Medical Device Development Lifecycle:

Demonstrating Clinical Utility

11 September 2014Mary Lewis

Senior Clinical Research SpecialistWe have studied clinical research

and regulatory compliance issues since 1999.

Plan and Conduct scientifically sound study

Ensure Protection of Human Subjects

Qualified personnel

Provide Adequate Monitoring

Current, complete, and accurate data

Data needed to support Efficacy and Safety determination

Elements of a Quality Clinical Study

Study Planning • Identification of clinical need

– Solutions for patients, clinician customers – Application of novel technology– New indication for an established product

• In concert with a scientific advisory board consisting of medical experts and statisticians– Target patient population– Identify the control– Design the study

Other Planning Considerations

• Time to market• Cost factors• Reimbursement • Pre-clinical and mechanical testing, toxicology,

and carcinogenicity/genotoxicity testing• Risk analysis• Endpoints and Measures

Evidence-Based Medicine

• Critical assessment techniques as reported in literature

• Objective evaluation quality clinical research• Clear eligibility criteria• Generalizability• Sufficient follow-up• Statistical power

Study Design Decisions• Start with pilot /feasibility study (an IDE)

– Multi-center or single center, randomized or non-randomized, controlled or open-label

– Identification of clinician learning curve• RCT (Randomized Controlled Trials)= Level 1

evidence- provide the most compelling evidence that the study treatment causes the expected effect on human health

Statistical Power• How big a difference (effect

size) is expected between groups• numbers of patients increase ability to

reliably detect the effect of the intervention This is described as the "power" of the trial

• The larger the sample size or number of participants in the trial, the greater the statistical power

Economics of Large Studies• in designing a clinical trial, statistical power

must be balanced with cost• more patients = a more expensive trial

The Clinical Study=One Critical PieceSystematic Approach to Quality

• Personnel roles and responsibilities• Training• Policies and Procedures- define controls to reduce/prevent errors• Auditing (QA) and Adequate Monitoring (QC)- identify potential

problems and course correct early• Document management, record retention and reporting • Corrective and Preventative Action (CAPA)

Study Conduct

Planning Stage

Identify, analyze, and strengthen weakness in

compliance areas• Regulations [812 or 312, 11,

50, 54, 56]• Protocol, DMP, SAP• Sponsor requirements/

SOPs/ Risk Analysis• Personal Qualifications and

Training/Site Selection• IRB Requirements• Agreements

Execution Stage

FDA and IRB Review• Overall Organization• Monitoring Activity• Data Collection and

Handling• Electronic Records• Product Accountability• Records Maintenance• Facilities/Equipment• Quality Assurance

Close-Out Stage

Regulatory inspection preparation

• Database lock/ Analysis/ Results Reporting

• Record Retention• Quality Assurance

Planning Stage-Protocol is Written Next?

• Site Selection- # investigators, medical specialty, experience, published in field of interest, geographic location, cost, available staff, worked with site on past studies, FDA restricted?

Planning Stage-Risk Analysis

• Required by law (21 CFR Part 820 Quality System Regulation)• Identifying design problems before distribution eliminates

costs associated with recalls• Offers a measure of protection from product liability damage

awards• Regulatory submissions (PMA and 510k) call for inclusion of

risk analysis• It is the right thing to do

Planning Stage• Monitoring Plan• Data Management Plan

database set-up, data entry methodology, data processing (quarantine), delta checks & queries

• Statistical Analysis Plan• Project Tracking Systems

site payments and performance (accrual, % received, % audited, % queried), AE databases, protocol deviations

Study Conduct

Planning Stage

Identify, analyze, and strengthen weakness in

compliance areas• Regulations [812 or 312, 11,

50, 54, 56]• Protocol, DMP, SAP• Sponsor requirements/

SOPs/ Risk Analysis• Personal Qualifications and

Training/Site Selection• IRB Requirements• Agreements

Execution Stage

FDA and IRB Review• Overall Organization• Monitoring Activity• Data Collection and

Handling• Electronic Records• Product Accountability• Records Maintenance• Facilities/Equipment• Quality Assurance

Close-Out Stage

Regulatory inspection preparation

• Database lock/ Analysis/ Results Reporting

• Record Retention• Quality Assurance

Obtain Approvals

• Regulatory Authority• IRB/EC• Other committees- O.R. product approval

committees, Hospital Research Committees• CMS

Study Initiation

• Select qualified investigators• Build Regulatory Binder (Investigator Brochure)• Ensure proper monitoring- site initiation,

routine monitoring (QC), audit plan (QA) (what variables, at what level and what frequency)

• Shipping Investigational Product and Master Test article accountability

Monitoring Procedures

• Domestic and/or OUS• % SDV- all data or primary endpoint data?• Who, when, and how often?

Human Subject Protection

• Informed Consent= Process• Requirements 21 CFR Part 50

Consent Materials

• “generic” Sponsor-written ICD submitted with IDE• IRB of record is final authority on ICD content• Written at a 8th Grade reading Level or below• 8 required elements, 6 additional elements and

clinical trial registry databank info

Informed Consent Process

• Well informed participants– Understand study requirements– May be less likely to drop-out and more compliant

Qualified Personnel21 CFR 812.43

Investigators• Qualified by training and

experience to investigate the device– Adequate time– Adequate resources– Necessary equipment– Aware of differences between

clinician and clinical investigator

– Knowledge of GCP– Commitment to research

Monitors

• Qualified by training and experience to monitor the investigational study in accordance with the applicable regulations– Specific study protocol

training/therapeutic area– Regulatory knowledge– Human factors concerns– Importance of consent

process

Adequate Monitoring21 CFR 812.46

• Securing compliance [FAIR Shake™]– Federal Regulations– Agreements– Investigational Plan– Requirements of the IRB

Promptly either secure compliance or discontinue shipments of the device to the investigator and terminate their participation in the study

Adequate Monitoring• Set sites up for success• Early and frequently enough to catch

problems and course-correct • Combination of remote and on-site activities• Regular data verification may reduce queries

and avoid late database problems• Provide training/re-training opportunities for

new or current staff

Study Conduct

Planning Stage

Identify, analyze, and strengthen weakness in

compliance areas• Regulations [812 or 312, 11,

50, 54, 56]• Protocol, DMP, SAP• Sponsor requirements/

SOPs/ Risk Analysis• Personal Qualifications and

Training/Site Selection• IRB Requirements• Agreements

Execution Stage

FDA and IRB Review• Overall Organization• Monitoring Activity• Data Collection and

Handling• Electronic Records• Product Accountability• Records Maintenance• Facilities/Equipment• Quality Assurance

Close-Out Stage

Regulatory inspection preparation

• Database lock/ Analysis/ Results Reporting

• Record Retention• Quality Assurance

Auditing versus Monitoring

Auditing Monitoring

Current Complete Accurate Data

Evaluable Data

Efficacy

EligibilitySafety

In Summary

• Clinical trial processes• Issue/Re-Audit CAPA

• Conduct compliant study

•Write Protocol• SOPs

PLAN DO

CHECKACT

Monitoring Function

Auditing Function

SAY WHAT YOU DO DO WHAT YOU SAY

PROVE ITIMPROVE IT

Questions?