1. Cardiovascular Device Development in the United States: An FDA Division of Cardiovascular Devices Perspective
Bram Zuckerman, MD, FACC
Director, FDA Division of Cardiovascular Devices
Office of Device Evaluation
Center for Devices and Radiological Health

2. Outline of Today’s Talk
Introduction to FDA
Basics of Medical Device Regulation
Improving Medical Device Review in the U.S.
Improving Medical Device Innovation in the U.S.
Total Product Life Cycle Evaluation and Regulation

3. FDA Organizational Chart 2010
Department of Health and Human Services
Center for Tobacco
Products
Center for Food Safety
And Applied Nutrition
Center for Veterinary
Medicine
Food and Drug Administration
Office of the Commissioner
National Center for
Toxicological Research
Center for Biologics
Evaluation and Research
(CBER)
Center for Drug Evaluation
And Research
(CDER)
Center for Devices and
Radiological Health
(CDRH) 3

4. FDA and Public Health
“The ultimate measures of the FDA’s success should reflect its fundamental goals and go beyond such intermediate measures as the number of facilities inspected or drugs approved.” 4 4

5. CDRH’s mission is: Risks Benefits
Getting safe and effective devices to market as quickly as possible…
… while ensuring that devices currently on the market remain safe and effective.
Risks
Benefits
We also help the public get science-based accurate information about medical devices and radiological products needed to improve health 5

6. II. Basics of Medical Device Regulation

7. Comparison of Device versus Drug Development
Developmental Feature Device Drug
Rate of technology change High Low Ease of in vitro assessment High Low Reimbursement during clinical trials Frequent Rare Influence of physician technique on results High Low Ability to visualize performance after use High Low Definition of “Orphan” (number of patients) , ,000
Number of full scale studies usually required
Number of Regulatory Classes

8. Medical Device Definition
An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is:
1) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease in man, or
2) intended to affect the structure or any function of the body of man, and which does not achieve its primary intended purposes through chemical action within or on the body of man and which is not dependent upon being metabolized for the achievement of its primary intended purposes.
Section 201, Food Drug and Cosmetic Act

9. New Device Legislation (FDAAA)
Medical Device Definition
Risk-based classification
Adverse events reporting
Implantable device tracking
Postmarket surveillance
Mandatory recalls
User Fees
Performance Goals
New 3rd Party Review
Office of Combination Products
1970
1980
1990
2000
GMP regulations
UDI
e-Registration & Listing
Pediatric medical device safety
“Least Burdensome”
Design controls
3rd Party Review
Humanitarian devices
Quality Systems regulations

10. Risk-Based Paradigm Medical Device Classes: Additional Classification:
General Controls
Most exempt from premarket submission
Class II
Special Controls
Premarket Notification [510(k)]
Class III
Premarket Approval
Require Premarket Application [PMA]
Additional Classification:
De Novo
Device "types" that have never been marketed in the U.S., but whose safety profile and technology are now reasonably well understood
Humanitarian Device Exemption (HDE)
Devices for orphan diseases intended to benefit patients in diagnosis and/or treatment of disease or condition affecting or manifested in fewer than 4,000 patients per year in the United States

11. 510(k) Moderate risk devices Substantial equivalence
10-15% require clinical data
Performance testing

12. PMA Higher risk devices
Establish reasonable assurance of safety and effectiveness
Bench - Animal - Human
Similar to new drug approval process

13. III. Improving Medical Device Review in the U.S.

14. CDRH’s Workload Submissions Received
TYPE OF SUBMISSION (received)
2000
2001
2002
2003
2004
2005
2006
2007
Original PMAs 67 71 49 54 51 38 39
PMA Supplements
546
641
645
666
635
478
629
581
Original IDEs
311
284
312
242
226
232
262
225
IDE Supplements
4,388
4,811
4,724
4,415
4312
4287
4519
4376
510(k)s
4,202
4,248
4,320
4,247
3,635
3,650
3853
3680
Original HDE 11 5 10 9 6
HDE Supplements 16 29 32 24
513(g)s 59 82
104
156
270
313
297
408
Total
9,594
10,158
10,175
9,819
9,167
9,025
9,635
9,339

15. Phased Approach to Medical Device Development
Pre-Clinical
Early Clinical
Trial to Support Market Entry
Post Marketing Trials

16. Improving the IDE process
Early interaction with FDA is a key to addressing and resolving issues
Sufficient safety evidence is needed to begin clinical studies in U.S. – most disapprovals based on inadequate bench and/or animal testing
Need to address FDA concerns that are raised in Pre-IDE discussions

17. Pre-IDE Discussion Before the IDE…
Based on the proposed device design, development of appropriate nonclinical testing (bench, software, fatigue testing, animal, shelf-life)
Based on the proposed indication, development of an appropriate clinical protocol, statistical analysis plan
Need to address FDA concerns that are raised in Pre-IDE discussions

18. FDA Review Timelines Application MDUFMA I MDUFMA II
Original PMA & Panel-track Supp
50% in 180 days
90% in 320 days
60% in 180 days
90% in 295 days
Modular PMA
n/a
70% in 90 days
90% in 120 days
180-day PMA Supplement
90% in 180 days
85% in 180 days
95% in 210 days
Real-time PMA Supplement
80% in 60 days
90% in 90 days

19. FDA Device Approval: Critical Issues
1. Pre-clinical Testing
Are bench and animal studies acceptable?
2. Pivotal Trial
Design: Minimize bias and confounding
Execution: Minimize amount of missing data
Analysis: Rule out chance (i.e., several prospectively chosen, clinically relevant hypotheses with plan for alpha allocation)
Have clinically meaningful results been clearly demonstrated?
3. Manufacturing
Can device be built safely for commercial distribution?
4. Is the Device Label truthful and accurate? 19 19

20. Analysis of Pivotal Device Trials
Statistical significance is different from clinical significance
There is no perfect device surrogate –
CDRH deals with partial device surrogates
Understand their limitations
Composite endpoints have limitations –
A combined endpoint needs to retain its interpretability
The basic unit of analysis is the patient and not the device
Advisory panels offer advice to the FDA in an open and transparent environment
Totality of data in a device trial should indicate a beneficial risk/benefit ratio 20 20

21. Research Conducted Outside the US (OUS)
OUS clinical data can be used to support approval of devices in the US
Generalizability of OUS study results to the patient population in the US is a key issue.
Sponsor must address factors such as demographics, standard of care, protocol employed
Clinical studies should be conducted in compliance with applicable standards and with adequate human subject protection to ensure data quality
Good Clinical Practices (GCPs) – see International Conference on Harmonisation (ICH) E6 guideline
A global clinical trial may be a useful alternative to consider 21

22. IV. Improving Medical Device Innovation in the U.S.

23. FDA Critical Path Initiative
Basic
Research
Prototype
Design or
Discovery
Clinical
Development
FDA Filing/
Approval &
Launch
Preparation
Preclinical
Critical Path
Approval
Market
Application
The Critical Path Initiative is FDA's effort to stimulate and facilitate a national effort to modernize the sciences through which FDA-regulated products are developed, evaluated, and manufactured.

24. What is FDA doing?
Third Workshop on Computer Methods and Modeling for Cardiovascular Devices
Date: June 10-11, 2010
Sponsored by FDA, NHLBI/NIH and NSF
Purpose: Lay groundwork for the development of computer modeling methods
Document the best-practices and unmet needs related to modeling the cardiovascular system and predicting safety and efficacy of cardiovascular devices
Review best practices in other industries in simulation-based engineering sciences.
Establish a strategy to promote the development, application and validation of computational methods for cardiovascular device design and evaluation

25. Clinical Trials and Transformantion Initiative (CTTI)
Current challenges in clinical research
Quality
Efficiency
Increasing movement of clinical trials research overseas
Public–private partnership, the Clinical Trials Transformation Initiative (CTTI)
Modernize clinical trials infrastructure and conduct 
CTTI will bring together all interested stakeholders to identify practices that through broad adoption will increase the quality and efficiency of clinical trials

26. Additional Avenues Development of global device development strategy
European and Japanese data are important
FDA/Japanese HBD Program
FDA contact:
Role of NHLBI in Device Development
Pediatric and Adult LVAD programs
CTS and ROC Clinical Trials Network
Role of Pharmaceutical Industry in Device Development

27. FDA CDRH Medical Device Fellowship Program (MDFP)
Intended to add expertise to FDA CDRH and the investigator community
Opportunities for cardiologists, cardiac surgeons and engineers
Opportunities for junior to senior people
Competitive 1-2 year program, paid salary
Either full-time in Wash DC or negotiated on-site/off-site work schedule
For information on the FDA Medical Device Fellowship Program: 27

28. V. Total Product Life Cycle Evaluation and Regulation

29. The Total Product Life Cycle
Regulation of device technologies requires a total product life cycle approach.
HHS/FDA/CDRH

30. Striking the Right Balance Between Pre- and Post-market Evaluation
Use appropriate amount of pre-market data to make primary decisions about approvability of new devices (safety, effectiveness)
Use postmarket data to
supplement our understanding about device and operator performance
identify device malfunctions and take corrective action as necessary
modify pre-market expectations for next generation devices.

31. Health Care Provider Involvement is a Vital Cog in the Process
Death
Serious Injury (only if manufacturer unknown) work days
User Facility
FDA
Death & Serious Injury - 10 work days
Death
Serious Injury Malfunction
30 work days
Manufacturer (& Importer)

32. How Can Post-market Reporting be Improved?
Coordinate a standard for data collection regarding CV devices and procedures?
Develop agreements between and among industry, clinicians, and FDA to establish common data bases?
One size will certainly not fit all
Use of registry data must not subvert the IDE regulation: patient experimentation must be conducted under strict rules
Funding must be sustainable by added value of the effort

33. Conclusion Complex and challenging technology
No shortcuts but improved efficiency possible
Start working with the FDA early in the process
Innovation not at the expense of safety and effectiveness