BME-IDEA Workshop, September 28, 2005 Fostering Innovation on the Critical Path to Medical Device Development BME-IDEA Workshop, September 28, 2005 Donna-Bea Tillman, Ph.D Director, Office of Device Evaluation Center for Devices and Radiological Health

FDA Mission: Historical Basis Protect the public from unsafe products I’d like to start my talk by looking back at the historical roots of FDA, which trace back to a public health protection problem. 107 people, mostly children, died when sulfanilamide, the first “wonder drug” was formulated into an elixr containing the toxin ethylene oxide. Exisiting laws did not require the drugs manufacturer to test the formulation for safety before it was sold. Congress corrected this weakness in the law the next year when it passed the Federal Food, Drug, and Cosmetic Act. This law, for the first time, required companies to prove the safety of new drugs before putting them on the market.

Over the next hundred years, Congress continued to give FDA new responsibilities , including the requirement that drugs and medical devices be proven effective as well as safe before they can be sold. This is the only painting in the series wherein Perez caricatures a recognizable, well-known doctor-former U.S. Surgeon General, C. Everett Koop. Dr. Koop receives this honor because Jose Perez has been so impressed by Koop's leadership in national and global public health. God bless our unheralded public-health doctors.

FDA Mission Today Promote Protect Today, FDA’s mission has broadened beyond public health protection to also include public health promotion – ensuring the availability of new products that promote the health of the American people. When most people think of FDA, they think of our public health protection role: -Historical roots of FDA -Methods well understood -Good business – basis of public confidence in medical products However, many of FDA’s most difficult challenges lay in the public health promotion arena.

The world today… Technological changes occur at lightning speed Medical devices are more complex than ever The Internet is the new “snake oil” salesman The American public is demanding great control over healthcare decisions The global marketplace means global regulation

Technology trends Miniaturization Smart devices Minimally invasive Biotechnology revolution Combination Products Home use Special Populations New technology is smaller, uses computer intelligence, and allows less invasive procedures. New materials, sometimes tissue derived and combined with pharmaceuticals create new combination products with features of both a drug and a device. Some of these innovations are referred to as “disruptive technologies” because they change the way we do business and they change how medical devices deliver value. Consider if a hand held ultrasound could be added to the stethoscope as a tool for your doctor. No longer would your doctor thump your back, or poke at your liver, or listen to your neck. Your doctor could easily see if you have gall stones, carotid artery narrowing, a bicuspid aortic valve, a pleural effusion, ascities, a renal cyst, or fibroid uterus. All this in about the same time as a normal exam, and only requiring a referral to the radiologist for more detailed or specialized images.

Disruptive Technologies That change the nature of medical devices That change how medical care is delivered That change health outcomes, hopefully for the better …that change how the industry and FDA do business.

Challenges to Innovation Basic biomedical science investment & progress has surpassed medical product development investment and progress

Challenges to Innovation We are using the evaluation tools and infrastructure of the last century… to develop this century’s advances.

Challenges to Innovation This has resulted in a bottleneck at the “critical path” for delivering new products to patients

Critical Path Research Leverages basic science knowledge Leverages cumulative research experiences Does not compromise safety and effectiveness evaluations

Critical Path for Medical Devices Market Application Approval Basic Research Prototype Design or Discovery Preclinical Development Clinical Development FDA Filing/ Approval & Launch Preparation Critical Path The journey from medical product candidate to full-scale production and marketing

Why is FDA interested? Because of the significant benefit of bringing innovative products to the public faster Because of our unique perspective on product development -- we see success, failure and missed opportunities Because it will help us to develop guidance and standards that foster innovation and improve chances of success

What does FDA want to accomplish? Work together with industry, academia and patient care advocates to modernize, develop and disseminate solutions (tools) to address scientific hurdles impacting industry-wide product development.

What are the Critical Path tools? The methods and techniques used for: Assessment of Safety – how to predict if a potential product will be harmful? Proof of Efficacy - how to determine if a potential product will have medical benefit? Industrialization – how to manufacture a product at commercial scale with consistent quality?

Devices are not drugs!

Drugs Yesterday Drugs Today Drugs Tomorrow

Devices HHS/FDA/CDRH

Devices are Different: Development Complex components Designed Drugs Pure molecules Discovered How do devices differ from drugs? What are the challenges that must be met to assure that such products are safe and effective? Drugs are chemically synthesize pure molecules while devices complex products assembled out of many components. Drug toxicology establishes the pharmacologic problems that occur from metabolites or in special situations such as pediatrics or pregnancy, while we examine devices from an engineering perspective, looking at issues ranging from mechanical integrity, to electrical safety and biocompatibility.

Devices are Different: Life-cycle Short product life-cycle Durable equipment Drugs Long market life Short half-life How do devices differ from drugs? What are the challenges that must be met to assure that such products are safe and effective? Drugs have long market lives, protected by patents which can be extended by FDA approval, while Devices have rapid product cycles with continuous incremental improvement. Drugs have short half lives while devices are durable equipment, often still in use long after manufacturing has ceased.

Devices are Different: Adverse Events Drugs Drug interactions Wrong drug/wrong dose Devices Malfunction User error How do devices differ from drugs? What are the challenges that must be met to assure that such products are safe and effective? With drugs we worry about drug interactions, name confusion, dosage errors, while with devices we worry about mechanical failure and malfunction and problems with user errors.

Devices are Different: Regulatory Requirements Drugs Clinical trial Clinical endpoints Devices Risk-based Surrogate endpoints How do devices differ from drugs? What are the challenges that must be met to assure that such products are safe and effective? Drugs are almost always studied clinically while over 90% of devices are studied at the bench for performance characteristics. Clinical trials for drugs almost always involved clinical endpoints. Devices frequently have well-understood mechanisms of actions, so surrogate endpoints are frequently used.

Risk-Based Classification of Medical Devices Class I: simple, low risk devices General controls Most exempt from premarket submission 8% class III, 46% class I, 46% class II-substantial equivalence to a legally marketed device-decision usually based on descriptive information, sometimes bench or animal, rarely clinical data. Determination of risk based on technology and intended use. These two aspects must be assessed in concert.

Risk-Based Classification of Medical Devices Class II: more complex, higher risk Special controls Premarket Notification [510(k)] Substantial equivalence 10-15% require clinical data Performance testing 8% class III, 46% class I, 46% class II-substantial equivalence to a legally marketed device-decision usually based on descriptive information, sometimes bench or animal, rarely clinical data. Determination of risk based on technology and intended use. These two aspects must be assessed in concert.

Risk-Based Classification of Medical Devices Class III: most complex, highest risk Data “soup to nuts” Premarket Application [PMA] Establish safety and effectiveness Bench - Animal - Human May include post-approval study requirements 8% class III, 46% class I, 46% class II-substantial equivalence to a legally marketed device-decision usually based on descriptive information, sometimes bench or animal, rarely clinical data. Determination of risk based on technology and intended use. These two aspects must be assessed in concert.

Critical Path is Different for Devices Device Regulation Least Burdensome Provision of FDAMA Quality Systems and Design Controls Device Innovation Process Biocompatibility Iterative Process User learning curve Performance and durability Device Industry is Represented by Small Manufacturers

Some Critical Path Tools… Biomarkers Bayesian statistics Animal models biomarkers Clinical trials design Computer simulations Quality assessment protocols Post-market reporting Suggestions???

Medical Device Critical Path Projects of Interest Validation of biomarkers Blood panel to assess sensitivity and specificity Peripheral vascular stents Computer models of human physiology to test and predict failure (before animal and human studies) Intrapartum fetal diagnostic devices Clear “Regulatory Path” -- with consensus from the Obstetrics community)

Medical Device Critical Path Projects of Interest Permanently implanted devices Practice guidelines for appropriate monitoring -- with medical specialty organizations Neural tissue contacting materials Extent of neurotoxicity testing

Are you interested? Web Address http://www.fda.gov/oc/initiatives/criticalpath Open Docket http://www.fda.gov/dockets/ecomments Docket # 2004N-0181 CDRH webpage (under news and events) provides links to the critical path white paper and docket http://www.fda.gov/cdrh

Questions? One does what one is; one becomes what one does. Robert von Musil