T-015-001 Clinical Evaluation Plan_YYYY_nnn

Scope

The Clinical Evaluation Plan defines methods for creating and updating the Clinical Evaluation Report. This plan is updated later by the post-market clinical follow-up, e.g., to include new search criteria for the literature search.

Medical device information

Manufacturer contact details

	Manufacturer data
Legal manufacturer name
Address
SRN
Person responsible for regulatory compliance
E-mail
Phone
Fax

Medical device description and specification

	Product information
Product or trade name
Model and type
Product version
General description of the device
Intended purpose
Intended users
Basic UDI-DI
Intended patient population
Medical condition(s)
Indications
Contraindications
Warnings
List and description of any variants and/or configurations coverred by this plan
List of any accessories covered by this plan
Certificate number (if available)
EMDN code(s)
Class
Classification rule
Clinical benefits

Identification of General Safety and Performance Requirements (GSPR)

The table below indicates the General Safety and Performance Requirements (GSPR) that required support from relevant clinical data as well as the risks related to each applicable GSPR. The identification of the applicable GSPR for PRODUCT is the foundation of the clinical development plan based on the MDR (Article 61 and Annex XIV Part A) and the Guidelines MEDDEV 2.7/1, MDCG 2020-1 and MDCG 2020-5.

General requirements	Applicable? (YES/NO)	Related hazard or hazardous situation risks
GSPR 1: The product shall achieve the intended performance and be suitable for its intended purpose. The product shall be safe and effective and shall not compromise the clinical condition or the safety of patients.
GSPR 2: Eliminate or reduce risks as far as possible without adversely affecting the benefit-risk ratio.
GSPR 3: Establish, implement, document and maintain a risk management system. Establish and document a risk management plan, identify and analyze the known and foreseeable hazards, estimate and evaluate the risks, eliminate or control the evaluated risks, and evaluate the impact of information from the production phase and post-market surveillance system and amend control measures if necessary.
GSPR 4: Manage risks so that the residual risk associated with each hazard as well as the overall residual risk is judged acceptable. eliminate or reduce risks as far as possible through safe design and manufacture, take protection measures in relation to risks that cannot be eliminated, provide information for safety and, when appropriate, training to users. Inform users of any residual risks.
GSPR 5: Eliminate or reduce risks related to use error.
GSPR 6: The characteristics and performance shall not be adversely affected during the lifetime of the product.
GSPR 7: The characteristics and performance shall not be adversely affected during transport and storage.
GSPR 8: All known and foreseeable risks shall be acceptable when weighed against the evaluated benefits to the patient and/or user.
GSPR 9: For the devices referred to in Annex XVI, the general safety requirements set out in Sections 1 and 8 shall be understood.
GSPR 10: Chemical, physical and biological properties.
GSPR 11: Infection and microbial contamination.
GSPR 12: Products incorporating a medicinal product absorbed by the human body.
GSPR 13: Products incorporating materials of biological origin.
GSPR 14: Construction of products and interaction with their environment.
GSPR 15: Products with a diagnostic or measuring function.
GSPR 16: Protection against radiation.
GSPR 17: Electronic programmable systems.
GSPR 18: Active products and products connected to them.
GSPR 19: Particular requirements for active implantable products.
GSPR 20: Protection against mechanical and thermal risks.
GSPR 21: Protection against risks posed by products supplying energy or substances.
GSPR 22: Protection against risks posed by medical products intended by the manufacturer for use by lay persons.
GSPR 23: General requirements regarding the information supplied by the manufacturer. Information on the label. Information on the packaging which maintains the sterile condition of a device (‘sterile packaging’). Information in the instructions for use.

Risk management

Methods to examine clinical safety

note

Include a specification of methods to be used for examination of qualitative and quantitative aspects of clinical safety with clear reference to the determination of residual risks and side-effects.

The methods used to evidence the medical device clinical safety are based on preclinical and clinical data analysis, and the acceptability of the benefit/risk ratio derived from this analysis.

Acceptability of the benefit-risk ratio

note

To include an indicative list and specification of parameters to be used to determine, based on the state of the art in medicine, the acceptability of the benefit-risk ratio for the various indications and for the intended purpose or purposes of the device.

The risk/benefit acceptability is based on the analysis of the possible risks of the product in relation to its benefits.

Once per XXX, the conclusions extracted from the preclinical and clinical data analysis will be used to confirm the benefit/risk ratio of the device. This analysis will be drafted in the T-015-002 Preclinical and clinical evaluation record.

The parameters used to determine, based on the state of the art, the global acceptability of the benefit/risk ratio for the intended purpose of the device are:

• No adverse effects should be found in the preclinical data evaluation.
• Current literature should support XXX and should evidence XXX.
• Current literature should also show the feasibility of XXX in comparison with current alternatives and solutions. The advantages of XXX should be clear.
• No significant risks should be identified in relation to XXX.
• PRODUCT’s positive impact should be strongly evidenced on XXX.
• The use of PRODUCT, as a XXX, should be proven necessary due to its multiple advantages. Based on PRODUCT’s characteristics, the device should not have side-effects specifically related to its use and should have a high benefit/risk ratio.

Benefit-risk issues relating to specific components

note

To include an indication how benefit-risk issues relating to specific components such as use of pharmaceutical, non- viable animal or human tissues, are to be addressed.

Clinical development plan

As required by the MDR 2017/745, we continuously generate, collect, analyse and assess the clinical data related to PRODUCT in order to verify the safety and performance, evaluate the undesirable side-effects and the acceptability of the benefit-risk ratio throughout the device’s life cycle. We plan, conduct and document a clinical evaluation in accordance with the requirements established in the MDR (Article 61 and Annex XIV Part A) and following the Guidelines MEDDEV 2.7/1, MDCG 2020-1 and MDCG 2020-5.

Data identification and selection

Sufficient amount and quality of data shall be identified and analyzed to build relevant evidence that allows performing a non-biased and objective assessment of whether the device under evaluation is safe and achieves the intended clinical benefits, when used as intended by the manufacturer. This is performed through:

• Analysis of preclinical data to identify:
  • Applicable and/or harmonized standards, according to the Technical File.
  • Related and/or governmental publications that may be observed in relation to the product.
  • Similar devices that provide data related to similar features, previous experience, and similar:
    • Intended use.
    • Principles of operation (safety & performance).
    • Functional elements.
  • State of the art publications about the related medical fields, medical conditions, technology and available alternative treatments.
• Analysis of clinical data relating to the safety, performance, design characteristics and intended purpose of the device under evaluation and/or an equivalent device:
  • Clinical investigation(s) of PRODUCT performed by the manufacturer.
  • Clinical investigation(s) or other studies reported in scientific and clinical literature, of a device for which equivalence to PRODUCT can be demonstrated.
  • Reports published in peer reviewed scientific and clinical literature on other clinical experience of either PRODUCT or a device for which equivalence to PRODUCT can be demonstrated.
  • Clinically relevant information coming from post-market surveillance, in particular the post-market clinical follow-up.

Responsible evaluators

The process of data identification and selection is developed and executed by professionals with expertise in information retrieval and understanding of the scope of the clinical evaluation set out by us. More details about the clinical team can be found below.

Data sources

The evaluation of data is based on a critical and analytical assessment of the available literature. The different sources utilized are:

• Preclinical data:
  • National and international institutions and medical devices regulatory bodies webs:
    • https://www.aemps.gob.es/
    • http://imdrf.org/safety/safety.asp
    • https://www.medtecheurope.org/
    • https://ec.europa.eu/growth/single-market/european-standards/harmonised-standards/medical-devices_en
    • https://ec.europa.eu/info/policies/public-health_en
    • https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/search.cfm
    • https://www.cisa.gov/cybersecurity
    • https://www.enisa.europa.eu/
    • https://www.nbog.eu/
  • Other manufacturers’ similar devices websites.
  • State of the art publications in renowned journal databases.
• Information generated by the manufacturer.
• Clinical data:
  • Renowned journal databases to support scientific validity:
    • https://pubmed.ncbi.nlm.nih.gov/
    • https://onlinelibrary.wiley.com/
    • https://link.springer.com/
    • https://www.sciencedirect.com/
    • https://scholar.google.es/
  • Clinical trials registry platforms to identify relevant investigational studies:
    • https://www.who.int/clinical-trials-registry-platform/the-ictrp-search-portal
    • https://clinicaltrials.gov/

Search filters

When using the search tool of specific websites or when searching in journal databases, at least the first NUMBER results are considered for their further evaluation. If the same scientific publication appears under different search characteristics, the repeated source is ignored and the following source is analysed instead. The scientific and clinical publications are already sorted out by relevance. Moreover, a time filter (last XX years) is applied in order to ensure that the most recent information is evaluated. Relevant citations referenced in the scientific and clinical literature already selected from the previous sources might also be considered for evaluation.

Research questions and keywords

The technical documentation of PRODUCT as well as the state of the art is used to develop the clinical research questions and keywords. The method PICO is chosen to help breaking down into four components the research questions. These identify the key problem of the patient, what treatment or tests are available for the patient, what alternative treatment or tests are being considered (if any) and what is the desired outcome to promote or avoid.

• P = Patient Population: it describes the most important characteristics of the patient. This may include the primary problem, disease, or co-existing conditions.
• I = Intervention, prognostic factor or exposure: it describes the main intervention, prognostic factor, or exposure.
• C = Comparator: it describes the main alternative to compare with the intervention. This can be different devices, tests or placebo. Sometimes the clinical question may not always have a specific comparison.
• O = Outcomes: it describes performance and safety a) What intervention wants to accomplish, measure, improve or affect. This can be to relieve or eliminate the symptoms or reduce the number of adverse events. b) Currently known risks or evidence on safety of the intervention or comparators.

Database search steps

The defined research keywords are used and the search filters are applied in the clinical data sources previously specified to retrieve relevant information allowing a systematic assessment of the available literature.

Step 1: Use PICO to formulate the search strategy.

		Selectet terms
# 1	Patient population
# 2	Intervention
# 3	Comparator
# 4	Outcomes

Description

Patient population AND Intervention AND Comparator AND Outcomes (Performance OR Safety)

Scheme

# 1 AND # 2 AND # 3 AND # 4

Search

note

Describe de combination of terms used for the search

Step 2: Search parameters.

Randomized Control Trials (RCTs) are often considered the gold standard and represents the cornerstone of Evidence-Based Medicine (EBM) due to the rigorous methodology used. RCTs allow avoidance of bias related to confounding factors (through a control group), selection bias (through randomization) and interpretation bias (through double blinding). Moreover, they elementary aspects of the scientific report are included such as adequate statistical methods and controls. Likewise, meta-analysis studies provide high evidence, and clinical trials are considered to report high-quality data. Therefore, the search parameters are:

• Type of trials: randomized controlled trials, meta-analysis and clinical trials.
• Publication time: last XX years.
• Species: humans.
• Number of publications: first NUMBER results of the first page.

Additionally it is required to look at search details to look for contraindications and adverse events reported, meaning that "contraindication" OR "adverse event" should be considered in the search parameters established.

Device equivalence

As described at the corresponding Device equivalence section of the GP-015 Clinical evaluation procedure, the equivalence table from the Guideline MDCG 2020-5 is used to identify the supporting data to demonstrate device equivalence. We place emphasis on the differences between PRODUCT and a marketed device rather than the similarities. In line with the MDR 2017/745 requirements, we consider the following characteristics to claim device equivalence:

1. Technical Characteristics (add a separate row for each of the assessed characteristics)	Device 1 (under clinical evaluation) Description of characteristics and reference to specifying documents	Device 2 (marketed device) Description of characteristics and reference to specifying documents	Identified differences or conclusion that there are no differences in the characteristic
Device is of similar design			1.1
Used under similar conditions of use			1.2
Similar specifications and properties including software algorithms			1.3
Uses similar deployment methods where relevant			1.4
Has similar principles of operation and critical performance requirements			1.5

Scientific justification why there would be no clinically significant difference in the safety and clinical performance of the device, OR a description of the impact on safety and or clinical performance (use one row for each of the identified differences in characteristics, and add references to documentation as applicable)	Clinically significant difference Yes / No
1.1
1.2

2. Biological Characteristics (add a separate row for each of the assessed characteristics)	Device 1 (under clinical evaluation) Description of characteristics and reference to specifying documents	Device 2 (marketed device) Description of characteristics and reference to specifying documents	Identified differences or conclusion that there are no differences in the characteristic
Uses the same materials or substances in contact with the same human tissues or body fluids			(The characteristic must be the same for the demonstration of equivalence) 2.1

Scientific justification why there would be no clinically significant difference in the safety and clinical performance of the device, OR a description of the impact on safety and or clinical performance (use one row for each of the identified differences in characteristics, and add references to documentation as applicable)	Clinically significant difference Yes / No
2.1

3. Clinical Characteristics (add a separate row for each of the assessed characteristics)	Device 1 (under clinical evaluation) Description of characteristics and reference to specifying documents	Device 2 (marketed device) Description of characteristics and reference to specifying documents	Identified differences or conclusion that there are no differences in the characteristic
Same clinical condition or purpose, including similar severity and stage of disease			3.1
Same site in the body			(The characteristic must be the same for the demonstration of equivalence) 3.2
Similar population, including as regards age, anatomy and physiology			3.3
Same kind of user			(The characteristic must be the same for the demonstration of equivalence) 3.4
Similar relevant critical performance in view of the expected clinical effect for a specific intended purpose			3.5

Scientific justification why there would be no clinically significant difference in the safety and clinical performance of the device, OR a description of the impact on safety and or clinical performance (use one row for each of the identified differences in characteristics, and add references to documentation as applicable)	Clinically significant difference Yes / No
3.1
3.2

Summary

In the circumstance that more than one non-significant difference is identified, provide a jsutification whether the sum of differences may affect the safety and clinical performance of the device.

For every single characteristic incorporated in the table, scientific justification must be elaborated to show that there is no clinically significant difference in the safety and performance of PRODUCT. For the identification of characteristics that may affect safety and for the assessment of equivalence regarding safety, we implement a risk-based approach. Both favorable and unfavorable data from PRODUCT as well as from the devices for which equivalence can be demonstrated must be identified. This data may come from:

• Scientific and clinical literature
• Common specifications
• Harmonized standards
• Other established technical specifications

All this data progresses to data appraisal and analysis in order to evaluate whether they are providing sufficient clinical evidence for the purpose of confirmation of conformity with the applicable GSPR.

Data appraisal

Once the data is identified in the current literature, the content is appraised to evaluate its suitability for establishing the safety and performance of the device. The manufacturer’s clinical team evaluates each piece of information taking into consideration three parameters: the methodological quality of work and scientific validity of the information, the relevance to the device and its intended use, and the contribution to the overall evaluation. Then, the clinical team accepts or rejects the data after applying the following weight-based system:

Data characteristics	Methodological quality Q	Relevance, R	Contribution, C	Weighted value, W (W=Q+R+C)	Appraisal data	Notes
Very relevant information in relation with the product and its intended use	30	30	30	W ≥ 70	Accepted	Pivotal data
Relevant information in relation with the product and its intended use	20	20	20	30 < W < 70	Accepted	Other data
Little relevant information in relation with the product and its intended use	10	10	10	W ≤ 30	Rejected	No contribution, rejected

These three indicators allow a systematic weighted evaluation:

• Methodological quality and scientific validity: examination of the methods used to generate and collect the data, and evaluate to which extent the observed outcomes are the result of the device/technology under evaluation or are due to confounding influences, bias, random error, inadequate disclosure of information or misinterpretation. The methodology is accepted when:
  • Data is extracted from RCTs (Randomized Clinical Trials), meta-analysis and clinical trials, from publications based on scientific evidence or from previous experience on the market.
  • The study design is adequate in terms of type, sample size, relevance of endpoints, randomization of patients, inclusion and exclusion criteria, stratification of patients, prognostic factors, follow-up, recording and reporting of serious adverse events, reliability of the methods used for quantifying outcomes, or procedures for retrieving complete information.
  • Data consists of an adequate number of observations that can confirm or refute the claims of the device under evaluation.
  • The methods for data processing and statistics are suitable.
  • It complies with Good Clinical Practice (GCP) according to EN ISO 14155 or equivalent standards.
  • The information is disclosed in an adequate manner, including summary, introduction, methods, results, discussion and conclusions.
• Relevance: examination of whether the data directly demonstrates adequate clinical performance and clinical safety of the device under evaluation, or whether the data serves as indirect supportive role. The information is relevant when:
  • It is representative of the device under evaluation, including data concerning the medical conditions that are managed with the device, other devices and medical alternatives, or equivalent devices.
  • The aspects covered are related to clinical safety and performance, claims, hazards and hazardous situations, management of risks, establishment of current knowledge and state of the art, determination and justification of the benefit/risk ratio and the acceptability of undesirable side-effects, or the determination of equivalence.
  • It is representative to the intended purpose or claims of the device under evaluation.
  • It is representative to the user group, patient population, medical indication, age group, gender, type and severity of the medical condition, or range of time.
• Contribution:
  • Device and/or related techniques intended use. The contribution of the analyzed data in relation to the device or techniques features and in relation to the intended use must be strong and clear.
  • Device and/or related techniques risk analysis. The contribution of the analyzed data in relation to the device or techniques risk analysis must be strong and clear, based on keywords definition.

On the other hand, the information is rejected when:

• There is a lack of information (only the abstract is available).
• The information comes from reviews, editorials or opinion papers.
• The study design and/or statistical methods are inadequate.
• The topic discussed is not related to the device and/or technology under evaluation.
• Bias or influencing factors are present (conclusions are inconsistent and can lead to misinterpretations).
• The information is inaccessible or repetitive.

Therefore, the information meeting the inclusion criteria and obtaining a value W > 30 after going through the weighted-based system will be accepted. On the contrary, the information with a value W ≤ 30 will be rejected. Proper justification for the decisions made, whether the information is accepted or rejected, must be given under the column named “DATA ANALYSIS AND CHARACTERISTICS EXTRACTION” of the T-015-002 Preclinical and clinical evaluation record.

PMS and PMCF data appraisal

The PMS data will be analyzed according to the General Procedure GP-007 Post-market surveillance. The same criterion, which is documented and structured in the Preclinical and clinical evaluation record (T-015-002 Preclinical and clinical evaluation record), will be applied to identify, and select preclinical and clinical data from the available literature.

Periodically and according to the PMS and PMCF plans, the clinical evidence as well as new data will be revised, appraised, and evaluated objectively every XXX to confirm the product’s intended use, the acceptable benefit/risk ratio and the accomplishment of the GSPRs.

Clinical investigations

If necessary, generate, through properly designed clinical investigations in accordance with the clinical development plan, any new or additional clinical data necessary to address outstanding issue.

We will carry out a clinical investigation study based on a Clinical Investigation Plan (T-015-004 Clinical Investigation Plan (CIP)) and a investigator brochure (T-015-005 Investigator's Brochure). The results will be documented in the Clinical Investigation Report (T-015-006 Clinical Investigation Report (CIR)).

As established in the Guideline MEDDEV 2.7/1, the clinical evaluation will identify aspects that need to be addressed systematically during post-market through the clinical investigations, as well as through the post-market surveillance and other post-market clinical follow-up studies. Aspects such as residual risks, any uncertainty or unanswered question, rare complications, uncertainties regarding long-term performance and/or safety under wide-spread use will be evaluated during post-market. Moreover, the planned clinical investigations will generate clinical evidence to support scientific validity and clinical performance, as stated in the Guideline MDCG 2020-1.

Proof of concept studies or other studies

note

If necessary, generate from other studies any new or additional clinical data necessary to address outstanding issue.

Proof of concept studies will generate clinical evidence to support scientific validity and technical performance, as indicated in the Guideline MDCG 2020-1.

Data analysis

The data accepted from the appraisal is analyzed in order to reach conclusions about the safety and clinical performance of the device including its clinical benefits and possible adverse events.

Data analysis is performed qualitatively, although some aspects can be analyzed quantitatively such as the number of incidents or serious adverse events. The appraised data is evaluated to find consistency of results related to performance and safety characteristics, risks and benefits to patients, users and other persons associated with the intended purpose of the device under evaluation, and the confirmation of usability.

Moreover, following the MDCG 2020-1, three key components are taken into consideration to analyze the clinical evidence of PRODUCT:

• Valid clinical association: the extent to which the software’s output, based on the inputs and algorithms selected, is associated with the targeted physiological state or clinical condition defined in the intended purpose.
  • Evidence generated through the previous literature research, proof of concept studies or manufacturer’s own clinical investigations/clinical performance studies.
• Technical performance: ability to accurately, reliably and precisely generate the intended output from the input data (principle of operation).
  • Evidence generated through verification and validation activities.
• Clinical performance: ability to yield clinically relevant output in accordance with the intended purpose. It assesses clinical safety, effectiveness and performance. It supports the demonstration of clinical benefits against foreseeable or known risks associated with the product (benefit/risk ratio acceptability) and compared with current processes, expected benefits and diagnostic/therapeutic/monitoring improvements.
  • Evidence generated through device equivalence in the target population and for the intended use, contraindications and undesirable effects, and through clinical investigations.

Lastly, it is analyzed the alignment and consistency between the current knowledge and state of the art, the clinical evaluation, the information materials supplied by the manufacturer, and the risk management documentation for the device under evaluation.

GAP analysis

We carry out a gap analysis to confirm whether the existing data are sufficient to verify that the device under evaluation is in conformity with the applicable GSPR. As a result of this gap analysis, the creation of new clinical data may be considered necessary. The manufacturer may conclude that additional data is required, for example, in the form of further clinical investigations studies.

Clinical Evaluation Report (CER)

A final T-015-003 Clinical Evaluation Report (CER) will be drafted. The essential content is:

• Summary
• Scope of the clinical evaluation
• Clinical background, current knowledge and state of the art
• Device under evaluation
• Analysis of the clinical data
• GAP analysis
• Conclusions
• Date of the next clinical evaluation
• Qualification of the responsible evaluators
• References

This report shall contain sufficient data and effective conclusions related to the safety and performance characteristics, the undesirable side-effects and the acceptability of the benefit-risk ratio of the device PRODUCT. Every XXX, said report (T-015-003 Clinical Evaluation Report (CER)) must be updated in relation to:

• Device intended use.
• Device characteristics.
• Safety and performance of the device. GSPR accomplishment and relationship.
• Users group, target population, and related medical fields and conditions.
• Side-effects and complications.
• Benefit/risk ratio.
• Applicable harmonized standards.

This update will be evidenced in the Preclinical and clinical evaluation record (T-015-002 Preclinical and clinical evaluation record).

Responsible evaluators

The qualifications and experience of the responsible evaluators are provided in the T-015-003 Clinical Evaluation Report (CER) to demonstrate that the responsible person(s) fulfil the requirements to evaluate the product clinical evaluation.

Name	Position	Company	Role in the evaluation	Declaration of interest	CV
			Editor	Yes	Yes
			Reviewer	Yes	Yes
			Approver	Yes	Yes

Record signature meaning

• Author: JD-004 Author name
• Review: JD-003 Reviewer name
• Approval: JD-005 Approver name

Template signature meaning

info

Delete this section when you create a new record from this template.

• Author: JD-004 María Diez
• Review: JD-005 Mr. Alfonso Medela
• Approval: JD-001 Ms. Andy Aguilar