Clinical Study Design for Medical Devices Greg Campbell, Ph.D. Director, Division of Biostatistics Center for Devices and Radiological Health U.S. Food and Drug Administration Kitasato-Harvard Symposium, October 24-25, 25, 2006, Tokyo
Outline The nature of medical devices and their regulation Difference between devices and drugs Therapeutic device design issues Diagnostic device design issues Bayesian statistics in medical device trials Challenges 2
What Are Medical Devices? Definition by exclusion: any medical item for use in humans that is not a drug nor a biological product intraocular lenses MRI machines breast implants surgical instruments thermometers (drug-coated) stents home kit for AIDS diagnostic test kits bone densitometers artificial hips PRK lasers pacemakers defibrillators spinal fixation devices glucometers artificial hearts hearing aids latex gloves artificial skin software, etc 3
Cardiovascular Devices Bare Metal Stents Drug Eluting Stents (DES) Balloon angioplasty Pacemakers Distal protection for AMI Heart valves Ventricular Assist Devices (VADs( VADs) Patent foramen ovale (PFO) closure devices Defibrillators Abdominal aortic aneurysm (AAA) devices 4
What is a Drug-Eluting Stent? Example: Cordis Cypher Sirolimus-Eluting Coronary Stent Components Stent Platform & Delivery System Carrier(s) Drug 5
The Nature of Medical Device Studies Whereas drugs are discovered, devices evolve. Devices are constantly being improved. Life length of a particular model of a device is often 1-21 2 years. Rapidly changing technology 6
Devices Not Drugs -- The Differences A Trial with a Sham Control may not be possible Masking (blinding) may be impossible for patients, health care professionals, investigators Bench/Mechanical Testing not PK/PD Mechanism of Action often well understood Effect tends to be localized rather than systemic, physical not pharmacokinetic Pre-clinical Animal Studies (not for toxicity) Implants (skill dependent; learning curve) 7
The Differences in the Two Industries Number & Size of Device Companies in US 27,635 registered firms, of which 22,838 are US Median device company size-- --under 50 employees (Many are new start-up companies.) Many fewer (and generally much larger) pharmaceutical firms 8
Commonalities in Design between Pharmaceuticals and Medical Device Trials Superiority trials Active non-inferiority trials Multiple endpoints Surrogate endpoints Multi-center trials Interim monitoring Use of Data Monitoring Committees (DSMBs( DSMBs) ) (FDA has a newly released guidance document on DMCs: http://www.fda.gov/cber/gdlns/clintrialdmc.htm )... 9
Types of Controls for Device Studies Randomized control (RCT) Non-randomized concurrent control Historical control Pseudo two-treatment treatment comparative study One-arm study, compared to historical control Patient-level data of historical control is available and used in treatment comparison. Propensity score statistical analysis Single-arm study against a fixed target value Compared to a fixed target value obtained from multiple historical trials 10
Regulatory Differences in US Between Drugs and Devices Different law and regulations for devices due to the nature of devices Different Alphabet Soup IDE -- Investigational Device Exemption PMA -- PreMarket Approval 510(k) -- Substantial Equivalence--- ---not bioequivalence A Single Confirmatory Trial (not 2). Usually don t t use Phase I, IIA, IIB, III, IV FDA guidance for international officials http://www.fda.gov/cdrh/manual/ireas.html 11
Diagnostic Devices Can be used for Diagnosis Screening Monitoring disease or medical condition Types of devices In vitro diagnostic devices Imaging devices Others Combination therapeutic-diagnostic device Example: implantable cardioverter defibrillator (ICD) 12
Diagnostic Devices Diagnostic devices require a completely different approach FDA Statistical Guidance on Reporting Results from Studies Evaluating Diagnostic Tests; Draft Guidance for Industry and FDA Reviewers http://www.fda.gov/cdrh/osb/guidance/1428.html 13
Some Design Issues in Diagnostics Plan the type of study design; more than one design is possible. Potential problem is that FDA usually does not require an Investigational Device Exemption (IDE) for a diagnostic test. The Randomized Clinical Trial (the premier design for therapeutics) is of limited use in many diagnostic evaluations of tests. It is generally more efficient to use patient as his/her own control if new test is compared to a reference method. 14
Bayesian Initiative 15
Why FDA s s Bayesian Initiative in Medical Device Trials? Mechanism of action is often physical and local. Often a great deal of prior information on very similar devices often exists: clinical trials overseas, data registries, historical controls and pilots Use of good prior information can appreciably reduce the size and perhaps the length of a trial. One can arrive at the same decision in a much more timely manner. A Bayesian approach has some appeal to clinicians since the focus is on the patient. 16
Bayesian Statistics in Device Trials Use available prior information Prior planning of the design and analyses stages is crucial in a Bayesian paradigm. Identify the source of prior information before current experiment begins. In addition, there is a need to agree upon the weight of the prior evidence. Not a substitute for good science. Still need randomization, blinding, precision, low bias 17
Bayesian Draft Guidance Draft Guidance for the Use of Bayesian Statistics in Medical Device Trials,, released in May, 2006 http://www.fda.gov/cdrh/osb/guidance/1601.html Public meeting in Rockville MD in July, 2006 http://www.fda.gov/cdrh/meetings/072706 bayesian.html for document and slides from meeting presentations. 18
Challenges Adaptive trials Combination products and the use of biomarkers using advances in imaging, genomics, proteomics Post-market concerns Global development and internationalization 19
Changes in Device Trials Modifications during the course of the trial to the protocol in terms of Inclusion/exclusion criteria Endpoints Control group Statistical analysis plan 20
Adaptive Trials Monitor sequentially and possibly stop early for success or futility. Increase the sample size Change the randomization ratio The important point is that to be successful, one needs to plan for adaptation at the start of the trial. 21
Combination Products Drug Eluting Stents Heart Valves Cardiovascular devices that both detect a condition and deliver a therapy (ICDs) Diagnostic tests for pharmacogenomics to guide the use of cardiovascular drugs FDA Drug/Diagnostic Co-development Concept Paper www.fda.gov/cder/genomics/pharmacoconceptfn.pdf 22
Postmarket Activities INTERMACS Inter-agency Registry for Mechanically Assisted Circulatory Support A joint effort by NHLBI, CMS and FDA to provide comprehensive post market national registry on all patients receiving mechanical circulatory support therapy in the US beginning in 2006. www.intermacs.org 23
International Opportunities Global Harmonisation Task Force GHTF Similar to ICH Goal: To harmonize regulation of medical devices among members. GHTF website: www.ghtf.org 24
Harmonization by Doing One important program to meet the increasing public health challenges of the 21 st century It involves FDA and MHLW as well as industry and academia in US and Japan. Market approval goal: to conduct simultaneous clinical studies in Japan and in US in order to obtain regulatory market approval at the same time. 25
FDA s s Critical Path Opportunities List #1 Biomarker Qualification One of five questions is What types and levels of evidence are needed to accept a biomarker as a surrogate endpoint for product efficacy? #6 Surrogates Outcomes for Cardiovascular Drug Eluting Stents #23 Imaging Biomarkers in Cardiovascular Disease http://www.fda.gov/oc/iniatitives/criticalpath/reports/opp_list.pdf pdf 26
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Thank you! greg.campbell@fda.hhs.gov 28
Total Product Life Cycle (TPLC) for Devices Ensuring the Health of the Public Throughout the Total Product Lifecycle L 29... It s s Everybody s s Business
CDRH s s Vision of the Pipeline 30