The Clinical Evaluation Plan

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BSI Clinical Masterclass 2023

Session 1

 The Clinical Evaluation Plan

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What can you expect from the Clinical Masterclass 2023 series?

5 sessions focusing on the best practice for detailing your key

clinical evaluation documents including:

- The Clinical Evaluation Plan

- The Clinical Evaluation Report

- The Post Market Clinical Follow Up Plan

- The Post Market Clinical Follow Up Report

- The Summary of Safety and Clinical Performance

At the end of these sessions, we will be providing you with a specific best practice

guide for documenting your clinical evaluation.

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Documenting a Clinical

Evaluation Plan. (CEP)

Annex XIV Part A

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Topics covered in the Clinical Evaluation Plan Session:

• The MDR Requirements

• Documenting a Clinical Evaluation Plan

• State of the art and defining objectives

• Legacy Device Clinical Evaluation Plans

• Clinical Development Plans

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What is the purpose of a Clinical Evaluation Plan?

• The clinical evaluation plan is the foundation of the overall

clinical evaluation process and provides the roadmap for the

process.

• The clinical evaluation plan sets out the required steps to

define the scope, the regulatory pathway and necessary

steps to gather the required clinical data in a methodological

and systematic approach for the device under evaluation.

‘Behind every good clinical evaluation report is a perfect

clinical evaluation plan’

Establish

Identify

Appraise

Generate

Analyse

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The MDR Requirements of the Clinical Evaluation Plan

The MDR is prescriptive on the requirements of the CEP:

The CEP needs to identify

the general safety and

performance requirements

that require clinical data

The intended purpose of

the device

Intended target groups, clear

indications and contra-indications

Intended clinical benefits to patients

with relevant and specified clinical

outcome parameters

Methods used for qualitative and

quantitively aspects of clinical

safety to determine residual

risk/side effects

Parameters to be used to determine

State of the Art and acceptability of

benefit/risk for all indications

Benefit-risk issues relating to

specific components such as use

of pharmaceutical, non- viable

animal or human tissues

A clinical development plan….

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Where and how should I document my Clinical Evaluation Plan?

The Clinical

Evaluation

Plan

The clinical evaluation plan should be clearly highlighted/titled

within the technical documentation.

The plan can be presented either as a separate document or

as part of the clinical evaluation report. It is essential that

wherever the plan is documented the information is easily

identifiable, and the complete information is presented.

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Considerations when documenting the requirements.

Requirement: an identification of the general safety and performance requirements that require support from relevant

clinical data;

Devices shall achieve the performance intended by their manufacturer and shall be designed and manufactured in such a way that, during

normal conditions of use, they are suitable for their intended purpose. They shall be safe and effective and shall not compromise the

clinical condition or the safety of patients, or the safety and health of users or, where applicable, other persons, provided that any risks

which may be associated with their use constitute acceptable risks when weighed against the benefits to the patient and are compatible

with a high level of protection of health and safety, taking into account the generally acknowledged state of the art.

In eliminating or reducing risks related to use error, the manufacturer shall: (a) reduce as far as possible the risks related to the ergonomic

features of the device and the environment in which the device is intended to be used (design for patient safety), and (b) give

consideration to the technical knowledge, experience, education, training and use environment, where applicable, and the medical and

physical conditions of intended users (design for lay, professional, disabled or other users).

All known and foreseeable risks, and any undesirable side-effects, shall be minimised and be acceptable when weighed against the

evaluated benefits to the patient and/or user arising from the achieved performance of the device during normal conditions of use.

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Tips when documenting the GSPRs that will require clinical data.

- Document the GSPRs clearly with consideration of a table format to identify and where possible

explain the rationale for clinical data.

- This rationale will help understand the thought process and can assist the Notified Body in

determining whether the manufacturer has adequately identified all the applicable GSPRs that

require support from relevant clinical data for the device under assessment.

GSPR #

Requirement

Justification

14.5

Devices that are intended to be

operated together with other

devices or products shall be

designed and manufactured in

such a way that the interoperability

and compatibility are reliable and

safe.

The implantable device may be

used with other manufacturer

configurations. The is a lack of data

on longer term safety and

performance for these

combinations. Longer term clinical

data from investigations is required

to support claims of compatibility

with other devices for the lifetime.

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Tips when documenting the GSPRs that will require clinical data.

- Avoid generalised statements covering all GSPRs. – This potentially demonstrates that the

manufacturer is not applying an appropriate thought process to the device under evaluation.

- Understand the definition of Clinical Data – Article 2(48)

- Clinical data is not:

- Animal studies

- Toxicology testing

- Bench testing

- Expert opinion not related to clinical experience

- Compliance with CS or standards

- Clinical experience not published in peer-reviewed or scientific literature.

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Considerations when documenting the Intended Purpose.

Requirement: a specification of the intended purpose of the device;

Intended Purpose:

means the use for which a device is intended according to the data supplied by the manufacturer on the label, in

the instructions for use or in promotional or sales materials or statements and as specified by the manufacturer in

the ‘intended purpose’ clinical evaluation; (Article 2 (12))

In the clinical evaluation planning phase, it can be difficult to determine your intended purpose before your

collection of clinical data.

The intended purpose should be reflective of what you intend the device to achieve.

N.B: Intended purpose is synonymous with intended use (MDCG 2020-6 (1)) and is different to a device’s

indication.

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Considerations when documenting the Intended Purpose

Requirement: a specification of the intended purpose of the device;

The following information should be considered within the Intended purpose of the device:

✓ exact medical indications (if applicable)

✓ name of disease or condition/ clinical form, stage, severity/ symptoms or aspects to be

✓ treated, managed or diagnosed

✓ patient populations (adults / children / infants, other aspects)

✓ intended user (use by health care professional / lay person)

✓ organs / parts of the body / tissues or body fluids contacted by the device

✓ duration of use or contact with the body

✓ repeat applications, including any restrictions as to the number or duration of reapplications

✓ contact with mucosal membranes/ invasiveness/ implantation

✓ contraindications

✓ precautions required by the manufacturer

✓ single use / reusable

✓ other aspects

Example

- The Notified Body device is a permanent implant situated in either the right or left atrium, intended to treat the symptoms of

stage 4 heart failure and unstable angina, in adults over the age of 80 years, by improving coronary vasodilatation and

should only be implanted by those trained in interventional cardiology procedures with on-site surgical facilities.

- The device is contraindicated in patients with a systolic blood pressure <90mmHg. Patients should be suitable for

anticoagulation therapy to be eligible for implant.

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Tips when documenting the Intended Purpose within the CEP

• The intended purpose of the device should be

clear and unambiguous. Statements that are

vague or nebulous will invite scrutiny from the

Notified Body and so it is important to be

concise, specific and accurate.

• Ensure that, in all instances in which the

intended purpose is cited within the technical

documentation, the wording exactly matches

what is stated within the CEP.

• If during the clinical evaluation process, the

intended purpose changes then it is important to

document this and explain the rationale for

changing the intended purpose of the device.

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Considerations when documenting Intended Target groups

Requirement: — a clear specification of intended target groups with clear indications and contra-indications;

‘Patients’ ‘Users’

Gender, Age, Stage/severity

of disease, mobility

Healthcare professionals, nurses,

scientists, doctors, stage of

seniority, sub-specialities

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Indications

‘indication’, ‘indication for use’: refers to the clinical condition that is to be diagnosed, prevented, monitored, treated,

alleviated, compensated for, replaced, modified or controlled by the medical device. It should be distinguished from

‘intended purpose/intended use’, which describes the effect of a device. All devices have an intended purpose/intended use.

(MDCG 2020-6 Section 1)

When considering writing indications for the device, they should be thought of

as a checklist of eligible criteria that qualifies the patient to receive the device.

This means they should be specific and unambiguous.

Not all devices have an indication, but these are typically devices such as

sterilisers or disinfectants. Any absence of an indication should always be

strongly justified

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Poll Question

Q: Can the indications be identical

to the intended purpose?

• Yes

• No

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Poll Question

Q: Can the indications be identical

to the intended purpose?

• It Depends…

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Contraindications

Tell when a device should not be used (contraindications). Contraindications are

conditions under which the device should not be used because the risk of use

clearly outweighs any possible benefit. There may be persons in whom the device

should not be used because of their health status. For example, the device may be

contraindicated for pregnant women.

Contraindications typically are where this is clear evidence of known harm

to patients/users.

Warnings and precautions tell the reader about hazards, other than those that are

contraindications to device use. Warnings and precautions provide information on

how to avoid these hazards, i.e., sources of harm in the use of the device.

Guidance on Medical Device Patient Labelling; Final Guidance for Industry and FDA Reviewers Document issued on:

April 19, 2001

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Considerations when documenting the clinical benefit

Requirement: a detailed description of intended clinical benefits to patients with

relevant and specified clinical outcome parameters;

• The MDR requires that manufacturers describe the intended clinical benefits to patients in the CEP. In many cases,

these will align with the intended purpose statement.

• However, manufacturers can sometimes have difficulty expressing the clinical benefits as benefits afforded to the

patient. It is useful therefore to ask the following questions:

• How does the use of the device improve the health of the patient?

• What is the positive outcome of using the device, from the perspective of the patient?

‘clinical benefit’ means the positive impact of a device on the health of an individual, expressed in terms of a

meaningful, measurable, patient-relevant clinical outcome(s), including outcome(s) related to diagnosis, or a positive

impact on patient management or public health; (Article 2(53))

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Considerations when documenting the clinical benefit

Further, the MDR expects that manufacturers specify the relevant outcome parameters that enable them to

demonstrate that these benefits are delivered by the device. It can be thought of in the following way:

If device x is going to have positive outcome y on the patient, what aspect of y can be measured to confirm that

the outcome is achieved?

By way of example, a relevant outcome parameter for an orthopaedic device could

be an improvement in mobility score reported at x weeks post-surgery.

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Tips when documenting the clinical benefits

✓ The intended target group may be specific in the case of some devices and broad in the case of others. In

either case, it is important that manufacturers demonstrate an awareness of the groups of patients that will

benefit from the use of the device.

✓ When appropriate the target population should also be clarified considering, gender, age, co-morbidities and

other clinical aspects of which the data reflects.

✓ Users of the device should also be defined. This should be accompanied with the expected education, grade

and experience of the users that can use the device safely as demonstrated by the clinical data.

Consideration should also be given when devices are to be used under certain supervision.

✓ Where appropriate, the specification should include details such as the grade/stage of disease that the device

is indicated for, as well as any limitations that apply. For example, there may be (sub)groups of patients for

which use of the device would not be appropriate and this should be clearly stated within the CEP.

✓ Where the use of a device by particular group(s) and/or circumstances is deemed hazardous, the

manufacturer is expected to include a list of contra-indications along with warnings and precautions.

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Tips when documenting the clinical benefits

✓ When clinical benefit scoring systems are to be used, where possible these should ideally be validated

national/international agreed scoring systems. E.g. WHOQOL

✓ For many devices, the relevant outcome parameters will be obvious. However, for some devices - for

example, those used for imaging patients for a variety of purposes - it may be challenging for manufacturers

to define relevant outcome parameters. In this case, other performance parameters may be indirectly related

to patient benefit. Where the clinical benefit is not directly afforded to the patient, manufacturers should

clearly state this and provide a justification as to why the specified clinical performance parameters were

selected.

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Considerations when documenting aspects of safety

Requirement: 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 MDR expects manufacturers to specify, within the CEP, the methods they will use to evaluate the risks posed by use

of the device. It is important, therefore, to describe in detail the methods by which information relating to the risks

posed by use of the device will be gathered and analysed – both qualitatively and quantitatively.

▪ This requirement is related to the risk assessment, which should include risks that are identified as part of the clinical

evaluation of the device. Manufacturers should include details of how they intend to identify clinical risks as part of the

clinical evaluation and should also make clear their intention to determine the residual risks (i.e., post-mitigation) and

side-effects associated with the device.

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Considerations when documenting the parameters based on State of the Art .

Requirement: 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;

‘state of the art’: IMDRF/GRRP WG/N47 provides the following definition:

Developed stage of current technical capability and/or accepted clinical practice in regard to products,

processes and patient management, based on the relevant consolidated findings of science, technology and

experience.

Note: The state-of-the-art embodies what is currently and generally accepted as good practice in technology

and medicine. The state-of-the-art does not necessarily imply the most technologically advanced solution. The

state-of-the-art described here is sometimes referred to as the “generally acknowledged state-of-the-art’

Reproduced from MDCG 2020-6 (1. Definitions)

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State of the Art & Defining Objectives

Understanding the safety and performance profile of similar devices from State of the Art allows the manufacturer to develop an acceptable safety

and performance profile for the device under evaluation. This allows the manufacturer to compare its data against those other technologies to

confirm its safety and performance is equal or better than those available devices and ultimately its right to have a position on the market.

State of the Art Results should drive the

Safety and Performance objectives for the

device under evaluation

Results of SoTA Search

Risk identified - Thrombosis at 12 months – 6-9%

Performance identified – Patency at 5 years – 82-86%

3 Stents identified from State-of-the-Art Search

Stent under Evaluation

Objectives for Device under Evaluation

Safety Objective - Thrombosis at 12 months – < 9%

Performance Objective – Patency at 5 years – >82%

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MDR 2017/745 Article 2 (23) – Safety Objectives

The term risk includes the words probability, so there is always a need for quantification.

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Safety Objectives

Safety Objectives should be quantified

according to;

1. magnitude, (extent, amount, intensity)

this should be measurable and patient

group specific

2. Probability based on patient

populations should be considered.

Statements to reflect general

population may not be appropriate.

3. Duration - Think quantity!

Outcomes of clinical evaluation activities the input for Risk

Management.

Clinical risks are identified through:

• literature reviews

• Clinical investigations,

• PMCF related activities

Outcomes of Risk Management Activities the input for clinical

evaluation.

Clinical risks are identified:

During development process from clinical experts

Relating to foreseeable misuse (or assessing questions of

EN ISO 14971 Annex C)

Post Market Surveillance Activities

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Safety Objectives.

The main task of the clinical evaluation activities is now to strengthen the confidence of these

assumptions through the targeted identification of clinical data e.g. search terms or safety

endpoints which relate to specific clinical risks.

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MDR 2017/745 – Measurable Objectives.

Clinical Performance

Objectives look at ‘clinical

benefit’ and here is the

expectation that clinical

benefit is measurable and

meaningful.

Article 2 (53)

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Performance Objectives

Performance objectives should be clinically meaningful:

• Positive impact on clinical outcomes such as reduced probability of

adverse events or improvement of impaired body function,

• Patients Quality of Life (freedom from symptoms). Considering international

recognized scoring systems

• Outcomes related to Diagnosis (Earlier detection, Sensitivity and specificity

of diagnosis)

• Positive impact from diagnostic devices on clinical outcomes,

(Pharmacological intervention sooner).

• Public Health Impact (Ability of a diagnostic tool to prevent spread of

disease).

• Valid Surrogate endpoints can be used if there is a validated predictor. (e.g.

measurements of biochemical markers)

Performance Objectives should be

quantified according to;

1. magnitude, (extent, amount intensity)

this should be measurable and patient

specific

2. Probability based on patient

populations should be considered.

Statements to reflect the general

population may not be appropriate.

(Think Meaningful!)

3. Duration - Think quantity!

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Considerations when documenting specific components

Requirement: 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; and

Some medical devices feature hazardous components such as pharmaceutical, viable animal or human tissues. Since the

action(s) of these may need to be considered separately from the overall device, the manufacturer should explain how

they intend to assess the benefits and risks posed by these components as part of the overall clinical evaluation of the

device. Where the long-term exposure of the drug or material in its particular application is not fully known, this may

also point to a requirement for follow-up studies within the PMCF Plan (Annex XIV, 6.1a)

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Clinical Evaluation Plans for

Legacy Device

MDCG 2020-6 Appendix A

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Expectations of clinical evaluation plans for legacy devices

There is no justification for an absence of a CEP

for a legacy device – remember the CEP is the

foundation of your clinical evaluation and this is a

continuous process.

MDCG 2020-6 Appendix II provides the minimum

information expected for legacy device CEP.

Remember this is for devices that have not had

design modifications or expansion of indications.

This list can form the titles for the various

sections of your CEP, allowing the notified body

to locate information easily and quickly.

Don’t forget the clinical development plan!

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Documenting a Clinical

Development Plan.

Annex XIV Part A (1) (a) Indent 8.

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The Requirement (MDR 2017/745)

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Clinical Development Plan in 1 Slide (Annex XIV Part A)

*Off label studies are not PMCF studies and are subject to the same scrutiny and processes

of the Competent Authority as non-CE marked investigations.

The clinical development plan

defines how you will collect

sufficient clinical data for later

clinical evaluation. It is the

first step of the overall clinical

evaluation plan.

The Clinical Development Plan

should indicate potential

acceptance criteria.

This may include exploratory

investigations, first-in-man

studies, feasibility and pilot

studies, to confirmatory

investigations; an outlook for

possible PMCF activities is

also possible at this stage.

CDP

List all investigations/studies

performed from pre-clinical to

post market studies, detailing

the expected outcomes of

these investigations.

If these outcomes are not

reached what decisions and

actions are required to fulfil

those unanswered questions.

This may also include

information where the

manufacturer intends to

perform clinical

investigations* ‘off-label’ to

expand the indications of the

medical device in the future.

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Documenting a Clinical

Development Plan for New

MDR Devices.

Annex XIV Part A (1) (a) Indent 8.

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Key Components of a CDP

Prospective Patients

Scientific Rationale for Development

Commercial Rationale for Development

Clinical Data (Emphasis on Clinical Investigations)

Strategic Planning

CDP

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Scientific Rationale for Development

Unmet Clinical Needs/Expansion of Clinical

Indications

Limitations of Current Therapies/Diagnostics

Drug/Device Interaction

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Commercial Rationale for Development

Unmet Market Need(s) – Unmet Clinical Need(s)

Market Size Assumption and Projections

International Considerations

Competitive Situation

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Clinical Investigations

Consider Compliance of CIP to ISO14155 Annex A & MDR Annex XV

Clearly Document within the CDP:

• Study design.

• Devices identified. – Think Accessories!!!

• Patient population.

• Patient numbers.

• Objectives and endpoints.

• Length of follow up and intervals.

• Study locations.

MDCG 2020-13 encourages NBs to review all this information. MDCG 2019-9 also provides a list of detailed information in relation to reporting clinical investigations.

Consider potential deviations.

The MDCG have published a

Clinical Investigations Reporting

Template (MDCG 2021-8)

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Strategic Planning

- Milestones

- Longer term plans (PMCF)

- Market Access (Controlled Roll Out?)

- No-go Criteria

- Risk assessment & Contingency Plans

- Regulatory Aspects

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Poll Question

Q: Is a Clinical Development Plan

Required for Legacy Devices?

• Yes

• No

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Poll Question

Q: Is a Clinical Development Plan

Required for Legacy Devices?

• Yes

• No

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Considerations

The Clinical Development Plan is a critical document for those wishing to gain consultation from the

Expert Panels as described in Article 61 (2) – Class III and Class IIb Rule 12 Administer or Remove

Medicinal Substances.

Consultation Process is likely to be available 2023 for a limited number of devices – Further

information is likely early 2023.

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Documenting a Clinical

Development Plan for

Legacy Devices.

Annex XIV Part A (1) (a) Indent 8.

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Legacy Devices and the CDP

ALL manufacturers are required to document a clinical

development plan to meet the requirements of MDR Annex XIV

Section 1a.

Premarket elements of the plan as described in the final indent of

MDR Annex XIV Section1a (first-in-man studies, feasibility and

pilot studies) are not generally relevant to legacy devices which

are unchanged in design or indications.

However, the context for the plan as described in indents 1-7 and

the basis for the PMCF as described in indent 8 of MDR Annex

XIV Section 1a are considered relevant and necessary for

demonstration of compliance to the MDR.

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Next Session Slide:

Next Session: Wednesday 25

January 2023

Clinical Evaluation Report Part I

How to document:

✓ Device Description

✓ Equivalence

✓ Similar Device Data

✓ Clinical Claims

✓ Literature Searches

✓ Updates and Competency

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https://www.bsigroup.com/en-GB/medical-devices/resources

Webinars White Papers and Articles

Brochures, Guides

and Documents

https://www.linkedin.com/showcase/bsi-medical-devices/

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