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

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

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

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

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

II. Basics of Medical Device Regulation

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) 4,000 200,000 Number of full scale studies usually required 1 2 Number of Regulatory Classes 3 1

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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  www.trialstransformation.org CTTI will bring together all interested stakeholders to identify practices that through broad adoption will increase the quality and efficiency of clinical trials

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

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: www.fda.gov/cdrh/mdfp 27

V. Total Product Life Cycle Evaluation and Regulation

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

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.

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

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

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