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Download the Final Guidance Document Design Considerations for Pivotal Clinical Investigations for Medical Devices Guidance for Industry, Clinical Investigators, Institutional Review Boards and Food and Drug Administration Staff Document issued on: November 7, 2013 The draft of this document was issued on August 15, 2011. For questions regarding this document that relate to devices regulated by CDRH, contact Gregory Campbell, PhD at (301) 796-5750 or by email at [email protected], if desired. For questions regarding this document that relate to devices regulated by CBER, contact Stephen Ripley at 301-827-6210. U.S. Department of Health and Human Services Food and Drug Administration Center for Devices and Radiological Health Center for Biologic Evaluation and Research Contains Nonbinding Recommendations Preface Public Comment Written comments and suggestions may be submitted at any time for Agency consideration to the Division of Dockets Management, Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD, 20852. Additional Copies Additional copies are available from the Internet. You may also send an e-mail request to [email protected] to receive an electronic copy of the guidance or send a fax request to 301- 847-8419 to receive a hard copy. Please use the document number 1776 to identify the guidance you are requesting. Additional copies of this guidance document are also available from: Center for Biologics Evaluation and Research (CBER), Office of Communication, Outreach and Development (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448, or by calling 1-800-835-4709 or 301-827-1800, or email [email protected], or from the Internet at http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformatio n/Guidances/default.htm. 2 Contains Nonbinding Recommendations Table of Contents 1 INTRODUCTION ................................................................................................................ 4 2 SCOPE............................................................................................................................... 5 2.1 Types of Studies Addressed in this Guidance ........................................................................................ 5 2.2 Types of Studies Not Addressed in this Guidance .................................................................................. 6 3 REGULATORY FRAMEWORK FOR LEVEL OF EVIDENCE AND STUDY DESIGN ............... 7 3.1 The Statutory Standard for Approval of a PMA: Reasonable Assurance of Safety and Effectiveness .. 8 3.2 Valid Scientific Evidence ....................................................................................................................... 9 3.3 Benefit-Risk Assessment ....................................................................................................................... 10 3.4 Clinical Study Level of Evidence and Regulation ................................................................................ 11 3.5 The Least Burdensome Concept and Principles of Study Design ........................................................ 12 4 TYPES OF MEDICAL DEVICES ....................................................................................... 13 4.1 Types of Devices Based on Intended Use ............................................................................................ 14 4.2 Special Considerations for Clinical Studies of Devices ...................................................................... 15 5 THE IMPORTANCE OF EXPLORATORY STUDIES IN PIVOTAL STUDY DESIGN .............. 16 6 SOME PRINCIPLES FOR THE CHOICE OF CLINICAL STUDY DESIGN ............................ 17 6.1 Types of Studies ................................................................................................................................... 18 6.2 General Considerations: Bias and Variability in Device Performance .............................................. 19 6.3 Study Objectives................................................................................................................................... 19 6.4 Subject Selection .................................................................................................................................. 20 6.6 Site Selection ........................................................................................................................................ 22 6.7 Comparative Study Designs ................................................................................................................. 23 7 CLINICAL OUTCOME STUDIES ...................................................................................... 24 7.1 Endpoints in Clinical Studies .............................................................................................................. 24 7.2 Intervention Assignment (Randomization) for Clinical Outcome Studies ........................................... 26 7.3 Blinding (Masking) .............................................................................................................................. 28 7.4 Controls in Comparative Clinical Outcome Studies ............................................................................ 29 7.5 Placebo Effect and Other Phenomena ................................................................................................. 31 7.6 Non-Comparative Clinical Outcome Studies ....................................................................................... 32 7.7 Diagnostic Clinical Outcome Studies .................................................................................................. 34 7.8 Advantages and Disadvantages of Some Clinical Outcome Studies ................................................... 35 7.9 Some Regulatory Considerations ........................................................................................................ 38 8 DIAGNOSTIC CLINICAL PERFORMANCE STUDIES ........................................................ 38 8.1 Consideration of Intended Use ............................................................................................................ 39 8.2 Clinical Reference Standard for the Target Condition ........................................................................ 40 8.3 Study Population for Evaluation of Diagnostic Performance ............................................................. 41 8.4 Study Planning, Subject Selection and Specimen Collection ............................................................... 42 8.5 Diagnostic Clinical Performance Comparison Studies ....................................................................... 43 8.6 Blinding (Masking) in Diagnostic Performance Studies ..................................................................... 44 8.7 Skill and Behavior of Persons Interacting with the Device (Total Test Concept) ............................... 44 8.8 Common Types of Bias in Diagnostic Clinical Performance Studies .................................................. 45 9 SUSTAINING THE QUALITY OF CLINICAL STUDIES ....................................................... 46 9.1 Handling Clinical Data ....................................................................................................................... 46 9.2 Study Conduct ...................................................................................................................................... 47 9.3 Study Analysis ...................................................................................................................................... 49 9.4 Anticipating Changes to the Pivotal Study .......................................................................................... 50 10 THE PROTOCOL ............................................................................................................. 50 11 GLOSSARY ..................................................................................................................... 51 3 Contains Nonbinding Recommendations Design Considerations for Pivotal Clinical Investigations for Medical Devices Guidance for Industry, Clinical Investigators, and Food and Drug Administration Staff This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. 1 Introduction This document is intended to provide guidance to those involved in designing clinical studies intended to support pre-market submissions for medical devices and FDA staff who review those submissions. Although the Agency has articulated policies related to design of studies intended to support specific device types, and a general policy of tailoring the evidentiary burden to the regulatory requirement, the Agency has not attempted to describe the different clinical study designs that may be appropriate to support a device pre-market submission, or to define how a sponsor should decide which pivotal clinical study design should be used to support a submission for a particular device. This guidance document describes different study design principles relevant
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