Mary Lewis presented "Medical Device Development Lifecycle: Demonstrating Clinical Utility" at the Regulatory & Quality Solutions’ Medical Device Breakfast Briefing held at JumpStart, September 11, 2014.

1. Medical Device Development Lifecycle:
Demonstrating Clinical Utility
11 September 2014
Mary Lewis
Senior Clinical Research Specialist
We have studied clinical research
and regulatory compliance issues since 1999.

2. Elements of a Quality Clinical Study
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

3. 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

4. Other Planning Considerations
• Time to market
• Cost factors
• Reimbursement
• Pre-clinical and mechanical testing, toxicology,
and carcinogenicity/genotoxicity testing
• Risk analysis
• Endpoints and Measures

5. Evidence-Based Medicine
• Critical assessment techniques as reported in
literature
• Objective evaluation quality clinical research
• Clear eligibility criteria
• Generalizability
• Sufficient follow-up
• Statistical power

6. 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

7. 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

8. Economics of Large Studies
• in designing a clinical trial, statistical power
must be balanced with cost
• more patients = a more expensive trial

9. The Clinical Study=One Critical Piece
Systematic 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)

10. 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

11. 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?

12. 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

13. 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

14. 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

15. Obtain Approvals
• Regulatory Authority
• IRB/EC
• Other committees- O.R. product approval
committees, Hospital Research Committees
• CMS

16. 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

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

18. Human Subject Protection
• Informed Consent= Process
• Requirements 21 CFR Part 50

19. 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

20. Informed Consent Process
• Well informed participants
– Understand study requirements
– May be less likely to drop-out and more compliant

21. Qualified Personnel
21 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

22. Adequate Monitoring
21 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

23. 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

24. 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

25. Auditing versus Monitoring
Auditing Monitoring

26. Current Complete Accurate Data
Safety
Efficacy
Eligibility
Evaluable Data

27. In Summary
SAY WHAT YOU DO DO WHAT YOU SAY
• Conduct compliant
study
Monitoring Function
PROVE IT
• Clinical trial
•Write Protocol
• SOPs
PLAN DO
ACT CHECK
Auditing Function
IMPROVE IT
• Issue/Re-Audit CAPA processes

28. Questions?