Dr Pete Wall Isca Healthcare Research CE2012 Birmingham, 20 th September 2012 © Isca Healthcare Research, 2012 Clinical Evaluation: what it is and how

Dr Pete WallIsca Healthcare Research

CE2012 Birmingham, 20th September 2012

© Isca Healthcare Research, 2012

Clinical Evaluation: what it is and

how should it be done

Context

© Isca Healthcare Research, 2012 CE2012 Birmingham, 20th September 2012

medical devices are distinguished from drugs by their mechanism of action

devices operate via physical or mechanical means not dependent on metabolism to achieve their primary mode of

action and effect

this fundamental difference has important implications for clinical trials involving medical devices, their validation and subsequent introduction into the market place

What is a clinical investigation ?


any systematic investigation of the safety and/or performance of a device in or on human beings, undertaken to generate clinical data intended to be used for the assessment of conformity of the device with the requirements of the directive

Why are clinical evaluations required ?


confirm, validate or supplement data from bench and/or animal testing

support novel design, new technology and/or new indications for use clinical portion of any medical device development plan should

always be considered in parallel with marketing goals provide data

for marketing authorisation to obtain coverage and reimbursement in the targeted markets support competitive claims

can be split into three categories, each fulfilling a specific functional role: pilot pivotal post-marketing

Objectives of a clinical investigation


verification, under normal conditions of use that device is designed, manufactured and packaged in such a way that it functions as described and achieve the performance intended as specified by the manufacturer

verification that device achieves the intended benefits to the patient as specified by the manufacturer

determination of any undesirable side-effects, under normal conditions of use, and assessment of whether they constitute acceptable risks when weighed against the intended device benefits

Fundamental differences - device and drug trials.…1


proof of efficacy is not a fundamental requirement for medical device registration - demonstration of safety and performance is the majority of devices in clinical use have no evidence for their efficacy those with demonstrated efficacy are usually more recent introductions to

the market or devices that have been comparatively tested in post-marketing clinical trials

evidence for safety and performance of medical devices is not restricted to carefully defined and well controlled clinical studies, but can come from a variety of sources e.g.: partially controlled studies studies and objective trials without matched control well documented case histories conducted by qualified experts reports of significant human experience with a marketed device



the standard for regulatory and marketing approval for medical devices differs from that of pharmaceuticals drugs frequently require multiple trials and replication of clinical findings devices frequently require a single pivotal study

the normal user of a medical device is a healthcare professional and therefore clinical outcomes measured in any study of a medical device are a function of the user as well as the interaction between device and patient a device always performs better in the hands of an experienced expert it is frequently impossible to blind users to the treatment intervention training in the use of any medical device used in a clinical study is a

fundamental component of any investigation of performance and the eventual marketing of the device post-registration



the design of well controlled prospective trials for medical devices presents unique challenges that differ widely from those faced in trials involving pharmaceutical compounds e.g. clinical outcomes in medical device trials are influenced not only by the

product under investigation and the patient, but also by the skill and discretion of the user, who is typically a healthcare professional, but may in some situations be the patient

the influence of the medical device user is a variable unique to medical device trials and is frequently the cause of the greatest degree of variability in the clinical outcome.

being aware of, and controlling for, the user influence on device performance is a critical consideration when designing a device clinical trial

Regulatory framework: EU MDDs


specify the ERs which must be met prior to any device being sold or used clinically devices must be designed so that they do not compromise the clinical

condition or safety of patients, safety and health of users devices must achieve the performance intended by the manufacturer any risks which may be associated with their use constitute acceptable risks

when weighed against the benefits

introduce controls covering safety, performance, specification, design, manufacture, labelling and packaging

specify requirements for pre-clinical assessment of clinical study investigation submissions

specify action(s) to be taken following any device related adverse event

specify a framework to ensure devices conform to the ERs

Essential Requirements


ER are mandatory and can be broken down into two groups: General requirements for safety and performance that apply to

all devices Specific technical requirements with regard to design and

manufacturing that may or may not apply depending on the nature of the device; e.g. requirement for electrical safety would not apply to a urinary catheter

only products complying with ER may be placed on the market and used and ER must be applied as a function of the hazards inherent to a given product

the need for clinical data in the CE marking process arises from general requirements for demonstrating safety and performance

Devices without the CE Mark


do not conform to the relevant ER in the Directives have not been demonstrated to be fit for intended purpose

and therefore

CANNOT be sold or marketed CANNOT be used to treat patients

unless they are part of a clinical investigation approved by the national Competent Authority and labelled accordingly

or have been approved by the national Competent Authority for

humanitarian use on a named patient basis

Device trials….1


pilot studies a.k.a. feasibility studies; usually confined to one clinical site, i.e. single centred,

and involve a limited number of patients designed to accomplish a number of objectives with a defined clinical testing programme

not usually designed as hypothesis testing studies, but to generate data in support of the design of a hypothesis testing trial

provide first opportunity to evaluate the role of the user in device performance

under clinical conditions and gather information on design considerations

pivotal studies pivotal studies provide objective evidence of the effectiveness of a medical device

via single or multiple clinical outcomes frequently the only clinical trial that many medical device manufacturers will

undertake a single well designed and implemented pivotal study can provide all the necessary

data needed for device registration

Device trials….2


post-marketing studies (two groups) mandated post approval studies (usually confined to Class II (US)

devices as a mandatory condition of PMA approval) post-market surveillance studies – these are undertaken by a

device manufacturer for a number of reasons: comparative studies with alternative or competing devices effectiveness claims expanded label claims

Exceptional Use


approval can be sought to supply non-complying devices on humanitarian grounds

guidance has been prepared by MHRA for clinicians and manufacturers to help clarify how, and under what circumstances they may make applications to the MHRA for the use of a non CE-marked device for an individual named patient in the interest of the protection of their health

UK clinical investigations....1


to CE mark any device, compliance with ERs has to be demonstrated

this will usually require provision of clinical data, via a critical evaluation of relevant scientific and clinical literature

covering safety performance, design characteristics and intended purpose to demonstrate (i) equivalence of the new device to the device data used and (ii) the data demonstrate ER compliance

OR a critical evaluation of the results of all clinical investigations made

with the new device OR a critical evaluation of the combined data from both of the above

sources

UK clinical investigations….2


a clinical trial WILL be required unless safety and performance can be adequately demonstrated by other means

the design of the trial must be such that: the performance of the device, as intended by the manufacturer,

can be verified any undesirable side effects that occur under normal conditions of

use can be identified and that an assessment can be made as to what, if any risks these side effects have when weighed against the intended performance of the device

user handling/preference trials should only be undertaken on CE marked devices UNLESS they form part of a safety assessment for CE marking

Stages of clinical evaluation (MEDDEV.2.7.1 Rev.3)


Practicalities: pre-study requirements


definition of research question(s) development of the protocol and associated study materials

e.g. IC, PIS, IVB, CRFs development and production of SAP qualification / selection of Investigator(s) and study site(s) budget; study contract; insurance approvals for the study (as required):

Competent Authority (ies) – MHRA (UK): all documentation REC: CIP, PIS; IC; IVB; Questionnaires; Advertising NHS R&D: CIP; PIS; IC; contract

preparation of TMFs (Sponsor and Investigator(s)) recruitment plan monitoring plan data management

DMP: database design, test & validation, data entry etc., Investigator Meeting (incl. device training)

Clinical investigation plan (CIP)aka the protocol….1


contents: introduction identification: i.e. title; reference number; version number; date;

summary of revision history to include all amendments; page numbers with reference and revision details on all pages, registration number(s)

name and address of study sponsor details of Investigator(s) and Site(s) synopsis details of investigational device justification for design of study risks and benefits of investigational device and study objectives and hypotheses of study study design, including: type of study; endpoints; comparators;

subjects; recruitment; duration of involvement; procedures; monitoring plan

Clinical investigation plan (CIP) aka the protocol….2


continued: statistical considerations data management amendments to protocol deviations from protocol device accountability statement(s) of compliance (i.e. Declaration of Helsinki, ISO, GCP

and regional/national requirements, insurance) consent process adverse events and safety reporting reporting early termination publication policy bibliography

Model Clinical Investigation Agreement


a model Clinical Investigation Agreement (mCIA) which is designed to be used without modification for company-sponsored commercial research involving medical devices in patients in hospitals throughout the NHS was launched in November 2008

versions of the agreement for use throughout the UK and guidance notes are all available on the UK Clinical Research Collaboration (UKCRC) website http://www.ukcrc.org/

The application process


made via the Integrated Research Application System (IRAS) www.myresearchproject.org.uk

IRAS is a UK-wide system that streamlines the process for applying for permissions and approvals to conduct health and social care research, including clinical investigations of medical devices CA, REC and NHS R&D

PCA1 and PCA2 forms Sterilisation Pro-Forma print and sign before making submission to MHRA

Fees


REC no fee for review (NRES), but some hospitals may charge

NHS R&D fees vary

MHRAClass I, IIa, or IIb other than implantable or long-term invasive

£3,020 (£2,120)

Class IIb implantable or long-term invasive, Class III, and active implantable £4,240 (£2,770)

MHRA submission documentation….1


all documentation must be in English – if any part of supporting information is in another language a translation must be provided plus an original copy in original language

signed statement confirming compliance with ERs other than those being evaluated in trial

signed statement indicating whether or not device contains as an integral part a substance or human blood derivative

signed statement indicating whether or not device utilises tissues of animal origin

sterilisation validation (as appropriate) signed copies of PCA1 and PCA2 forms



General Information date; contact details; submission status; other Member States

involvement; NB approvals and certifications Device details

device name; model - name and number; manufacturer; design drawings; circuit diagrams; test certificates; biocompatibility; materials data sheets; sterilisation methodology and validation; pre-clinical data; risk analysis; ER checklist; Standards listing; IFUs; photographs; software (plus separate risk analysis); classification; labelling; User Manual; packaging

Other CIP (signed); PIS; IC; CRFs; IVB; adverse event form; insurance

certificate; clinical literature review ; Investigator CVs REC and local NHS R&D approvals



1x hardcopy of the full submission and 8x rewritable CD-ROM’s are required printed and collated with all pages in their correct numbered sequence,

including reprints, diagrams, tables and other data the method of reproduction used must allow for legible presentation of the

text and any relevant drawings with their captions CD-ROMS - documents must be identical to those in printed copy and

arranged on the CD in such a way that they can be easily identified by title alone (it is recommended that each CD includes a document index and all documents are appropriately named)

the documentation should be clearly labelled ‘Documentation Only' and sent by recorded delivery

trial notifications will only be accepted by the MHRA once the signed forms, necessary supporting documentation and the appropriate fee have been received

Ethics Committees


the UK Competent Authority does not accept approvals from independent ethics committees

manufacturers should seek the opinion of a National Research Ethics Service (NRES) (or equivalent services in Scotland, Wales and Northern Ireland) appointed ethics committee in all cases unless they can demonstrate a reason why an NRES (or equivalent) appointed committees would not assess their clinical investigation

in such cases the manufacturer will need to demonstrate that any independent ethics committee appointed was constituted in line with NRES guidelines

REC submission documentation


REC submission letter REC checklist IRAS submitted REC form IRAS exported REC form CIP (signed) PIS IC IVB IFU GP letter insurance certificate Chief Investigator CV and GCP certification ER compliance letter

NHS R&D submission documentation


NHS R&D submission letter & NHS data protection number copies of MHRA submission letter and PCA1, PCA2 forms mCIA – applicable national version incl. budget NHS SSI form generated via IRAS NHS R&D form generated via IRAS CIP (signed) PIS IC IVB IFU GP letter insurance certificate Chief Investigator CV and GCP certification ER compliance letter

Review process


notice of receipt of application MHRA reference Number starting date for 60 day clock

at least 2 reviewers (14d) further information may be requested

notification via email and letter clock will not stop

decision “Objection“ - study cannot proceed; MHRA notifies other EU CAs and

Commission (re-submission may be made once reason for objection has been addressed)

“No Objection” – study may start when ALL approvals (MHRA, REC, local NHS R&D) in place

Managing the trial


CRO or in-house in-use training is essential for device trials GCP and ICH requirements Helsinki Declaration regular site monitoring

protocol compliance; accuracy and integrity of trial data; source document verification; rights and wellbeing of participants; study supplies reconciliation; AE and SAE reporting and follow-up

data management data query resolution Investigator and site responsibilities post-trial

Practicalities: study management


study initiation first patient in monitoring visits and reports, including safety reporting last patient out (completion of last patient, incl. all follow up) data management

data entry from CRFs and data query resolution database cleaning→database lock→analysis (according to SAP) statistical analysis report, review and sign-off

study report preparation, review and sign-off site(s) close out notification to REC and MHRA

safety report (12m); study completion; copy of final study report archiving of all study documentation(15y minimum)

Amendments to trial


any and all proposed changes to an approved trial, e.g. device, Investigator, site, safety information, MUST be notified in writing to MHRA (non-CE) and REC and not implemented until written approval is received from ALL authorities

requests for review and approval of amendments must include: MHRA trial reference number; proposed change(s) and their rationale;

signed statement from Manufacturer confirming that the proposed changes do not predictable increase risk to patient, user or third parties

confirmation that amendment has been submitted to REC and NHS R&D

Adverse Events


Manufacturers are required to report fully to the MHRA all adverse events occurring in the UK:

a serious adverse event shall mean any adverse event, related to the device intended for clinical investigation, to a comparator or the investigation procedure, consisting in an untoward medical occurrence, unintended disease or injury or any untoward clinical signs, including abnormal laboratory findings, in subjects to a clinical investigation, users or other persons, that• led to death• or led to a serious deterioration in health that either

• resulted in a life-threatening illness or injury• resulted in a permanent impairment of a body structure or a body function, or• required in-patient hospitalisation or prolongation of existing hospitalisation, or• resulted in medical or surgical intervention to prevent life-threatening illness or

injury or permanent impairment to a body structure or function,• or led to foetal distress, foetal death or a congenital abnormality or birth defect

Post-marketing clinical follow up (PMCF)….1


PCMF continuous process to collect and evaluate clinical data, gathered

systematically in the post-market phase, concerning the assessment of long term safety and performance of a device

undertaken in line with a PCMF plan if PCMF not deemed necessary or appropriate, documented justification

is required PCMF plan should contain documented methods and procedures to

proactively collect clinical data from actual use in human of a CE marked device within the intended purpose confirm safety and performance throughout expected lifetime monitor identified side effects and contra-indications identify and analyse emergent risks using factual evidence assure continued acceptability of benefit/risk ratio

Post-marketing clinical follow up (PMCF)….2


PCMF plan detail methods and procedures e.g. clinical data, complaints, user

feedback, literature screening rationale for appropriateness of methods and procedures used reference relevant parts of previously undertaken clinical

investigations Manufacturer

analyse findings, document results in evaluation reports to be incorporated into Technical File

update clinical literature review update risk management implement corrective actions as appropriate

MHRA Guidance Documents


Further information may be found in the following:

Guidance Note 1 - Guidance Notes for manufacturers on clinical investigations to be carried out in the UK

Guidance Note 3 - Information for clinical investigators Guidance Note 5 - Guidance on biocompatibility assessment Guidance Note 17 - Guidance Notes for manufacturers on

statistical considerations for clinical investigations of medical devices

Tips and Advice: 1


Tips and Advice: 2


~25% of submissions to MHRA are rejected because of inadequate documentation and/or poorly designed trials

common reasons for rejection are: poor or absent study end-points no/inadequate risk analysis flawed study design inadequate pre-clinical testing or assessment inadequate toxicological data no sterilisation validation inadequate electrical safety testing risks outweigh benefits

read the guidance documents that are available

Tips and Advice: 3


just reading the regulations (or having them on your bookshelf) does not make you an expert

for anything other than the most simple of devices, you will almost certainly need help to produce the required documentation to the necessary standard and ensure you have all the information needed to demonstrate compliance with all the ERs except those that are the subject of the clinical trial

unless you have in-house expertise (very unlikely) it is strongly recommended that you talk to, and engage, an expert with proven experience and a track record in the conduct of medical device clinical trials and MHRA submissions

Tips and Advice: 4


engage with the MHRA prior to making your submission respond promptly to MHRA requests for further information cite the unique MHRA study reference number on ALL

communications with MHRA notify the MHRA of any problems ensure that Adverse Events are reported within the

appropriate timeframes and to the appropriate authorities seek help and advice (from appropriately qualified and

experienced sources) as and when necessary

In vitro Diagnostics


there is no clinical investigation system for in vitro diagnostic medical devices

performance evaluations of in vitro diagnostic devices that are performed outside of the manufacturer’s premises should be notified to the MHRA in accordance with the Medical Devices Regulations 2002: Section 44

see MHRA Guidance Document 18

Contact details


Dr Pete WallIsca Healthcare ResearchHill HouseBelmont HillCaerleonNP18 1JX

Tel: 01633 423641 / 07813 799193Email: [email protected]

mailto:[email protected]