (SADE). Stinging and pain were for the same subject (stinging separate day; mild pain same day but different sensors at time of removal). No unanticipated adverse device effects (UADE).

Answer 50

Identified during a monitoring visit. The monitor discussed this with the site per the IMV follow-up letter. The site did not collect the second parent signature at visit 1. The second parent signed prior to visit 2 and provided a note confirming he/she agreed to their child’s participation prior to visit 1. This note is filed with the ICF. Site retrained the coordinator. Site will verify availability of both parents prior to scheduling V1.

Answer 51

One at Dr. Slover: Incorrect ICF version was signed. Site noticed the issue and reviewed the latest ICF with the subject the next day. Caught by the site (prior to the first IMV). Per IMV report, monitor reminded site to use caution in consenting with the correct ICF version. One at Dr.Kaiserman: Missed signature on the CA Bill of Rights. Site was going to get it signed at V2 but the subject withdrew prior to the visit due to anxiety with IVs. Discovered by the site while the site was filing documents. - Site plans to have a second study team member review the consent documents prior to the subject leaving the office at V1.

Answer 52

Previously, all subjects required a T1 or T2 diagnosis for at least 6 months. The amendment removed this restriction for 2-13 y.o. subjects, therefore, making it easier to enroll the 2-6 y.o. age group. It did not add any restrictions. Therefore, it was considered a minor change not requiring training per the training plan. Only four sites enrolled under version B, with two sites leveraging the updated criterion to enroll 4 subjects (3 at Liljenquist, 1 at Latif). Not all sites were recruiting this age group. Most sites had completed their enrollment under version A. The changes were sent to sites. **If asked, we also clarified the FST duration and that we recommend not completing the FST more than 15 minutes early. This was previously communicated to sites. Any deviations for this (would a deviation be required??)? Management agreed per the training plan.

Answer 53

It was considered minor changes. The data entry instructions did not change. We added an example for data entry on the Sensor Insertion Removal eCRF, noting time format for the time check fields (study clock, laptop, meter). If the format was not entered correctly, the system would still prompt them to enter it into the correct format. We updated an incorrect screenshot for I/E, however, the I/E in the CRF did accurately reflect the protocol. Could have initially been a placeholder and wasn’t removed prior to finalizing. The changes were sent to sites. Management agreed per the training plan.

Answer 54

Minor changes to support newly delegated staff following Q&A and discussion at the SIV. Updates did not stem from CIP changes. May need to pull Vickie in to review the change history. Changes went to sites. Management agreed per the training plan.

Answer 55

Minor changes. Clarified when to enter UNK for synchronization date if all time fields in the row were unknown on the Sensor Insertion/Removal CRF. There is a manual check in the DRG by data management to confirm the date field is not blank and that UNK is acceptable. “Date for study period should be after v3 and prior to v5.” All subjects had exited so not relevant to the u.s. cohort. This was more in anticipation for China. All U.S. subjects exited at the time of this amendment; the update was more in preparation for the China cohort. Management agreed.

Answer 56

Yes, we posted prior to the first subject enrollment. The results were also posted. It met the definition for an applicable clinical trial (ACT). What does the SOP say about maintenance during the study (updating site status, etc)?

Answer 57

Overview of how we will manage the study. Topics include: -study background (e.g., enrollment plan) -Record keeping (TMF) -> references the document management plan -Covered study (meaning, financial disclosure is collected) -Registering on ct.gov. Primary outcome measure relates to health outcomes. -Training requirements (references the training plan) -Timelines and Milestones (references CTMS) -Notes that the study team roster is maintained in CTMS and changes as team membership changes. -Lists vendors and responsibilities. No vendor issues required escalation per 056-P383 (escalation SOP). - Study communications and methods of communication (e.g., e-mails, meetings). -Types of meetings (examples only) -Oversight measures (site audits). This comes from our CCQC Global Clinical Audit program. -KQIs -Risk Management -Product Management -Study Finances (references eCATs and CTMS for invoicing and individual contracts)

Answer 58

The site will evaluate the area where the sensor was worn for redness, bumps, infection, etc. for each sensor worn regardless of duration.

Answer 59

One meeting to review the one SAE. I trained the committee to the protocol. I attended the meeting but did not lead it. Dr. Shulman was an investigator and CEC member for this adjudication, however, it was not an event at her site.

Answer 60

We work with monitoring management and they provide the monitors.

Answer 61

We coordinate with the manager overseeing each function (e.g., biostats manager), and they assign someone to the role (e.g., biostatistician).

Answer 62

A general direction of change.

Answer 63

It’s defined in our CSMP and/or in our SOP for escalating repeat issues.

Answer 64

It would be a collective effort to ensure it’s reported per the protocol. If I became aware of a potential complaint, I would request the site to report it to our technical support team per protocol and include safety and the monitor. That way, we have awareness and ensure the report is made. Per the SOP, all of clinical is to report potential complaints to the Complaint Handling Unit within a target of 48 hours of the notify date. If not all info is available, there should be no delay in reporting.

Answer 65

Nothing required escalation per the escalation SOP. Any other AEs?

Answer 66

The sites review a copy of the device complaints and will enter an AE CRF if needed. Monitors review these reports during the IMV.

Answer 67

KQIs are key quality indicators, which are metrics that measure the quality or excellence of the data. Examples: - Protocol compliance (rate of deviations by site) - Enrollment criteria compliance (total deviations) - Keeping pace with SDV (% of available data that have been SDV’d) - Site queries closed within 30 days - Age of MAIs (significant closed within 30 days; all closed within 60 days) -> recommended action is usually to review in deviation trending or determining frequency of monitoring visits. We define these in our Clinical Study Management Plan per stakeholder agreement. Some were met, however, they were already reviewed per the recommended action with our management team during deviation trending and didn’t require escalation per the Escalation SOP.

Answer 68

No obvious trends. Most repeat issues at sites occurred on the same date and were not repeated.

Answer 69

I am the clinical study manager, so I have oversight of the study. I collaborate with the SMEs and lead the study team through the start-up, execution, and closeout. I coordinate with stakeholders to ensure the enrollment and timelines are met.

Answer 70

A deviation is when something happens that goes against the approved procedure or plan.

Answer 71

The next IMV wasn’t until after the report was made. The IRB had no questions or concerns and were satisfied with the site’s plan to prevent this issue going forward. The protocol doesn’t state that there will be a deviation for not complying with the IRB policy. It simply reminds the sites that they “should” comply with the IRB policy. What’s important in terms of the deviation is that they reported it to Medtronic immediately: “**require** immediate sponsor notification upon awareness.” The table for investigator reporting responsibilities also doesn’t reflect this situation. Also, this wasn’t the sponsor’s submission.

Answer 72

This was not our data and was deidentified, therefore, it wasn’t a breach. We had the site delete the files. Issue started in late August 2020 (per Bode’s report). IMV report and FUL notes that the monitor trained Betsy on the YSI Data Logger and Box Upload Instructions (Ver. 3.0) on 8/31/20; Betsy trained those delegated YSI/FST on 9/1/20. Discovered by data management. Team reviewed the issue and updated the YSI Data Logger and Box Upload Instructions updated to Ver. 4.0 to help mitigate the risk that the Data Logger will contain older data. A refresher training was completed in October. Study team agreed to only train sites who were using YSI and had currently active subjects (regardless of whether or not they had this issue). Therefore, training request only sent to Slover (007), Bode (013), and Christiansen (004). No response from Christiansen, which was ok (LSLV was 10/13/20, plus he didn’t have this issue). Bode and Slover trained on 10/14/20 and 10/15/20, respectively. Mentioned in the IMV report: 013 (bode)

Answer 73

The monitoring plan says regularly, however, regularly isn’t specified. The study was so quick, the weekly team calls and KQI meetings were adequate to discuss MAIs. The Monitoring SOP states that MAI trending is defined in the monitoring plan “or” the CSMP.

Answer 74

Yes, 5 screen failures. - DKA within 6 months prior to enrollment. (1) - Hypoglycemic seizure within 6 months prior to enrollment. (2) - Hct >10% below the lower limit of the normal reference range. (2)

Answer 75

Only at Visit 1.

Answer 76

Have Vickie speak to these…. YSI error. E.g., RBCs in the sample or a short sip/sample. Sample error. E.g., not enough blood in the tube. Data entry error. Diluted sample. Rerun to confirm value. Sample was rerun for verification. (What does this mean?)

Answer 77

For both challenges, 2 BG measurements at least 30 minutes apart. These should be in a safe range of 70-200 mg/dL. These two may include the last FST measurements, otherwise, fingersticks may be performed with the study meter. For hypoglycemic challenge, provide a snack at discharge and remind subject to check their BG prior to going to bed the night of the challenge. Provide 24-hr contact info to subject. Site will contact the subject within 24-hours after discharge to assess subject status. Subject is reminded to complete fingersticks 4-7x per day.

Answer 78

14-80: 12 visits 7-13: 8 visits 2-6: 8 visits All training: visits 1-3

Answer 79

Yes, for moderate bruising (330013004). Bode.

Answer 80

Conflict of interest for whom? If conflict with internal stakeholders: We develop and agree on site selection criteria prior to nominating any sites and involve multiple stakeholders when selecting. For investigators: If they are on a committee, then they would either not be on this study committee or not adjudicate for their site. Double checking their FD and IRB submission for conflicts of interest.

Answer 81

Start of the study on the FD = when they’re invited to participate (selected). - Anderson removed her yes for significant payments (range did not start from the time of selection). -Kaiserman initially responded yes, however, that was for 12 months, not from site selection (2 months). Confirmed MDT only paid him $6,300 during these 2 months, so this was no (<$25,000). Reduced bias by not having him as a CEC member on this study. All other financial boxes are checked no on his IRB submission. The regulation states FD is “during the time the clinical investigator is carrying out the study and for 1 year following the completion of the study.” Kaiserman confirmed this in his updated FD. Investigator Agreement reg: “The sponsor shall obtain a commitment from the clinical investigator to promptly update this information if any relevant changes occur during the course of the investigation and for 1 year following completion of the study.” We remind the site of this in the closure letter (onus is on them).

Answer 82

First occurred within 4-6 weeks from first enrollment at each site. Frequency is based on number and timing of subjects enrolled, completeness and quality of data entry, and frequency of AEs and/or protocol deviations.

Answer 83

IRB and Informed Consent approval/expiry DoA

Answer 84

5 -2nd parent signature missed on the ICF for three subjects at Liljenquist. (3) -DoA not completed at the end of Christiansen’s SIV. (1)?? -Bode uploaded the incorrect, old data prior to uploading the new data. (1) *For Bode, site submitted an internal CAPA. Monitor conducted a YSI Data Logger & BOX Upload refresher training for those delegates the YSI/FST task. See training record. The issue did not occur again. What made these significant (definition)?

Answer 85

Yes, and they can customize them as they see fit.

Answer 86

CSMP states teleconferences “to monitor progress of lab vendor **start-up activities**.” Frequency per the CSMP: Monthly, assuming sufficient activity. A couple meetings were scheduled (July 23, 2020 and September 3, 2020). All kits had shipped by then. Issues resolved. The last subject was scheduled to enroll on October 15, 2020, so any updates via email, as needed, were considered sufficient.

Answer 87

FSE: 15-JUL-2020 LSE: 15-OCT-2020 LSLV: 16-NOV-2020

Answer 88

These are risks identified and agreed upon by stakeholders of the CSMP. Critical items pertaining to subject safety and data integrity risks. If digging deeper on how we chose these specifically (where did they originate)…. These are examples per the template that we wanted to leverage in this study for tracking risks around subject safety and data integrity.

Answer 89

The CSMP notes a “recommended” action, not a required action. The recommended action stated that we were to review with management during deviation trending meetings (we were). The CSMP says to escalate “if necessary.” These were not repeat issues and, therefore, did not meet the requirements of the SOP. Naturally, over time as enrollment increases, this rate will go down.

Answer 90

All occurred on the same day. Once discovered during the IMV (prior to each subject’s V2), the site reported them to sponsor immediately (same day as identified). Corrective action per site was re-educating their staff. The issue did not occur again.

Answer 91

Yes. It was hosted in October as we were approaching database lock. We provided a timeline of where we were and where we were headed. We provided reminders to prep for data cleaning. Why no minutes? It didn’t require minutes, it was more of just a status update for the study and where we were at, at that point in time. Any material for it? Yes. Don’t mention PPT unless needed. It was more of a deck on my end to guide the discussion; it was not provided to sites.

Answer 92

Risks are noted in our protocol. Subject safety and data integrity risks are tracked per our CSMP. Device risks are tracked per the Safety Plan. CSMP says “ongoing process throughout the study’s lifecycle.” This was a short, 4-month study, therefore, only the initial review was required.

Answer 93

eCATs and CTMS.

Answer 94

Clean and lock the database. -All queries closed. -Product returned. -All CRFs requiring verification are verified (all AEs are reported). -All CRFs requiring approval are approved. -Safety team ensures AEs requiring CEC review have been adjudicated and reported per the Safety Plan. Site Closeout -COVs: action items are closed. Work with payments and sites to ensure the sites have been fully compensated. Request that sites submit their final progress report to the IRB. Provide sites a copy of their data (through Box). Investigator, Vendor, and Committee Contracts are closed (part of the closure letter to sites). Biostats analyzes the data per the CIP and Stats Plan and produces statistical deliverables for the CSR. Develop the CSR with stakeholders (final CSR was after China) and provide to Regulatory for submission. Post study results on ct.gov (didn’t happen until after China).

Answer 95

RAD Agile BOX CareLink Personal Oracle Clinical ACM Cornerstone Learning Management Software (LMS)

Answer 96

Describes how documents will be managed (review, approve, and store).

Answer 97

At least annually; shows multiple reviews in CTMS (resulting from surveillance).

Answer 98

Unsure about sponsor. Site is per the CIP.

Answer 99

MAIs - something that needs to be resolved as a result of non-compliance. Significant MAIs are significant in nature. -Require immediate notification to the CSM. -Require documentation in the monitoring report. -30 days to resolve or documented as progressing towards resolution within 30 calendar days. If not, they must be evaluated for further escalation per 056-P383 (Escalation of Clinical Study Non-Compliance), which may include suspending enrollment at the site, terminating the study at the site, or transferring investigator responsibilities to another appropriate individual. The following MAIs are significant per the monitoring plan: (1) ICF: -not obtained at all -not obtained prior to first study-specific procedures -performed by an unauthorized person -obtained in a language the subject doesn’t understand -with additional required forms not completed (including HIPAA). (2) Ineligible subject enrolled (3) Unreported UADE or incidents that require immediate reporting (4) Missing investigational device or use of an investigational device in a non-study subject (5) IRB approval not obtained or lapse in IRB approval (6) Non-compliance that requires immediate reporting per regulation or IRB requirements Lack of PI oversight = follow-up item, as each noncompliance leading to this conclusion will be reported as MAIs. Lack of PI oversight = immediate reporting to the CSM (email or documented in the visit report that this was communicated by phone).

Answer 100

This was the initial version submitted to the FDA. We trained on A.3 knowing this version could be approved by the FDA. If not, we would train the sites to the FDA approved version and ensure IRB approval was in place for the FDA approved version before activating sites.

Answer 101

When the blood sugars are very high and insulin levels are very low.

Answer 102

We work with our Vendor Management Team. I confirmed with the VMO that ACM had a CDA in place. ACM was an approved vendor on our Medtronic Clinical Approved Supplier List (MCASL) and the sole approved blood lab on the list. Therefore, a request for information, qualification, and competitive bidding was not required. Since they were not a new supplier or providing a new service, a selection form was not required and we were able to move to negotiating a contract.

Answer 103

Yes, 8 subjects. No trends noted.

Answer 104

DA received: lot # from box Device Disposition: lot # from the inserter; sharpie used to write the sensor # (entered on CRF) Sensor Insertion/Removal: lot # from inserter, sensor # from sensor (sharpie), and sensor serial # DA Return: lot #

Answer 105

Failure Analysis plan only notes the DS5. DS5 returned that are not associated with a complaint were inspected as determined by R&D. DS5 returned with complaint were inspected by R&D. All analysis/testing methods and results were documented in a lab notebook or other record. Failure analysis results were communicated to the Failure Analysis team for entry into SmartSolve (summary of the analysis performed, failure analysis codes, results and conclusions, date of analysis, and who performed the analysis).

Answer 106

This occurred at visit 2 during the start of the training. This was not an FST. Reminder: BG > 500 or ketones >/= 3 during a challenge is an FST stopping rule.

Answer 107

Deviations are communicated to us through the deviation eCRF. Investigator reporting requirements are noted in the protocol: -Deviations to protect the life and physical wellbeing of a subject in an emergency shall be reported to the sponsor and IRB as soon as possible but no later than 5 working days after the emergency occurred. -Failure to obtain informed consent and assent prior to investigational device use shall be reported to sponsor and the IRB within 5 working days after device use. *Protocol notes examples of significant deviations that require immediate sponsor notification upon investigator awareness (e.g., failure to obtain informed consent/assent; informed consent/assent obtained after study procedures; continuation of a subject who did not meet eligibility; performing a procedure not approved by the IRB; failure to inform the IRB and sponsor or reportable AEs; investigational device dispensed without obtaining informed consent/assent). *Note: for those with consent/assent issues, these were reported immediately to sponsor upon investigator awareness. No devices were used by these subjects since the correction was made prior to visit 2.

Answer 108

Sponsor will notify the investigators and the IRB of any event that results in a safety report per FDA regulations (e.g., UADE within 10 working days or emergency deviation to protect the subject’s life or physical well-being within 5 working days). Determines, in collaboration with stakeholders, if any risk analysis needs to be updated.

Answer 109

Not required since we closed with the IRB prior to one year. We submitted the first APR to the IRB and sites even though the study was closed with the IRB.

Answer 110

The function/activity and division of responsibilities is noted in the CSMP under vendor management. Clearly states what they will do. Work order: Supply lab kits and associated supplies necessary for collection and testing of the hematocrit and A1C.

Answer 111

Lab director CV and license CAP accreditation (College of American Pathologists) - considered the gold standard for lab quality control. CLIA certification - allows the lab’s location (address noted) to perform lab testing of human samples for certain specialties (e.g., endocrinology, oncology) NGSP Certificate of Traceability - purpose of the NGSP is to standardize A1C results; this certifies that ACM’s A1C machine meets those standards.

Answer 112

We confirm the following: -FDA Debarment List (per investigator) -FDA inspections and any actions indicated (per investigator). -Warning Letters for the institution Completed for the PIs prior to selection and presented to stakeholders (not included with nomination); we learn about sub-Is during the SQV, so these are completed after but prior to selection (weren’t presented to stakeholders).

Answer 113

See the escalation SOP. The monitors discuss findings with sites at the IMVs and secure compliance.

Answer 114

No. If there had been a request, we would have gone through qualification and selection steps for the new investigator, ensured the change was reported by site to the IRB, and communicated the change to regulatory for FDA reporting.

Answer 115

Considered an applicable clinical trial (ACT) per the checklist. Primary outcome measure relates to health outcomes (per the CSMP). - Registered: - FSE: July 15, 2020 (US) - Primary Completion Date: April 12, 2022 (China) - Study Completion Date: April 12, 2022 (China) - Results submitted: April 4, 2023 CSR sent to sites on May 2, 2023. Results were initially posted within one year; latest update shows in ct.gov as May due to questions from ct.gov and updates needed.

Answer 116

Because our Biostats team was reviewing it per the Randomization and Blinding Plan. Monitors were noting it per the IMV reports. Why no deviations for those with the random assignment date after V2? The random assignment was correct for these subjects per the sensor insertion locations at V2. There were no FSTs during the training period. This subject followed the random assignment when it was critical to the endpoint, which is the study phase. The training period is just to get them familiar with the wear and fingersticks.

Answer 117

The rationale is that they meet the selection criteria. We have it further documented in the “list of potential investigators and sites” per 056-P373.

Answer 118

Most individuals, except Chavon, who ran the SQV approved the protocol prior to the SQV. For Chavon, she attended one (observed and completed the report) before leading her own. Additionally, Chavon is a seasoned monitor within Medtronic diabetes and has experience with these sites. The SQV is more to assess the site’s qualifications, which she has experience doing, vs protocol training.

Answer 119

The A1C reports were flagging low instead of high. The numeric value was not impacted and the A1C was not for eligibility. Notified by ACM on 7/21/20 and issue was corrected on 7/22/20. Impact was to 20 reports. ACM completed a triple QC prior to release to ensure they were correct. 20 reports were amended by ACM, as needed, and reissued to the sites. ACM confirmed it was added to their quality issue tool and brought to the attention of upper management. We received a CAPA letter noting they completed an investigation to identify the root cause and planned actions to address it.

Answer 120

The site. There is an audit trail in Oracle Clinical that shows all changes. Safety = MUO only.

Answer 121

Centralized monitoring supported remote review. End it there! Site monitors: review data at the investigational sites. Centralized monitoring: allowed for data review on a more continuous basis. Sent Site Action Notification (SAN) email to each site biweekly regarding: - missing CRFs > 14 days - required data entry > 14 days - open queries > 14 days - open RSOs. No email sent if it didn’t meet the SAN criteria. Safety team: supports the review of AEs. The inspector is simply looking for an explanation of how responsibilities are divided among site monitors, in-house or central monitors (if used), medical monitors, and any other personnel who evaluate data and compliance.

Answer 122

No audits during the study.

Answer 123

We complete an activation checklist at each site prior to sending the go-letter. The initial activation checklist at each site was under CIP Ver. A IRB approval (the checklists confirm the IRB approval). Two (Slover and Latif) show an activation checklist approval date the day after the go letter, however, that’s because it was UTC time zone (technically, it was approved the same date as the go letter). *Do not mention IRB approval checklists. Some weren’t completed until long after IRB approval.

Answer 124

No, the one SAE was not a UADE. Advarra requires pre-approval of any planned deviations. For unplanned deviations, they require reporting of deviations that may adversely affect data integrity or increase risk of harm for the subject (e.g., enrolling an ineligible subject).

Answer 125

Training per the training plan and communication either via e-mail or meetings. Site has access to our contact via the sponsor contact list (CRDS, monitor). CRDS observations during the first FST. Biweekly emails with study updates and reminders to sites?

Answer 126

We provided a copy of the amendment to the sites and sponsor team and collected a training record if required per the training plan.

Answer 127

Review EDC report for unreported AEs and potential complaints: - any new/changed AE data. - new/changed non-safety CRF data (certain fields and site responses) Sponsor assessment of each event is documented on the MUO eCRF. Review target is 48 hours from notify date. Any questions for the site are sent via a query and follow-up is tracked in EDC. Any potential UADE is investigated as initiated by the safety rep and reported to the Medical Advisor for further assessment. The investigation will be approved by the Medical Advisor and CSM. If a UADE is confirmed, the info is provided to the CSM and/or Reg Affairs for reporting to the FDA, IRB, and clinical investigators. Review redacted source documents for unreported AEs and potential complaints. Review target is 10 business days. Safety will forward potential complaints to our complaint handling team (reporting website through tech support’s sitebuilder). Review target is 48 hours from notify date. An “unknown” relationship to the product or procedure should still be reported as a potential complaint and not delay reporting.

Answer 128

-FST start time out-of-window (unless the FST is missed on the scheduled day). -FST sampling (however, deviation if 2 consecutive samples are missed or 3 or more total samples are missed, unless due to a safety issue or device issue). -Challenge targets aren’t met. -FST duration if FST is completed within 15 minutes prior to the end. -Missed SMBGs (unless site didn’t train on SMBG procedures)

Answer 129

The site had already exited all subjects by the time this IMV was completed. Site delays in getting the source and data uploaded. Allowed the visit to be extended to accommodate this review. AEs had been reported prior to the visit (none unreported). The deviations are noted as minor.

Answer 130

This was during covid, so understandably, it was a newer process for sites and took more time than usual to transfer documents into Box for monitors to review. However, sites did have them in their ISF.

Answer 131

CIP says “subject will be discharged per investigator discretion” and that these measurements “should” be in that range. See NTF for why.

Answer 132

Falls under ending the FST more than 15 minutes early (not missed samples). Garg: The deviations occurred after the IRB approved Version B. Christiansen: The deviation occurred after the CB was IRB approved. Note: when it comes to IV issues, 2/3 subjects completed the study (Garg and Christiansen) and one was withdrawn (Brazg). There’s correspondence with Brazg (withdraw) and Garg (stop the FST) but not Christiansen. Per the CIP, if there is an IV occlusion, the FST **may** be repeated per sponsor recommendation. Nothing about site having to reach out to us to ask. None of these subjects repeated the FST.

Answer 133

The site had already exited all subjects.

Answer 134

Verbal confirmation, video walk through, or photos. The monitors had onsite experience with these sites prior to covid.

Answer 135

To capture the times displayed on the study clock, study laptop, and study BG meter before the training period and study period. This helps us to understand if there were any mismatches on the times of these devices. If subjects did not know, they were to enter UNK. This is because this table wasn’t added until later in the study period per the request of bioinformatics (therefore, sites likely did not know/capture this info previously).

Answer 136

We develop the site activation checklist template with stakeholders. We complete an activation checklist for the site. If those items are met, we inform the investigator that the site can enroll their first subject. How? Through an e-mail. Avoid but if needed: If someone has not met these requirements, we’ll let the sites know what is needed for these individuals. It’s noted in the letter perky to remind the monitor to verify training during the first IMV (they are to review the activation letter is on file at the first IMV). We activate sites, not personnel, per the SOP. A site activation checklist is completed as new personnel are added to the study.

Answer 137

I would reach out to Finance to confirm prior Medtronic payments to the individual, and if there is a change to the reporting status (e.g., we confirm they were actually paid >$25,000 from mdt), I’ll let the individual know how we plan to report it to the FDA.

Answer 138

Investigator: Work with my director supervisor and legal. - Should we include this person in the study? - How to minimize bias if included in the study? Advisory committee member: Work with my direct supervisor. - Should this person be included on the committee? Document the outcome and any decisions/actions.

Answer 139

All investigators Advisory committee members

Answer 140

I would immediately escalate it to legal.

Answer 141

I complete a Periodic Evaluation Report and submit it to the VMO.

Answer 142

If it was a breach of a subject’s personal data or security systems, the vendor will notify me and the Privacy team immediately. Privacy will determine if the National Data Protection Authorities and/or data subjects need to be informed. CSM will notify VMO and Medtronic Incident Response Team of details of the data breach. VMO notifies stakeholders of data breach as applicable.

Answer 143

CRFs in EDC. We plan for study product using our Clinical Product Management Assessment Form (PMAF). Sites receive a delivery notice along with the product shipped. Sites review the content to ensure they match the delivery notice. They’ll enter the devices received from sponsor into the Site Received DA CRF if required. Sites will follow our study product return instructions to return product required per the CIP. Sites enter the devices and note if there is a complaint in the Site Returned DA eCRF. Supply Chain will refer to the PMAF for disposition upon receipt (if sensors, it was to defer to R&D for non-complaint and complaint; if complaint, action was to analyze the failure). I’ll ensure there’s a final review of the study product accountability for each site (collaborate with monitoring and clinical supply chain - review EDC and shipping records).

Answer 144

Centralized CEC Charter describes: - Membership - Roles and responsibilities - Adjudication process Study addendum: - Study overview. - What events will be adjudicated. Note: Medtronic employees may be present to assist in facilitating the meeting, however, they cannot vote.

Answer 145

We used a centralized CEC (per SOP, any investigators would abstain from voting on events for studies in which they participate). I work with safety to determine the requirements for membership (at least four requirements per the SOP): - one chair person - at least three members for majority voting - training/experience in the subject matter (subject matter experts) - independent of the sponsor, FDA, and IRB. There is already a charter since it’s a centralized CEC, so safety drafts a study-specific addendum. Safety manages the CEC (e.g., member selection, contracting, required meetings, termination of membership agreements). Note: the chairperson is appointed based on experience in previous CECs, is a SME on the device/therapy, and a scientific thought leader, if possible.

Answer 146

Obtained from Regulatory. Per the SOP, all steps in the SOP are for an investigators brochure, which wasn’t used in the U.S.

Answer 147

I collaborate with the ICF specialist, who authors the documents. The ICF specialist completes the checklists to ensure the required regulatory elements are met, and I approve.. Checklists were only needed for the adult and parent/guardian ICFs.

Answer 148

Per the SOP, this step is “as necessary.” The IRB reporting requirement is for UADEs, which is already being captured by our safety team. However, I would notify safety if there’s an update to the IRB reporting requirements.

Answer 149

CSM, safety rep, and medical advisor

Answer 150

I collaborate with monitoring management to assign a monitor. The monitors are qualified by education, training, and experience. At minimum: - informed consent process - Experience with the therapy. - training to SOPs, regulatory requirements, etc. I ensure the monitor receives study training per the training plan.

Answer 151

I’m notified by the monitor. If cancelled, the original and new date, if known, is included in the revised communication to the site.

Answer 152

At minimum: - Compliance - ICF - ISF (essential documents) - IRB (documents) - FUL (previous visit) and PVL (this visit) - PI is aware of relevant CIP updates - Discuss any findings/results with the PI. If a required activity is not performed, this must be documented with a rationale in the IMV report.

Answer 153

- Collect documents needed for sponsor’s files - Close open MAIs or a plan is in place to close. - Disposal of remaining study materials. - Database (e.g., CRFs complete, queries closed, current status of ongoing AEs is noted, device disposition is noted). - Discuss site responsibilities, including final IRB progress report and record retention. - Communicate record retention requirements to site in writing.

Answer 154

The monitor can complete the SIV Completion Certificate. Certified that site activation requirements per the SIV report are complete for that site.

Answer 155

This is allowed per the SOP. An updated letter must be sent if noted changes in the report result in changes needed to the letter (“results in information to be communicated to the PI”).

Answer 156

Data Manager completes the Database Snapshot or Lock Request Form. Once completed, the data manager provides copies of the site’s complete data to the CSM for distributing to sites. Examples on the form: CRFs entered, SDV status reviewed and acceptable, AEs reconciled, adjudication results available, CRFs approved.

Answer 157

It’s essentially the same thing: the site can’t enter data. We hold on revoking until the final study report is complete. The data manager will need to complete documentation justifying the need to unlock (what CRFs need updating) and for whom (restoring access). This document requires approval. Once updated, the DM will re-lock and a new PDR will be generated for the site.

Answer 158

We work with a contracts analyst on the study. I’ll collaborate with him on a budget tool and finalizing the CTA template and starting with a value that we feel is appropriate (don’t say fair market) given the amount of work involved in the study and at certain visits. The contracts analyst will present that to the site and they’ll go back and forth until we agree. Could increase based on region. FDA wants to ensure we’re not overpaying and influencing to skew the data.

Answer 159

Prior to database snap or lock if that data is being used for analysis.

Answer 160

CCG are instruction for data entry in the database. Data Entry Guidelines are for paper CRFs. Not used in this study.

Answer 161

Yes, they’re registered with the FDA (#) and OHRP (FWA#) and accredited with AAHRPP (certification). Office for Human Research Protections (OHRP) Association for Accreditation of Human Research Protection Programs (AAHRPP) certified

Answer 162

Safety Reports -Safety Data Management Report -SharePoint Potential Complaints Tool

Answer 163

The SharePoint Potential Complaints Tool (validated) is sent to safety for review of certain CRFs and fields within the CRF. The safety team will review it for the Protocol Deviation Term, Reason for Protocol Deviation, and Corrective Action. This is also something that requires reporting to the IRB by site within 5 working days, so we would receive that notification as well.

Answer 164

Avoid it: Say that we review the Deviation CRFs. If it goes into CDA, say it’s not a report we’re using for analysis; it’s a tool for the study team’s awareness. There could be a risk of missing one, however, we have monitoring reviewing the data within OC and safety reviewing validated safety reports listing certain deviation fields and changes to the CRF.

Answer 165

Yes, for batch loading the YSI data into the CRF.

Answer 166

Deviation CRF. Deviation trending. Emergency deviation to protect the subject’s life or physical well-being shall be reported to sponsor and the IRB within 5 working days. Failure to obtain informed consent and assent prior to investigational device use shall be reported to sponsor and the IRB within 5 working days. *subjects with consent issues were resolved before V2. Significant deviations require immediate notification upon investigator awareness (e.g., informed consent missed or after study procedures, device dispense without consent, ineligible subject continues, failing to inform the IRB of reportable events). Planned deviations require stakeholder review and prior approval by sponsor and the IRB (unless to protect the safety of the subject - still need to let us know within 5 working days). Unplanned deviations beyond the investigator’s control (e.g., missed visit), do not. Repeat or serious investigator noncompliance issues could result in a corrective action plan with the site, suspending enrollment until the issue is resolved, or terminating the investigator’s participation.

Answer 167

Non-compliance in the study was not considered to be critical, repeated, or fraudulent. Any noncompliance was isolated: one-time, low-risk/impact issues that can be resolved through routine channels (e.g., monitoring, data queries). Per the SOP, I would be notified by clinical personnel. I would review the issue and determine if additional evidence is required, review with stakeholders and **complete the escalation documentation**, communicate the course of action with stakeholders, ensure the **action plan** is implemented and **note the outcome in the clinical escalation documentation**, and determine if further action/escalation is needed (CAPA, suspension, termination). If there is suspicion of fraud, we’d involve legal and Clinical Compliance to ensure an audit is conducted. Definitions for non-compliance: - Isolated: one-time, low-risk/impact issues that can be resolved through routine channels (e.g., monitoring, data queries). - Critical or repeat: Issues that cannot be resolved through routine channels that may cause harm to a subject, result in an inability to utilize data, or be systemic in nature. - Fraud: deliberate reporting of false or misleading data or the intentional withholding of reportable data (e.g., falsifying data, manipulating IRB documentation, forging info).

Answer 168

We’ll receive the field corrective action notification and verify if the product is used in the study. We’ll conduct an impact analysis and define any action needed. The FCA will be communicated to the PI commercially, so we should consider notifying the site if there is no impact for the study as part of that package. We’ll confirm receipt with the PI. I’ll communicate the FCA to the study team and IRB. Implement any actions requested by the IRB.

Answer 169

May be the result of an escalation plan. May be due to site noncompliance (outcome of the escalation SOP), to protect subject safety or data integrity, or meet an IRB or FDA requirement. We’ll create an **action plan** reviewed by stakeholders (outlines the issue, decision, rationale, how long if suspending, how to ensure subject safety during a suspension, impact on timeline and endpoints, restart requirements (e.g., CAPA), and communication plan (to study team, site, IRB, FDA). We’ll obtain written confirmation from the investigator, IRB, and FDA. Complete CAPA (if they fail to complete, the site is terminated). Will review if they meet restart criteria, communicate the decision, and obtain acknowledgements as above. Similar instructions for termination. Timelines to enter data, instructions to manage/destroy/return product, and terminate the CTA.

Answer 170

6 months after FDA approval, then every 6 months thereafter. This is reviewed by stakeholders prior to being provided to FDA.

Answer 171

If I give 1 unit of insulin, I cover this # of carbs (grams).

Answer 172

If I give 1 unit of insulin, my BG decreases by this many points (mg/dL).

Answer 173

Helps us to compare BG values with the sensor values.

Answer 174

The subject safety and data integrity risks were identified and agreed on per the KQIs in the CSMP. The language under the risk management section immediately after states, “**additional** subject safety and data integrity risks are identified through the study-specific risk matrix and **if applicable** are tracked as KQIs.” We didn’t feel anything “additional” was required beyond the risks tracked in the preceding KQI section. The risk matrix template wasn’t available for use we were approaching the end of the study. Therefore, it was out of scope for the US but in scope for China.

Answer 175

Those who didn’t complete it either screen failed or withdrew. Per the protocol, all requirements that apply to the final visit “should” be completed “if possible.”

Answer 176

Completed for the BG and ketone meter. -Before each YSI/SMBG FST -When using a new vial of test strips

Answer 177

Bailey: the random assignment date is unfortunately the same date as V3. It’s likely they entered the data late and used this as the date of data entry. However, the training sensor insertions occurred at V2 and were per the random assignment (arm/arm). Castorino: Random assignment date is likely the date of data entry. It’s off by one day when no visit occurred. The training sensor insertion was at V2 and locations are per the random assignment (butt/butt/arm). Harrison: Random assignment date is likely the date of data entry. It’s off by one day when no visit occurred. The training sensor insertion was at V2 and locations are per the random assignment (arm/arm).

Answer 178

These are targets, not requirements. FUL: 21 days Report: 28 days

Answer 179

(1) Direct access to source (e.g., paper or the EMR; if EMR, the monitor’s login is tied to subjects only). (2) Certified copy of the source (could be a copy of the EMR) - have a dated signature or generated through a validated process that this is a true and complete reproduction of the original source. (3) Supervised access when direct access isn’t possible (depends on the institution’s requirements)

Answer 180

Yes, if the first and last day of the visit are not more than 28 calendar days apart. Example: Monday, Wednesday, Friday.

Answer 181

Within 3 months of study completion or termination of the investigation or the investigator’s part of the investigation.

Answer 182

5 working days

Answer 183

2 years (or longer if local laws require) after the study device is approved or the study is terminated, whichever is longer.

Answer 184

MUO database (CRFs) Assess: -Device related -Procedure related -Seriousness -Anticipated or Unanticipated

Answer 185

Safety Events: -Medical Dictionary for Regulatory Activities (MedDRA) Medications: -World Health Organization Drug (WHODrug) All coding must be completed prior to a database snapshot where the data is used for regulatory submission.

Answer 186

Yes. Visit 4 is a phone call or optional office visit; may be combined with V5 if, per the random assignment, the sensor insertion is at V5. The purpose of Visit 4 is to confirm they inserted the sensor in the correct location and time and provide SMBG reminders. Last two visits if the final FST and sensor removal are on the same day per the random assignment.

Answer 187

No; testing and services done **for the study** are at no charge to the subject. Also, costs will not be billed to their insurance or Medicare. However, we will not routinely pay for medical care or pay the subject if they are injured or become ill **because of** the study. However, we will pay the site back for any medical or surgical costs it provides the subject for illness or injury related to the subject’s study participation under certain circumstances noted in the ICF (i.e., related to a study device defect, not caused by site negligence, not a site protocol deviation, subject intentionally didn’t follow site instructions, illness/injury naturally progressed), happened before study closure at the site, site notifies us within one year of study closure at the site). Subject does not give up their legal rights nor release the sponsor or site from their negligence. Paid visit stipends. Subjects may also be paid back for any extraordinary travel costs (airfare, hotel, mileage); requires written sponsor permission.

Answer 188

The description of changes outlines the change and rationale for change; it’s essentially no different than speaking to it live. We’re always available if sites would prefer a live training or have any questions before signing that they acknowledge the changes. Provides flexibility as well.

Answer 189

No, per the CSMP vendor issue identification and tracking section, the issues will be discussed promptly and **may** require a corrective action plan. Repeat performance issue will be escalated for further review (for the study, this was low risk and not repeated and was not considered a data breach).

Answer 190

Marketing Survey: Not part of the endpoint. For marketing purposes. Conmeds: Because no medications are noted in the eligibility criteria. We have the CRF though because conmeds are required at baseline per the CIP. Random Assignment: reviewed by Biostats per the Randomization and Blinding Plan. Avoid these…. Visit CRF: simply asks for the visit # and visit date. No windows per protocol. What about the 24-hour follow-up after each FST? The CRF doesn’t capture a time, only a date; that would be in the site’s source and is noted on the source worksheets (visit date and time). Unscheduled Visit: Noted the purpose of the visit, which would also be captured elsewhere (e.g., “sensor replacement” is detailed in the sensor insertion/removal CRF; “device disbursement” is captured in the DI eCRF.

Answer 191

The subject was having multiple IV issues during the FSTs. Site reached out to sponsor per the CIP (“if subjects experience unresolved IV occlusions…. In-clinic procedures may be rescheduled per sponsor recommendation.” Advisement per Biostats was to have the subject not repeat due to the IV issues, and the medical advisor recommended hydrating very well before the next FST. Subject did well but then started having IV issues again. Leadership confirmed that without the YSI (analyzable) data, there is no value in keeping the subject in the study. They also felt there wasn’t much value in terms of length of wear and advised that the subject exit.

Answer 192

Those deviations were removed by site. Monitor queried to confirm that the situation did not meet the criteria for a protocol deviation (2 consecutive samples or three total samples missed during the FST).

Answer 193

No - nothing noted in the unscheduled visit for any subject.