A.1.1 Research and testing product(s)
a) Description of the exposure to the research and testing product(s), if used;
Exposure to the research product will only occur during the patient screening procedure (Phase 0-NS) and in Phases 1 and 2 with the performance of the LP.
b) justification for the choice of test(s);
There is no control group in the study because all the patients undergo both procedures.
c) List of any other medical device(s) or medications(s) to be used during the clinical investigation; None other than the conventional ones in the routine clinical practice of the patient with suspected meningitis.
d) Number of research devices to be used, together with a justification.
The number of research products is one; the Neosonics described in this application.
However, a consumable is also required for its use, which consists of a membrane that is placed on the tip of the probe to improve transmission of the US and the sensor rotation.
One consumable per patient will be used in Phase 0-NS, and more than one consumable can be used in Phases 1 and 2 to perform follow-up measurements on the same patient and view the efficacy of the treatment in patients diagnosed with meningitis. Scans can be performed every 24 hours in the first three days and every 48 hours until the completion of the treatment or the device does not detect cellularity.
If the consumable breaks it must be replaced with a new one. Regarding the device, one unit will be left in neonatology and it will be replaced in case of breakage or failure.
A.1.2 Subjects
a) inclusion criteria for subject selection;
Phases 0 and 0-NS: Premature newborns, term newborns and/or infants with an open fontanelle and who may or may not have signs of meningitis.
Informed consent by parents/guardians
Phases 1 and 2:
Newborn and infant with an indication for lumbar puncture and with an open fontanelle. Informed consent by parents/guardians
b) exclusion criteria for subject selection; In all phases:
History of cranio-encephalic trauma. Closed fontanelle.
Lack of informed consent by parents/guardians
c) criteria and procedures for the withdrawal or release of subjects;
The participants can leave the study whenever they wish; dropouts will be substituted with new cases so the number of patients is as outlined.
d) timing of inclusion;
Taking into consideration that Phase 0 aims to obtain transfontanellar imaging using a device marketed and approved for this purpose, this phase will begin from the date of the Clinical Research Ethics Committee’s (CEIC, abbreviated in Spanish) approval as it does not require express authorisation by the competent authority (Spanish Agency of Medicines and Medical Products) (AEMPS, abbreviated in Spanish).
However, the subsequent phases in which the research equipment will be used must be authorised by the Clinical Research Ethics Committee’s (CEIC, abbreviated in Spanish) and the
Spanish Agency of Medicines and Medical Products (AEMPS, abbreviated in Spanish). The inclusion of Phase 0-NS patients may be carried out in parallel to the inclusion of patients for Phase 1, as the patient profile is different and the study objective is also different. However, Phase 2 will begin once Phase 1 is completed.
e) total expected duration of the clinical research;
18 months
The duration of the study has been altered due to the emergence of Covid-19, as well as by the
availability of medical equipment at certain times.
f) expected time for the participation of each subject;
Scanning times is estimated at 20 minutes per patient with both devices.
g) number of subjects that need to be included in the clinical investigation and estimated time needed to select this number (i.e. inclusion time).
- Phase 0: 40 patients (10 premature, 10 newborns, 10 infants from 1-3 months and 10 infants from 4-12 months or older ones with an open fontanelle). Estimated inclusion time: 2 months
- Phase 0-NS: 60 patients (15 premature newborns, 15 newborns at term, 15 infants from 1-3 months and 15 infants from 4-12 months or older ones with an open fontanelle).
Estimated inclusion time: 2 months
- Phase 1: 16 patients (6 of which must be patients with LP-confirmed meningitis).
Estimated inclusion time: 3 months
- Phase 2: 170 patients (77 of which must be patients with LP-confirmed meningitis).
Estimated inclusion time: 9 months
A.1.3 Procedures
a) description of all procedures related to the clinical investigation that the subjects will undergo during its performance;
- Phases 0 and 0-NS:
Clinical procedure
Parents/guardians will be offered entry into the study for their child and will be given the information and informed consent document.
In Phase 0, if the patient's entry into the study is accepted by parents/guardians and after signing the informed consent document a member of the research team will perform the imaging tests with the standard equipment, following the current hospital protocol and carrying out the series of studies instructed by the medical team responsible for the patient.
In Phase 0-NS, if the patient's entry into the study is accepted by parents/guardians and after signing the informed consent, document a member of the research team will perform the imaging tests with the standard equipment, and consecutively with the design equipment, through the anterior fontanelle. The conventional neuroimaging procedure will follow the current hospital protocol, performing the series of studies instructed by the medical team responsible for the patient. Regarding the research device, once the device has been positioned according to the established recommendations, 3 consecutive acquisitions will be taken in the same
session with both devices.
Image acquisition and confidentiality measures (Phase 0-NS)
Transfontanellar sonography will be performed using the standard and high frequency ultrasound equipment selected for the study. In both cases, the images will be transferred to a laptop. The examination preparation will not take more than 10 minutes; neither will the scanning time exceed 20 minutes per device. A guiding line will be used (rectangular digital line or frame superimposed on the ultrasound image to guide the operator's positioning). When the frame is completely over the space where the CSF is located, the image is ready to be transferred and stored on the disk. Three acquisitions will be performed with the frame inside the CSF for further measurement accuracy studies.
A new file will be created for each patient which will not contain any personal information
in accordance with the Law of Confidentiality, in compliance with Spanish legislation and the new
European Regulation 2016/679 of the European Parliament and of the Council, dated 27 April 2016. The name of the file will be a code so that it is not possible to link the information to the patient. The link between the patient's personal and clinical data and the measurements obtained from the ultrasound data and any images of interest will be kept in a password-protected held by the principal investigator,
Ultrasound data processing
Structural and geometric measurements: The different layers that make up the fontanelle (skin, dura mater, arachnoid, CSF, pia mater) will be classified by an imaging expert. Then, the images will be used to take manual measurements of the layers using visualisation software (for example, ImageJ). The thickness of the different layers at the tissue interfaces is defined by an orthogonal digital line. This information is used to calculate the tissue attenuation.
Physiological measurements: The raw data from the acquisition with the ultrasound system will be used to define the acoustic properties of the segmented layers. First, the echoes at the interfaces between layers will be identified. Second, the range of these echoes will be used to calculate the acoustic impedance and attenuation presented by each layer following the Baddour and Kolios models [10]. After this processing, differences in the echogenicity of the layers between subjects will be assessed.
Ultrasound system parameters
The gain parameters of the ultrasound system will be adjusted to obtain an optimal signal from the CSF. These parameters are saved together with the image data and may be reviewed for subsequent data analysis. Regardless of the settings established, the ultrasound system is limited in power output so that it will always comply with the safety limit regulations set by the EC and FDA for transfontanellar ultrasonography (94 mW/cm2)9.
- Phases 1 and 2:
Clinical procedure
Parents/guardians will be offered the opportunity to enter their child into the study and will be given the information and informed consent document, although this must not delay the performance of the lumbar puncture for the meningitis screening, which has been decided by the doctor in charge of the patient, as the CSF is immediately sent to the central laboratory for analysis. Nor must the performance of neuroimaging studies (conventional ultrasound, MRI) be delayed, if they are indicated.
The lumbar puncture procedure will follow the current hospital protocol. The CSF analysis will be carried out in the Emergency Laboratory (Central Services), in accordance with the hospital’s standard practice. The CSF cell count procedure is performed by optical microscopy using the Fuchs-Rosenthal chamber. The analytical objective of the laboratory is a variable interobserver of 5% and interobserver of 15% and 5%, for low cell count and (>30 cells/μL) for high, respectively.
The conventional neuroimaging procedure will follow the current hospital protocol, performing the series of studies instructed by the medical team responsible for the patient.
If the patient's entry into the study is accepted by parents/guardians and after signing the informed consent document, a member of the research team will perform the imaging tests with the design equipment through the anterior fontanelle. 3 consecutive acquisitions will be taken in the same session. The operators, both in the laboratory and in the acquisition of images, will remain blinded to the result of the complementary test, i.e. image and CSF cell count by the laboratory, respectively. The results obtained with both methods will be compared. CSF samples contaminated with blood or in which the white blood cell count cannot be corrected will be discarded.
In the event that after preliminary analysis of the results it is identified that the number of
patients with a negative meningitis diagnosis is much higher than the number of diagnosed patients, recruitment of patients with a confirmed diagnosis by LP may be performed. In this case, once the results of the LP are known, the patient can be recruited for the study and once the signed informed consent document has been obtained, the imaging test will be performed with Neosonics as described above, in the shortest possible time.
Image acquisition and confidentiality measures
Transfontanellar ultrasonography will be performed using the high-frequency ultrasound equipment selected for the study and the images will be transferred to a laptop computer. The examination preparation does not take more than 10 minutes; neither will the scanning time exceed 10- 20 minutes. In Phase 1, with the assistance of the computer and special software, the user can view the image obtained and is guided where to position the probe on the measurement area. Image acquisition at this stage is done in the research phase and once the strobe has been placed on the measurement area. The images will be stored in the equipment and later transferred for analysis. In Phase 2, when the system is automated, the algorithm will calculate the cell concentration in the selected CSF space and a message will trigger the mechanism indicating that the measurement is complete.
A new file will be created for each patient which will not contain any personal information
in accordance with the Law of Confidentiality, in compliance with Spanish legislation and the new
European Regulation 2016/679 of the European Parliament and of the Council, dated 27 April 2016. The name of the file will be a code so that it is not possible to link the information to the patient. The link between the patient's personal and clinical data and the measurements obtained from the ultrasound data and any images of interest will be kept in a password-protected held by the principal investigator,
Semi-automatic call counting algorithm
The images obtained will be used to perform a manual and automatic count (see section II. Hypothesis 1.) using an algorithm developed by the group and based on cell tracking algorithms found in optical microscopy imaging tools. The manual count will assess the efficiency of the automatic method in detecting cells in the image.
Prior to the execution of the algorithm, Machine Learning algorithms will be used to segment the tissues of the fontanelle automatically and label the tissues in order to identify the CSF. These algorithms would be defined and tested with the images acquired in Phase 0-NS.
b) description of the activities carried out by the sponsor’s representatives (excluding the
testing);
N/A
c) any known or predicted factors that may compromise the outcome of the clinical investigation or the interpretation of the results.
Factors include the characteristics of the subject during the qualification period, concomitant medication, the use of other medical devices, and subject-related factors such as age, gender, or background, and will be described in the DCB.
The use of Neosonics in the clinical trial does not involve any change in the patient's treatment or medical care that they may receive, as the management will depend solely on the results obtained from the LP, in accordance with standard clinical practice.
Likewise, the date and time of the LP, as well as the date and time of the analysis of the CSF sample and the time of acquisition with the research equipment will be recorded in the DCB, so that possible differences can be analysed and traced.
A.1.1 Monitoring plan
The Monitoring Plan is intended to detail, subject to acceptance by the study sponsor, the scope and nature of the monitoring procedure appropriate to the clinical investigation.
To ensure proper monitoring of the study, the monitor will conduct an initial visit to the Spanish centres, Mozambique and Rabat. In terms of monitoring, two follow-up visits will be made (face-to-face or by telephone as appropriate), during which the following will be checked:
a) the maintenance of and compliance with the CIP as well as international standards and regulatory requirements
b) that only authorised people are taking part in the clinical investigation,
c) Neosonics is being used in accordance with the CIP or the instructions for use. In the event that amendments to the product, method of use or CIP are required, it will be checked that the sponsor is notified;
d) the research site resources, the availability of investigators, and that the diagnostic methods say correct during the trial;
e) the principal investigator continues to have access to an adequate number of research subjects and products;
f) signed and dated informed consent documents have been obtained for each subject at the time of inclusion or prior to any procedures related to the clinical investigation being undertaken, except where urgent treatment is required (see point 13).
g) source documents and other records of the clinical investigation are accurate, complete, up to date, and appropriately stored and maintained;
h) the DCBs have been registered on time and are consistent with the source documents;
i) appropriate corrections, additions or deletions have been made to the DCBs, including the date and explanation if necessary, and that they show the initials of the principal investigator or authorised designee; the monitor should not make any corrections, additions, or deletions in the DCB.
j) all adverse events and product deficiencies are reported to the sponsor, and all serious adverse events and product deficiencies that could have left serious adverse product effects are reported to the sponsor without undue delay;
k) research products are properly stored and the traceability procedure is followed;
l) all other reports, notifications, applications, submissions and correspondence are maintained in the investigator's files and are accurate, complete, submitted on time, legible, dated, and identify the clinical investigation;
m) current laboratory standards, and sterilisation service authentications are current and up to date.
n) subject withdrawals are documented; the monitor should discuss this with the principal investigator or authorised designee;
o) non-compliance of the subject with the requirements detailed in the informed consent is documented; the monitor should discuss this with the principal investigator or authorised designee;
p) the principal investigator and the research team are informed and aware of all relevant documentary updates relating to the clinical investigation;
- In the event that a serious adverse incident is detected, the monitor will be responsible for
communicating with the Spanish Medicines Agency to report the event. In addition, they will work with the research team to find the cause of the event and to minimise the risk introducing regulatory measures if necessary.
In addition to the follow-up visits, a monitoring report will be produced after each phase which will
should detail:
- date, centre identification, name of the monitor and name of the principal investigator or other individuals contacted, and
- a summary of the aspects reviewed and their observation(s) as to whether outstanding prior actions were completed, as well as significant findings, facts, deviations, conclusions and recommended actions to ensure compliance.
A copy of this report will be given to the principal investigator.
In order to ensure the monitoring and control of all these points, the monitor will have access to a computer system that collects all the relevant patient information (diagnostic tests, courses, documentation, reports, informed consent documents etc.), as well as to the database.
The monitor will confirm their ethical use of this database, to only consult the data relating to the clinical trial in progress.
In addition, the monitor will have access to all documentation relevant to the clinical trial:
- Clinical investigation plan (CIP),
- Investigator’s Manual (IM)
- Patient’s informed consent document and patient information form (IC)
- Data collection books (DCB)
- Instructions for use (IFU)
- Clinical trial safety policy
- and any other written agreement on the clinical investigation (CI)
A.2 Statistical considerations
With regard to chapters A.5 and A.6, the description of and justification for:
a) the design, method and statistical analysis procedures;
For Phase 0, the different soft tissue layers above and below the fontanelle should be identified and labelled. Together with the echo amplitude data of the tissue interfaces and their thickness, the attenuation of each tissue will be calculated. From the pial layer, a region will be chosen where there is orthogonality between the tissue and an imaginary line connecting to the centre of the transducer. This region will always be of the same size and the average of the intensity values will be calculated. From the thickness and attenuation measurements, averages and variances will be calculated as preliminary descriptors of the variability of the measurements. In conjunction with these descriptors, statistical methods allowing intra- and inter-group comparison may be used, and data will be expressed as mean ± SD.
For Phase 0-NS, the analytical method and procedure described in Phase 0 will be followed.
For Phases 1 and 2 and in order to compare the meningitis detection capability between Neosonics and the standard diagnosis ROC (Receiver Operating Characteristic) curves will be used which show sensitivity as a function of false positives (complementary to specificity) for different cut-off points. In addition, paired-data tests (Mc Nemar) will be used to buy cell numbers between techniques and linear regression analysis will possibly be used to assess treatment efficacy by repeated non-invasive measurements.
With the specific objective (sensitivity to cellularity in CSF) in Phase 2 the association of measurements between the two methods will be represented in a scatter plot (see Hypothesis 2b). To assess the differences between measurements the Bland&Altman analysis will be used, in which the bias between the methods and the variability between pairs of measurements will be observed. The sample size is based on the fact that 95% of the measurements are within clinically acceptable limits of agreement (see A7.b). The average difference between methods will be analysed using either the t-student for paired data or the Wilcoxon signed-rank test, depending on whether the data follow a normal distribution or not (and maintain symmetry), respectively.
The CSF cell concentration will be obtained from the cell count provided by the hospital's
analysis department and will constitute the reference. To obtain a measurement of the ultrasound data concentration, 660 sequential acquisitions will be taken in 10 seconds, equivalent to 220 lines per 3 measurements. To achieve 95% confidence in the detection of the cell concentration with an error of 3 cells/μL (d) with respect to the actual concentration and with a measurement variability between acquisitions of 10 cells/μL (σ), the total number of cells (N) to be detected is 96 (N = σ2Z2).
2
d2
Based on in vitro experiments this number is easily achievable even at concentrations below 5 cells/μL.
b) the sample size
There are different methods to estimate the sample size of the study depending on the objective: (1) Diagnostic sensitivity and specificity of the equipment (primary objective) or (2) concordance in CSF cell count (secondary objective).
1) According to FDA guidelines [11, 12] and previous literature [13, 14], the sample size in Phase II has been calculated taking into account that Neosonics has a sensitivity of 95% (FN of 5%; TP of 95%), a specificity of 80% (TN of 80%; FP of 20%) compared to lumbar puncture. With these values and having a 95%CI (94.73%-101.27%), a sample size of 77 patients with meningitis (confirmed by
LP, cellularity above the diagnostic threshold) and 77 without meningitis is estimated. Taking into account 10% deviations (technical, protocol, or loss of follow-up), the final sample size with suspected meningitis should be ~ 170 patients.
2) In line with the second objective, Phase II is designed as a technological feasibility trial to determine the ability of Neosonics to count cellularity in CSF compared to manual or haemocytometer cell counting. In this context, one of the main variables to be taken into account is the cell concentration (cell/ μL); a variable with which will be compared with the differences in cell count between the agreed methods of Bland & Altman [Bland & Altman]. For this purpose, taking into account the diagnostic criterion of meningitis (20 cells/μL and 9 cells/μL for newborns and children aged 29-90 days, respectively [39-41]), a degree of agreement between methods of ±3 cells/μL has been considered acceptable. Therefore, it is essential that the CI (95%) of the counting differences do not exceed these limits of agreement. The CI depends on the variability between methods and is obtained from the calculated standard deviation between the two measurement methods (haemocytometer counting or manual counting). Given the variability observed in the preliminary data, the standard deviation difference is equal to 1,24 cells/μL. Therefore, with a target recruitment of 154 patients (considering the final sample size without deviations) the 95%CI of the difference between the cellularity measurements, lies between 2.09 to 2.77 cells/μL above the defined limit of agreement. If 10% deviations are added to this sample size (as in the previous sample size estimation), a final sample size of 170 patients is estimated.
Therefore, a sample size of ~170 patients will provide sufficient evidence to answer both objectives: (1) sensitivity and specificity of the device vs. LP and (2) concordance in terms of cell count.
Considering that the incidence of patients with meningitis is low in the European population and
a distribution of 50% cannot be estimated, to ensure the recruitment of 77 patients with a diagnosis of meningitis, it is proposed to recruit patients with a confirmed diagnosis of meningitis by LP if preliminary analysis of the results suggests this.
c) the level of significance and statistical strength of the clinical investigation;
A value of p=0.05 will be considered as statistical value and a strength of 80%.
d) the expected dropout rates;
1%
e) the acceptance/rejection criteria to be applied to the results of the clinical investigation;
The study has been designed to demonstrate that the device is a suitable diagnostic tool, aiming for a sensitivity of 95% (FN: 5%, TP: 95%) and a specificity of 80% (TN: 80%, FP: 20%). However, market surveys of opinion leaders place the average expected sensitivity at around 91% (with a range between 80-99%), which is lower than the value used to calculate the sample size.
If attention focusses on the second objective of the study, the current design also allows the assessment of the concordance between the results of the cell count between the LP and Neosonics (estimated to be 3 cells/μL), however, the impact of this error in the cell count will be different if we are far from or close to the diagnostic threshold.
Therefore, if the results obtained at the end of the test are below these values in terms of sensitivity but the concordance of the results between cell counts is acceptable from the point of view of the diagnostic threshold for meningitis and is similar to the current method, the equipment is considered to be
a suitable diagnostic tool. Therefore, the need for re-analysis of the acquisitions obtained with the equipment will be assessed to improve the counting algorithms or to replicate the study with a larger sample size if necessary.
f) The provision of an interim analysis, where appropriate;
As discussed above, in Phases 1 and 2 it is envisaged that at least one interim analysis of the results will be carried out, to assess the quality of the results obtained and the rate and distribution of the patients recruited.
g) criteria for discontinuation of the clinical investigation based on statistical results.
Not applicable.
h) procedures for reporting any deviation from the original statistical plan; Any deviation from the original investigation plan will be communicated to the Spanish Agency of Medicines and Medical Products (AEMPS, abbreviated in Spanish);
Any observed deviations will be recorded in the Investigation Database Deviation Protocol
(IPDD-01PIC-UNITED) in accordance with the NBS-IDP.
i) subgroup specification for the analysis;
The subgroups considered are defined in the study design.
j) the procedures that take into account all the data;
All variables collected in the study will be stored in a prospective collection database.
k) the processing of missing, unused or spurious data, including dropouts and withdrawals;
In Phase 1, patients with poor quality images may be replaced by others. A double analysis will be performed considering patients with any relevant missing variable and excluding any patient with any relevant missing variable.
l) exclusion of information specific to the hypothesis trial, if relevant,
N/A
m) in multicentre clinical investigations, the minimum and maximum number of subjects to be included at each centre.
Special rationale and sample size(s) may be applicable for early stage clinical investigation(s), for example, feasibility clinical investigation(s).
In Phase 0-NS, recruitment is expected to be 40 patients from HULP and HUQM and 20 patients from HSJD.
In Phase 1 patients will be included from the HULP, HUQM and HSJD centres. Recruitment of 8 patients from HSJD (5 negative and 3 positive patients) is expected. The remaining patients will be recruited mainly from HULP. The recruitment ratio from HUQM is expected to be lower.
The financial support for these two centres has been approved by the medical team.
Regarding Phase 2, taking into account that the incidence of meningitis is similar to the European level, although it may be slightly higher in Morocco, it is expected that up to 60 patients could be recruited from the state centres (HULP, HUQM and HSJD).
A.3 Data management
The IP of each centre will review the data collection booklet prospectively to ensure that the information is complete and valid, as well as to check adherence to the protocol. Only the IP of each centre and the monitor will have access to the patient's demographic or other personal information, which will be stored on a password-protected server (FTP server_ File Zilla).
The data obtained from the ultrasound equipment will be anonymised immediately at the time of collection according to the new European data protection regulation (EU 2016/679). A numerical code will be applied to name the files and anonymise data. The files will be transferred from the ultrasound equipment to an external disk and shared with NBS via password-protected encrypted protocols for subsequent data processing. The original informed consent documents will be stored under lock and key at each institution and/or digitised and uploaded to the patient's medical records. Electronic data collection from the participants will also be encrypted.
A weekly back-up of the database containing all the parameters described in the data collection
notebook will take place. A copy of the prospective collection database will be kept for up to 10 5 years after the end of the study and will be treated with the same degree of confidentiality as the rest of the data in the patients' medical records.
A.4 Amendments to the CIP
The IB, CIP, CRF, informed consent document, and other subject information, or other clinical investigation documents will be amended as necessary during the clinical investigation including a by including a justification statement with each amended section of a document.
Proposed amendments to the CIP should be agreed between the sponsor and the principal investigator.
Amendments to the CIP and to the subject’s informed consent document should be reported
to, or approved by, the EC and regulatory authorities, if required. The changes, version number and date of the amendments will be documented in accordance with UNE-EN ISO 14155:2012
A.5 Deviations from the clinical investigation plan
The investigator will not deviate from the CIP except:
- Upon justified request and approval by the Ethics Committee.
- In emergency circumstances, deviations from the CIP to protect the rights, safety, and welfare of human subjects may take place without prior approval by the sponsor and the Clinical Research Ethics Committee (CEIC, abbreviated in Spanish). Such deviations should be documented and reported to the Clinical Research Ethics Committee (CEIC, abbreviated in Spanish) and the Spanish Agency of Medicines and Medical Products (AEMPS, abbreviated in Spanish) as soon as possible.
NOTE: For non-substantive changes [e.g., minor logistical or administrative changes, change of phone numbers, renewal of insurance policy] that do not affect the rights, safety, and welfare of the
human subjects and are not related to the objectives or assessment criterion of the clinical investigation, a single notification to the Clinical Research Ethics Committee (CEIC, abbreviated in Spanish) and, where appropriate, the regulatory authorities may be sufficient.
The requirements and procedures for recording, reporting and analysing deviations from the CIP will be in accordance with UNE EN ISO/IEC 17025-1 and performed as soon as possible.
A.6 Product recording
Access to research products will be controlled and will only be used in clinical research and in accordance with the CIP.
The manufacturer will maintain records to document the physical location of all research products from shipment to the research centres until their return or disposal.
The principal investigator or an authorised designee will maintain the records documenting receipt, use, return, and disposal of the research products. The records will include:
a) date of receipt;
b) identification of each research product (batch number/unique serial code number);
c) expiry date, if applicable;
d) date(s) of use;
e) date on which the research product was withdrawn, if applicable;
f) the return date of research products that have not been used, have expired or are faulty, if applicable.
Meanwhile, NBS as manufacturer will store the documentation of all devices and consumables supplied to the centres and related to the customer relationship (delivery notes,
returns, ...) as well as any documentation associated with their manufacture.
A.7 Compliance declarations
The Declaration of Compliance is attached to the documentation to be submitted to the Spanish AEMPS, in which the following requirements are detailed:
a) that the clinical investigation must be carried out in accordance with the ethical principles to be complied with in the Declaration of Helsinki
b) international standards and any regional or national regulations, as appropriate;
c) that clinical investigation using the device for the study will not commence until approval/a favourable decision has been obtained from the AEMPS;
d) That any additional requirement of the Clinical Research Ethics Committee (CEIC, abbreviated in Spanish) or the AEMPS has been met;
e) The CI subjects are entitled to insurance, as indicated in the informed consent document
A.8 Informed consent procedure
Patients who are candidates for the study may come from the Emergency Department or from the paediatric and neonatal hospitalisation units of these centres.
The Principal Investigator as well as the doctors participating in the study, will be responsible for informing the patient's parents or guardians about the inclusion in the clinical study during the consultation. The doctor will inform the family about the potential benefits and risks of the device and will resolve any of the patient's doubts. This will be recorded in the patient’s records. Upon approval by the patient and at the request of the family, the doctor will provide the patient with a copy of the informed consent document.
Once all doubts have been resolved, the informed consent document will be signed by the person in charge and the researcher.
- When it is not possible to obtain the subject's prior informed consent, and their legally authorised representative is not available, the subject may still be included in the study if their treatment is clearly likely to improve their health. In this case, the subject or the subject's legally authorised representative should be informed as soon as possible; by supplying them with all the required information.
This document will be incorporated into the hospital's documentation system to constitute its viability.
Appendices 8-10 contain the current revisions of the information and informed consent pages for each phase of the study.
A.9 Adverse events, serious adverse events and product deficiencies
a) definitions of adverse events, serious adverse events and product deficiencies:
Section A.14 follows that described in MDCG 2020-10/1 entitled “Safety reporting in clinical investigations of medical devices under the Regulation (EU) 2017/745”.
- Adverse event (AA): Any untoward medical incident, unanticipated illness or injury, or adverse clinical sign, including an abnormal analytical result, that occurs in subjects, users or other people within a clinical investigation, whether or not related to the research device;
- Serious adverse event (SAE): All adverse events that has any of the following results:
a) death,
b) serious deterioration in the subject's health resulting in: (i) life-threatening illness or injury, (ii) permanent deterioration of the subject's health, of a bodily structure, iii) hospitalisation or prolonged hospitalisation of the patient, (iv) medical or surgical intervention to prevent a potentially life-threatening illness or injury or permanent deterioration of a bodily function or bodily structure, (v) chronic illness,
c) foetal distress, stillbirth or a physical or mental impairment or congenital malformation;
- Product deficiencies; any inadequacy in the identity, quality, durability, reliability, safety or efficacy of a research product, including malfunction, user error or a lack of information provided by the manufacturer;
a) Procedure for notification of events
By the sponsor to the Competent Authority:
Currently, due to the transition period to the new regulation and the inactivity of some Eudamed modules, the AE notification procedure may vary depending on development status of the platforms.
In accordance with the MDCG 2020-10, the following table summarises the formats to be used
for the communication of AEs
By the investigator to the Sponsor:
The investigator should use the NBS-generated event reporting format, which collects critical data
which collects the critical data needed for future reporting.
a) Reportable events
Once all the information has been collected, in accordance with Art. 80 of the MDR, the investigator should report the event if:
a) it is an adverse event which may have a possible causal effect on the research device, or the clinical investigation plan
b) any device deficiency that could have resulted in an adverse event/serious adverse event.
If appropriate action not been taken, or circumstances had been less fortunate;
a) c) any new findings in relation to any event referred to in points a) and b).
b) the time period within which the principal investigator is required to report all adverse events and product deficiencies to the sponsor and, where appropriate, to the EC and the regulatory authority;
Reporting period following identification of an incident by the sponsor to the Competent Authority.
· When the event signals an imminent risk of death, serious injury or serious illness and requires prompt corrective action for other patients/subjects, users or other persons or a new finding: Immediately, but no later than 2 calendar days after the sponsor becomes aware of a new reportable event or new information regarding a new event already reported.
This includes events that are of a significant and unexpected nature, so as to become a potential public health hazard of concern. This also includes the possibility that multiple deaths may occur in short intervals.
These concerns may be identified by the Competent Authority or the manufacturer.
· Any other reportable event as described in section A.14.a or a new finding/update on the event: Immediately, but no later than 7 days after the date the sponsor is made aware of the new
reportable event or new information in relation to one already reported.
Reporting period following identification of an incident by the investigator to the Sponsor:
In the case of an event, the investigator should send a report of what happened using the NBS incident report . The time frame for reporting should be as soon as possible, and no later than 3 days after the research centre study personnel become aware of the event.
c) Causality assessment
The relationship between the use of the medical device (including the medical-surgical procedure) and the occurrence of each adverse event will be assessed and categorised.
During the causality assessment exercise, clinical judgement will be used and relevant documents, such as the investigator's file, the Clinical Investigation Plan, or the Risk Analysis in which the expected risks are identified should be consulted.
The presence of confounding factors, such as concomitant medication/treatment, the patient's medical history, or other diseases should also be considered.
These considerations will be taken into account in the analysis of serious and non-serious adverse events.
For the purpose of consistent reporting each AE will be classified according to four different levels of causality:
1. Unrelated
2. Possible
3. Probable
4. Causal relationship
These 4 situations are described in the MDGC 2020-10-01.
During the investigation, the sponsor together with the investigator should identify which event
is related to the product itself and not to other events or situations.
d) List of anticipated adverse events and expected adverse effects of the product, together with their incidence, mitigation or possible handling;
No potential adverse effects have been identified in the use of the device.
e) Emergency contact information for reporting serious adverse events and product serious adverse effects;
The details for AE reporting to the Competent Authority, until Eudamed is fully operational are below.