CONVERGENCE of COMPLIANCE & TECHNOLOGY How Technology Has Changed Regulatory Compliance in the Past Decade MATTHEW M. LOWE ABOUT THE AUTHOR Matthew M. Lowe, executive vice president at MasterControl, is a mechanical engineer with over fifteen years of medical device experience in product development, product management, and regulatory compliance. Prior to joining MasterControl in 2006, he worked in product development and product management at Ortho Development Corp. and Bard Access Systems. He has successfully launched more than a dozen medical devices and has four patents issued. His regulatory compliance experience includes writing a 510(k) that was cleared by the FDA and managing a multisite, multiyear post- market clinical study for orthopedic devices. He received a bachelor’s degree in mechanical engineering from University of Utah and an MBA from Indiana University. Published by MasterControl Inc., 6330 S. 3000 E., Suite 200, Salt Lake City UT 84121 DEDICATION Copyright © 2016 by MasterControl Inc. To my wife for supporting me in my career these many years and raising our three beautiful children to be extraordinary young people in spite of the fact that All rights reserved. No part of this book may be reproduced in any I am their father. Family is everything. form or by any means without the prior written consent of the publisher, except for brief quotes in book reviews. The content of this book is the expression of the author’s opinions and ACKNOWLEDGMENTS do not necessarily reflect the policy or position of MasterControl. I want to recognize my editor, Cindy Fazzi, without whom this work would Publisher: Curt Porritt have never come to fruition. Her vision and encouragement was instrumental Executive Editor: Jason Clegg in bringing forth what I think is a very innovative e-book format. I would also Editor: Cindy Fazzi Art Director: Mike Hansen like to thank my many colleagues, past and present, who have shared their Cover Design, Illustrations, and Layout: Deserei Koker insights and knowledge with me over the past seventeen years. Together we Video: John Johannesmeyer can continue to shape the future of how technology enables and advances regulatory compliance. First edition: September 2016 Published in the United States of America Contents 01 VIDEO: CONVERGENCE OF COMPLIANCE AND TECHNOLOGY 02 PREFACE CHAPTER 1: THE RECENT PAST REVISITED 04 The Old Manual Process The MRR Bottleneck Murphy’s Law Other Life Science Companies CHAPTER 2: THE MOVEMENT TOWARD AUTOMATION 10 The Heart of 21 CFR Part 11 How Part 11 Became a Big Deal Early Days of Automation When Compliance is Adversarial CHAPTER 3: REGULATIONS THAT HELPED SPUR TECHNOLOGY USE 14 Compliance and Technology: Important Milestones CHAPTER 4: NO TIME LIKE THE PRESENT 19 Approval of Novel Drugs Approval of Medical Devices Greater Onus Software Industry’s Response Evolution of Quality Software Manual Process as Part of Obstacle Course CHAPTER 5: THE FUTURE STARTS NOW 25 Prediction versus Observation Part of the Tech Movement Future Collaboration CHAPTER 6: PREPARE TO SUCCEED 31 How Best to Prepare CHAPTER 7: CONCLUSION 34 Positive Regulatory Relations Software Providers as Part of Collaboration Right Place, Right Time 36 REFERENCES 01 Preface In terms of pharmaceuticals, the drug called Ivacaftor (brand name: Kayledeco) is the first medicine to treat the cause—instead of symptoms—of cystic fibrosis in patients with the G551D mutation.2 Not the stuff that Hollywood films are We live in a time of rapid change and information overload. It helps to pause made of, but incredibly important for patients suffering from the potentially fatal and ponder the state of things once in a while. In the software industry, the disease. Agile principles call for regular evaluation to sustain constant development work. In the quality field, the concept of continuous improvement is embedded Breakthroughs such as these happen, thanks in large part to faster and more in the quality management system (QMS) as a never-ending cycle of changes efficient, technology-driven clinical trials, regulatory submissions, and approval based on reviews and audits. process. I feel very fortunate to be part of this movement that advances society’s ability to deliver life-changing products to market. If you work in the My background in both medical device and software technology has instilled life science industry or a regulated environment or the compliance technology in me the value of the Agile and quality approaches to contemplation. Whether sector, then you’re part of this movement. it was implementing a rework due to a nonconformance back when I was a product development engineer at a med tech firm or helping a pharmaceutical I hope this book helps increase awareness and understanding of this common company automate its quality system in my current role, the need for path we share. This is not a history book, but just the same, it’s an opportunity assessment is the same. Reflection is necessary in order to learn, adapt, and to look back at the most important developments in the recent past that have improve. shaped regulatory compliance for life science companies. Writing this book is an opportunity for me to do exactly that—to reflect not just on the medical device sector but the life science industry in general, as well as the software development business. If our society were a city, then writing this book is a chance for me to offer you a snapshot of the highway where life science and technology merge in order to deliver medical solutions to the rest of the world. That on-ramp where the two merge is regulatory compliance. Without compliance, there can be no product approval, which means no matter how cutting-edge your device or how innovative your medicine, it will not reach the people who need them. In this metaphor, the individual life science companies are the different vehicles on the highway of compliance that deliver life-changing products to the global market. This book will explore how the use of technology in the past decade or so has helped both regulated companies and regulatory agencies in easing the pains of delivering those products to patients and consumers worldwide. Regulatory milestones enforced by the FDA helped define the book’s scope. In the past decade, we have seen numerous breakthroughs in the life science industry. For example, the BrainGate2 Neural Interface System is in the early stage of clinical trial to test the ability of paralyzed patients to control assistive devices with their thoughts.1 While telekinesis makes for great fiction, technology-driven telekinesis by implanting a sensor in the brain might just be a The cochlear implant worn by this woman alleviates certain types of reality soon. hearing loss, one of the many med device breakthroughs. 02 03 01 THE RECENT PAST REVISITED Life science companies face enormous scientific, economic, and regulatory challenges during development of medical products. While the growth of R&D has always been intertwined with technological advances, it has not been the case for regulatory compliance. The watershed regulation, 21 CFR Part 11, established the criteria for the use of electronic records and electronic signatures by organizations under the jurisdiction of the U.S. Food and Drug Administration (FDA). Part 11 was controversial from the start. Critics complained it was too broad and confusing. Companies said it was too costly to implement. Part 11 went into effect in August 1997, but it took the FDA two guidances (in 2001 and 2003) to explain the regulation’s scope and application. The 2003 guidance signaled that, at last, the FDA had embraced technology for compliance purposes. It served as a catalyst for software companies to develop compliance solutions tailored to Part 11 and for the industry to automate quality processes. It’s no coincidence that in 2004, the Pharmaceutical Research and Manufacturers of America (PhRMA) issued the SAFE (Signatures and Authentication for Everyone) digital signature standard. “Part 11 confirmed the dire need for improvement of processes.” Before the advent of laws regulating the life science industry, leeches* and snake oil were sold as medicine. 04 THE OLD MANUAL PROCESS Imagine standing before a long table with an array of stamps and different colors of ink pads with your piles of documents. Perhaps you would need a blue stamp for “proposed” documents, a green stamp for “approved” and black To understand how technology revolutionized the compliance process, it’s for “released.” Talk about watermarking! You would stamp each copy with the important to put this story in the right context. Let me describe what a paper- appropriate stamp. You would then attach your documents to the CO form and based process was like when I worked in the med tech industry. submit everything to doc control, cross your fingers, and hope you didn’t miss anything. In my first job in a med device firm, I was a product development engineer (PDE). The process for getting a new drawing through the system required a If doc control took issue with anything, it would involve re-printing, revisiting the lot of time and effort. Bear with me and imagine the process we endured back table for re-stamping, and re-submitting the change packet. Are you tired yet? then. Wait, we’re not yet finished. First, you would start with an informal redline of the paper drawing among your Once the doc control team members were satisfied, they would then consult peers (e.g., other PDEs and the manager). Once done with that, you would the signature matrix and ensure the CO form had the right signatories. The list incorporate the changes and print a new copy. You would have to print an old was often bloated—by design—as there would be several individuals on the list copy and manually go through the drawing and redline it to reflect the changes included only as a safeguard in the new proposed copy.