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Medical Device Post-Marketing Studies in Europe

Vytis JuseviciusProjects DirectorAptivSolutions

26th AnnualEuroMeeting

25-27 March 2014ACV, Vienna

Austria

Agenda

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• What the Post Market Surveillance is?

• Legal basis

• What Notified Bodies are Looking For

• PMS Implementation

• PMCF Implementation

• Registries vs Clinical Trials

• Applicable Standards

• Performing PMCF

• Risk-based Monitoring In PMCF

PMS – What is it?

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The obligation to operate a system forobtaining feedback from the marketto monitor and control risks.

PMS – Why?

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•Medical Devices Directive require clinical data (whetherby literature review or clinical trial) to gain a CE mark

•Once CE mark is obtained – the Medical Devices Directive requires that post market surveillance / proactive activiesare conducted

•If a PMCF is required and carried out the results of the investigation will contribute to the retention of a CE mark depending on whether these results are positive or negative

PMS – Legal Basis

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European Directives:• Active Implantable Medical Devices Directive (AIMDD

90/385/EEC - Article 8 and Annexes II, IV, V) • Medical Devices Directive (MDD 93/42/EEC - Article 10 and

Annexes II, IV, V, VI, VII) • In-Vitro Diagnostics Devices Directive (IVDD 98/79/EC - Article

11 and Annexes III, IV, VI)

PMS: Legal Basis

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Quality Management Standards:• ISO 9001:2000• ISO 13485:2003• Risk Management Standard ISO 14971

PMS: Ethical / Business

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PMS is not only regulatory-driven:• Considered as good business practice• Helps the manufacturer to obtain an understanding of the

performance of the device once placed on the market• Provides continuous feedback to maintain a high standard of

product quality and consumer satisfaction• Helps to minimize exposure arising from incidents• Brings value added to the product/company

What Notified Bodies Are LookingFor

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Notified Bodies will check:•Evidence that PMS data have been collected by both proactive

and reactive ways•If the trials been completed or if in process•What the results of the trials are•If the PMS data (results of the clinical trial or registry) have

been incorporated into the risk management plan

PMS: Positive Results

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• If the results are positive and concur with the initial plan then nothing will need to be adjusted

PMS: When data consistentlypositive

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PMS: Negative Results

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•If the results are negative i.e. there are more adverse events than anticipated or if the endpoints are not met or have not been met during the trial – the risk management plan would have to be updated

•The FMEA (failure modes and effects analysis) would need to be revised

•If the results are very bad then the termination of the trial should be considered

PMS: When data worse thanexpected

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PMS: Implementation

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Post Market Surveillance may include a number of strategies in addition to complaint handling and vigilance (reactive): • Active supervision by customer surveys (proactive) • Inquiries of users and patients (reactive)• Literature reviews (proactive) • Post Market Clinical Follow-up (PMCF) (proactive):

- through clinical studies and/or registries

(From MedDev 2.12-2)

PMCF is not needed when:• Medium/long term performance and safety are known• There is fully transferable experience with equivalent devices

(MEDDEV2.7.1)

PMS: Implementation (no-PMCF Route)

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What actions to be taken when no PMCF is done:• Systematic review of complaints and AEs (including literature

review)• Review publicly available data with similar devices (especially

when CE marking is based on equivalence)

PMS: Implementation (no-PMCFRoute)

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• Guidance document for manufacturers and Notified Bodies on how to carry out PMCF to fulfill post market surveillance obligation

• Issued in May 2004• Not a legally binding document• Reflects positions taken by representatives of all interested

parties

PMCF: MEDDEV 2.12-2

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PMCF - Importance

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PMCFU through clinical studies and registries are important as there is a need for «real world» clinical, safety and economic data•Limitation of pre-market studies:

– Duration of follow up– Number and homogeneity of subjects– Device used in a controlled environment

When should PMCF be considered:• Possible emerging risks are identified• Long term safety and performance data are critical

PMCF IMPLEMENTATION: Definingthe Need

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Risks to be considered when planning PMCF:• Innovation• Severity of disease• Sensitive target population• Risky anatomical location• Well known risks from literature• Identified acceptable risks during pre-CE clinical evaluation• Difference of pre market follow up and expected life of

product

PMCF IMPLEMENTATION: IdentifyingEmerging Risk

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What actions to be taken when PMCF is done:• Same as in no PMCF situation (slide 15) AND:

- PMCF data analysis

NB: Formal protocol of PMCF should describe the duration of the PMCF, identify patient population and data to be collected.

PMCF IMPLEMENTATION:Defining The Need

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Forms of PMCFs:1. Extended follow up of patients enrolled in pre-market trials2. Prospective studies after device is placed on the market3. Combination of 1 and 24. Open registries

PMCF: Planning

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What should be taken into account when planing PMCF:• Results from clinical investigations (including AEs)• Average life expectancy of the device• The claims made by the manufacturer for the device• Performances for which equivalence is claimed• Any new information that becomes available

PMCF: Planning

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Additional points to be considered while planning PMCF:• Commercial information to support the company’s sales

(Particularly important in large scale indications)• Economic value to achieve reimbursement approvals which

varies per country• Moving towards continuous studies (i.e. pre and post

marketing combined)

PMCF: Planning

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PMCF: Registries & Clinical Trials

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A PMCF can be a registry study or clinical trial

Registry:• Device is CE and used within intended use• Registry guideline• Standard medical care practices• No hypothesis – observational• Performed by Physicians

PMCF: Registries & Clinical Trials

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A PMCF can be a registry study or clinical trial

PMCF study:• Device is CE and used within intended use• Clinical Investigation Plan (Protocol)• Inclusion/exclusion criteria• Statistical hypothesis• Performed by Investigators

ISO14155 and ICH/GCP whendata going to be submitted toFDA• Sections 4.5.2, 7.1.2: Institutional Review Board

membership and procedures must follow US regulations as described in 21 CFR part 56

• Sections 4.7.3.4, 4.7.4-5: Informed consent content and procedures must follow US regulations 21 CFR part 50

• Sections 6.4.1, 8.2.4.5.j-k, 8.2.5, 9.7-8. Annex A.14, Annex F: Adverse Event Reporting procedures must be consistent with US regulations

• NOTE: In addition, Financial Disclosure requirements for investigators must be met

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PMCF: Applicable Standards

PMCF: Factors influencing dataquality and integrity

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• A well-designed Clinical Investigation Plan (CIP)• A well-designed case report forms• Monitoring (combination of in-house and on-site activities) as

element of a multi-dimensional approach that produces quality trial data

PMCF: Clinical Investigation Plan(CIP)

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CIP should identify and where needed justify at a minimum:• The study population (corresponding to the CE-mark scope)• Inclusion/exclusion criteria• Rationale and justification of the chosen study design

including use of controls/control groups (where relevant; randomized or not)

• List of sites and investigators• Study objectives and related study endpoints and statistical

considerations

PMCF: Clinical Investigation Plan

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CIP should identify and where needed justify at a minimum (cont’d):• Number of subjects involved• Duration of patient follow-up• Data to be collected• Analysis plan including any interim reporting where

appropriate to ensure continuous risk management based on clinical data; and procedures/criteria for early study termination

• Ethical considerations• Methods of quality control of data where appropriate

PMCF: Getting Study Approval

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• The Studies will always have to be approved by the EthicsCommittee (Central, Local, or Both)

• Competent Authority approval may be needed in somecountries in case trial is considered to be interventional (e.g. randomization, additional procedures)

• Data Protection submission may be needed depending on country

Note: there may be some other country-specific requirements

Monitoring: What Has To BeGuaranteed?

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• Patient safety and well-being

• Good data quality and regulatory compliance

• Proper management of sites

• Proper risk management and mitigation methods

• …And all that with limited resources and funds

Monitoring: Regulations AllowAlternatives

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• ISO14155:2011 does not require 100% SDV on site• 2011 the European Medicines Agency issued the Quality Risk

Management document (ICH Q9)• 2011, the MDC/DH/MHRA Joint Project released Risk-adapted

Approaches to the Management of Clinical Trials of Investigational Medicinal Products

• In August 2013, the FDA released their final Guidance for Industry: Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring

Risk-Based Monitoring (RBM)Components

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• Central monitoring evaluating e-CRF data through checks, algorithms, statistical monitoring programs

• Data Surveillance For The Detection Of Fraud using statistical techniques to detect unusual data that may indicate fraudulent reporting (e.g. repeated measures of the same variable over time)

• Detection Of Outcome Events by computerized screening of reported events and hospitalizations for key words that might suggest event has occurred

• On-Site Monitoring with Targeted SDV• Site Management, Communication And Documentation• Regulatory / Study File review

Conclusions

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• PMS is a duty imposed by standards and laws• PMCF objective is to confirm clinical performance and safety

throughout the expected lifetime of the medical device• Good PMCF program will also serve as marketing tool and

create added value for the company• Current legislation and new technologies open new

possibilities for adaptive and flexible approach to management of studies and potential cost saving

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