SAGE Sourcebook of Modern Biomedical Devices: Business Environments in a Global Market
Publication Year: 2007
Subject: Clinical Medicine (general)
SAGE Sourcebook of Modern Biomedical Devices: Business Markets in the Global Environment is the first accessible, broadly available source of information that presents and quantifies the commercial success of numerous types of biomedical devices available in the global market. It is of great importance, for both the research and the business communities, to identify specific biomedical device types, per major therapeutic areas, most commercially successful in today’s global economic markets, such as in the biggest market (U.S.), in the Pacific Rim, and in the newly expanded European Union. Currently, such vital information is not available anywhere else, definitely not in a unified source and not in a detailed, well-substantiated, reliable, and easy-to-read form.
- Front Matter
- Subject Index
- Chapter 1: US Markets for Interventional Cardiology
- Chapter 2: US Markets for Coronary Stents
- Chapter 3: US Markets for PTCA Balloons
- Chapter 4: US Markets for Plaque Modification Devices
- Chapter 5: US Markets for Interventional Cardiology Accessory Devices
- Chapter 6: European Markets for Interventional Cardiology
- Chapter 7: European Markets for Coronary Stents
- Chapter 8: European Markets for PTCA Balloons
- Chapter 9: Japanese Markets for Interventional Cardiology
- Chapter 10: Asia Pacific Markets for Interventional Cardiology
- Chapter 11: Latin American Markets for Interventional Cardiology
- Chapter 12: Global Markets for Vascular Closure Devices
- Chapter 13: US Markets for Peripheral Vascular Devices
- Chapter 14: European Markets for Peripheral Vascular Devices
- Chapter 15: Japanese Markets for Peripheral Vascular Devices
- Chapter 16: Asia Pacific Markets for Peripheral Vascular Devices
- Chapter 17: Latin American Markets for Peripheral Vascular Devices
- Chapter 18: Canadian Markets for Peripheral Vascular Devices
- Chapter 19: US Markets for Plaque Modification and Thrombus Management
- Chapter 20: US Markets for Transcatheter Embolization and Occlusion Devices
- Chapter 21: European Markets for Transcatheter Embolization and Occlusion Devices
- Chapter 22: Emerging European Markets for Transcatheter Embolization and Occlusion Devices
- Chapter 23: Latin American Markets for Transcatheter Embolization and Occlusion Devices
- Chapter 24: US Markets for Electrophysiology Mapping and Ablation Devices
- Chapter 25: European Markets for Electrophysiology Mapping and Ablation Devices
- Chapter 26: Japanese Markets for Electrophysiology Mapping and Ablation Devices
- Chapter 27: European Markets for Cardiac Rhythm Management (CRM) Devices
- Chapter 28: Japanese Markets for Cardiac Rhythm Management (CRM) Devices
- Chapter 29: US Markets for Vascular Access Devices
- Chapter 30: European Markets for Vascular Access Devices
- Chapter 31: Japanese Markets for Vascular Access Devices
- Chapter 32: US Markets for Cardiac Surgery Devices
- Chapter 33: European Markets for Cardiac Surgery Devices
- Chapter 34: US Markets for Heart Valves
- Chapter 35: European Markets for Heart Valves
- Chapter 36: US Markets for Cardiac Assist Devices
- Chapter 37: Global Markets for Coronary Artery Bypass Grafting (CABG) Devices
- Chapter 38: US Markets for Large-Joint Reconstructive Implants
- Chapter 39: US Markets for Small-Joint Reconstructive Implants
- Chapter 40: European Markets for Orthopedic Reconstructive Implants
- Chapter 41: Japanese Markets for Orthopedic Reconstructive Implants
- Chapter 42: Global Markets for Hip Resurfacing
- Chapter 43: US Markets for Orthopedic Trauma Devices
- Chapter 44: European Markets for Orthopedic Trauma Devices
- Chapter 45: Japanese Markets for Orthopedic Trauma Devices
- Chapter 46: US Markets for Spinal Implants
- Chapter 47: European Markets for Spinal Implants
- Chapter 48: Asia Pacific Markets for Spinal Implants
- Chapter 49: Brazilian Markets for Spinal Implants
- Chapter 50: Canadian Markets for Spinal Implants
- Chapter 51: Chinese Markets for Spinal Implants
- Chapter 52: Indian Markets for Spinal Implants
- Chapter 53: US Markets for Minimally Invasive Spinal Fusion Technologies
- Chapter 54: Global Markets for Minimally Invasive Vertebral Compression Fracture Treatments
- Chapter 55: US Markets for Orthopedic Biomaterials
- Chapter 56: European Markets for Orthopedic Biomaterials
- Chapter 57: Japanese Markets for Orthopedic Biomaterials
- Chapter 58: Global Markets for Hyaluronic Acid Viscosupplementation
- Chapter 59: US Markets for Dental Implants
- Chapter 60: European Markets for Dental Implants
- Chapter 61: Asia Pacific Markets for Dental Implants
- Chapter 62: US Markets for Dental Biomaterials
- Chapter 63: European Markets for Dental Biomaterials
- Chapter 64: Asia Pacific Markets for Dental Biomaterials
- Chapter 65: US Markets for Orthodontic Appliances
- Chapter 66: Global Markets for Powered Surgical Instruments
- Chapter 67: US Markets for Craniomaxillofacial Devices
- Chapter 68: Latin American Markets for Orthopedic Devices
- Chapter 69: US Markets for Arthroscopic Devices
- Chapter 70: European Markets for Arthroscopic Devices
- Chapter 71: US Markets for ENT and Bronchoscopy Devices
- Chapter 72: European Markets for ENT and Bronchoscopy Devices
- Chapter 73: US Markets for Gastrointestinal Endoscopy Devices
- Chapter 74: European Markets for Gastrointestinal Endoscopy Devices
- Chapter 75: Japanese Markets for Gastrointestinal Endoscopy Devices
- Chapter 76: Canadian Gastrointestinal and Pulmonary Procedure Volumes
- Chapter 77: US Markets for Laparoscopic Devices
- Chapter 78: European Markets for Laparoscopic Devices
- Chapter 79: European Markets for Visualization Devices
- Chapter 80: US Markets for Video and High-Tech Hardware Devices
- Chapter 81: US Markets for Bariatric Surgery Devices
- Chapter 82: European Markets for Endoscopy Devices
- Chapter 83: Japanese Markets for Endoscopy Devices
- Chapter 84: US Markets for Urological Devices
- Chapter 85: European Markets for Urological Devices
- Chapter 86: Japanese Markets for Urological Devices
- Chapter 87: Competitor Insights for Urological Devices
- Chapter 88: US Markets for Urodynamics Devices
- Chapter 89: US Markets for Gynecological Devices
- Chapter 90: European Markets for Gynecological Devices
- Chapter 91: Global Markets for Vaginal Slings
- Chapter 92: European and Japanese Markets for Hysterectomy Alternatives
- Chapter 93: US Markets for Facial Aesthetics
- Chapter 94: European Markets for Facial Aesthetics
- Chapter 95: Asia Pacific Markets for Facial Aesthetics
- Chapter 96: Canadian Markets for Facial Aesthetics
- Chapter 97: Brazilian Markets for Facial Aesthetics
- Chapter 98: Mexican Markets for Facial Aesthetics
- Chapter 99: US Markets for Aesthetic Lasers
- Chapter 100: European Markets for Aesthetic Lasers
- Chapter 101: US Markets for Ophthalmic Devices
- Chapter 102: European Markets for Ophthalmic Devices
- Chapter 103: Japanese Markets for Ophthalmic Devices
- Chapter 104: Asian Markets for Ophthalmic Devices
- Chapter 105: US Markets for Cataract and Refractive Devices
- Chapter 106: US Markets for Glaucoma and Retinal Devices
- Chapter 107: US Markets for Ophthalmic Diagnostic Devices
- Chapter 108: US Markets for Diagnostic Imaging Systems
- Chapter 109: US Markets for X-Ray Systems
- Chapter 110: US Markets for Diagnostic Ultrasound Systems
- Chapter 111: European Markets for Diagnostic Imaging Systems
- Chapter 112: Japanese Markets for Diagnostic Imaging Systems
- Chapter 113: US Markets for Image Guided Surgery
- Chapter 114: European Markets for Image Guided Surgery
- Chapter 115: Japanese Markets for Image Guided Surgery
- Chapter 116: US Markets for Radiotherapy and Radiosurgery Systems
- Chapter 117: US Markets for PACS and RIS
- Chapter 118: European Markets for PACS
- Chapter 119: Asia Pacific Markets for PACS
- Chapter 120: RSNA Survey 2006: US and European PACS
- Chapter 121: US Markets for Acute Care Clinical Information Systems
- Chapter 122: US Markets for Critical Care Patient Monitoring Devices
- Chapter 123: European Markets for Critical Care Patient Monitoring Devices
- Chapter 124: US Markets for Electronic Medical Records
- Chapter 125: US Markets for Digital Dermoscopy Devices
- Chapter 126: US Markets for Varicose Vein Treatment
- Chapter 127: US Markets for Neurosurgery Devices
- Chapter 128: US Markets for End-Stage Renal Disease (ESRD) Dialysis Devices
- Chapter 129: US Markets for Respiratory Management Devices
- Chapter 130: US Markets for Medical Lasers
- Chapter 131: US Markets for Soft Tissue Repair
- Chapter 132: European Markets for Soft Tissue Repair
- Chapter 133: Japanese Markets for Soft Tissue Repair
- Chapter 134: US General Surgery: Market Opportunities
- Chapter 135: Global Electronic Ambulatory Infusion Devices
- Chapter 136: Global Markets for Hyaluronic Acid-Based Medical Devices
Copyright © 2007 by SAGE Publications, Inc.
All rights reserved. No part of this book may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, without permission in writing from the publisher.
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Library of Congress Cataloging-in-Publication Data
SAGE sourcebook of modern biomedical devices: business environments in a global market.
ISBN 978-1-4129-5054-1 (cloth)
1. Biotechnology industries. 2. Biomedical materials. 3. Medical instruments and apparatus industry. 4. Diagnostic imaging. 5. Medical informatics. 6. Market surveys. I. Sage Publications, Inc. II. Title: Sourcebook of modern biomedical devices.
This book is printed on acid-free paper.
07 08 09 10 11 10 9 8 7 6 5 4 3 2 1
Publisher: Rolf A. Janke
Project Editor: Tracy Alpern
Proofreaders: Andrea Martin, Jennifer Withers, Jennifer Ang, Penelope Sippel
Typesetter: C&M Digitals (P) Ltd.
Indexer: Janet Perlman
Cover Designer: Ravi Balasuriya
Marketing Manager: Carmel Withers
List of Entries
- US Markets for Interventional Cardiology
- US Markets for Coronary Stents
- US Markets for PTCA Balloons
- US Markets for Plaque Modification Devices
- US Markets for Interventional Cardiology Accessory Devices
- European Markets for Interventional Cardiology
- European Markets for Coronary Stents
- European Markets for PTCA Balloons
- Japanese Markets for Interventional Cardiology
- Asia Pacific Markets for Interventional Cardiology
- Latin American Markets for Interventional Cardiology
- Global Markets for Vascular Closure Devices
Peripheral Vascular Devices
- US Markets for Peripheral Vascular Devices
- European Markets for Peripheral Vascular Devices
- Japanese Markets for Peripheral Vascular Devices
- Asia Pacific Markets for Peripheral Vascular Devices
- Latin American Markets for Peripheral Vascular Devices
- Canadian Markets for Peripheral Vascular Devices
- US Markets for Plaque Modification and Thrombus Management
Transcatheter Embolization and Occlusion Devices
- US Markets for Transcatheter Embolization and Occlusion Devices
- European Markets for Transcatheter Embolization and Occlusion Devices
- Emerging European Markets for Transcatheter Embolization and Occlusion Devices
- Latin American Markets for Transcatheter Embolization and Occlusion Devices
- US Markets for Electrophysiology Mapping and Ablation Devices
- European Markets for Electrophysiology Mapping and Ablation Devices
- Japanese Markets for Electrophysiology Mapping and Ablation Devices
- European Markets for Cardiac Rhythm Management (CRM) Devices
- Japanese Markets for Cardiac Rhythm Management (CRM) Devices
Vascular Access Devices
- US Markets for Vascular Access Devices
- European Markets for Vascular Access Devices
- Japanese Markets for Vascular Access Devices
Cardiac Surgery Devices
- US Markets for Cardiac Surgery Devices
- European Markets for Cardiac Surgery Devices
- US Markets for Heart Valves
- European Markets for Heart Valves
- US Markets for Cardiac Assist Devices
- Global Markets for Coronary Artery Bypass Grafting (CABG) Devices
Reconstructive Orthopedic Devices
- US Markets for Large-Joint Reconstructive Implants
- US Markets for Small-Joint Reconstructive Implants
- European Markets for Orthopedic Reconstructive Implants
- Japanese Markets for Orthopedic Reconstructive Implants
- Global Markets for Hip Resurfacing
- US Markets for Orthopedic Trauma Devices
- European Markets for Orthopedic Trauma Devices
- Japanese Markets for Orthopedic Trauma Devices
- US Markets for Spinal Implants
- European Markets for Spinal Implants
- Asia Pacific Markets for Spinal Implants
- Brazilian Markets for Spinal Implants
- Canadian Markets for Spinal Implants
- Chinese Markets for Spinal Implants
- Indian Markets for Spinal Implants
- US Markets for Minimally Invasive Spinal Fusion Technologies
- Global Markets for Minimally Invasive Vertebral Compression Fracture Treatments
- US Markets for Orthopedic Biomaterials
- European Markets for Orthopedic Biomaterials
- Japanese Markets for Orthopedic Biomaterials
- Global Markets for Hyaluronic Acid Viscosupplementation
- US Markets for Dental Implants
- European Markets for Dental Implants
- Asia Pacific Markets for Dental Implants
- US Markets for Dental Biomaterials
- European Markets for Dental Biomaterials
- Asia Pacific Markets for Dental Biomaterials
- US Markets for Orthodontic Appliances
- Global Markets for Powered Surgical Instruments
- US Markets for Craniomaxillofacial Devices
- Latin American Markets for Orthopedic Devices
- US Markets for Arthroscopic Devices
- European Markets for Arthroscopic Devices
- US Markets for ENT and Bronchoscopy Devices
- European Markets for ENT and Bronchoscopy Devices
- US Markets for Gastrointestinal Endoscopy Devices
- European Markets for Gastrointestinal Endoscopy Devices
- Japanese Markets for Gastrointestinal Endoscopy Devices
- Canadian Gastrointestinal and Pulmonary Procedure Volumes
- US Markets for Laparoscopic Devices
- European Markets for Laparoscopic Devices
- European Markets for Visualization Devices
- US Markets for Video and High-Tech Hardware Devices
- US Markets for Bariatric Surgery Devices
- European Markets for Endoscopy Devices
- Japanese Markets for Endoscopy Devices
Urology and Gynecology Devices
- US Markets for Urological Devices
- European Markets for Urological Devices
- Japanese Markets for Urological Devices
- Competitor Insights for Urological Devices
- US Markets for Urodynamics Devices
- US Markets for Gynecological Devices
- European Markets for Gynecological Devices
- Global Markets for Vaginal Slings
- European and Japanese Markets for Hysterectomy Alternatives
- US Markets for Facial Aesthetics
- European Markets for Facial Aesthetics
- Asia Pacific Markets for Facial Aesthetics
- Canadian Markets for Facial Aesthetics
- Brazilian Markets for Facial Aesthetics
- Mexican Markets for Facial Aesthetics
- US Markets for Aesthetic Lasers
- European Markets for Aesthetic Lasers
- US Markets for Ophthalmic Devices
- European Markets for Ophthalmic Devices
- Japanese Markets for Ophthalmic Devices
- Asian Markets for Ophthalmic Devices
- US Markets for Cataract and Refractive Devices
- US Markets for Glaucoma and Retinal Devices
- US Markets for Ophthalmic Diagnostic Devices
- US Markets for Diagnostic Imaging Systems
- US Markets for X-Ray Systems
- US Markets for Diagnostic Ultrasound Systems
- European Markets for Diagnostic Imaging Systems
- Japanese Markets for Diagnostic Imaging Systems
- US Markets for Image Guided Surgery
- European Markets for Image Guided Surgery
- Japanese Markets for Image Guided Surgery
- US Markets for Radiotherapy and Radiosurgery Systems
Health Care Information Technology
- US Markets for PACS and RIS
- European Markets for PACS
- Asia Pacific Markets for PACS
- RSNA Survey 2006: US and European PACS
- US Markets for Acute Care Clinical Information Systems
- US Markets for Critical Care Patient Monitoring Devices
- European Markets for Critical Care Patient Monitoring Devices
- US Markets for Electronic Medical Records
- US Markets for Digital Dermoscopy Devices
Other Medical Device Areas of Interest
- US Markets for Varicose Vein Treatment
- US Markets for Neurosurgery Devices
- US Markets for End-Stage Renal Disease (ESRD) Dialysis Devices
- US Markets for Respiratory Management Devices
- US Markets for Medical Lasers
- US Markets for Soft Tissue Repair
- European Markets for Soft Tissue Repair
- Japanese Markets for Soft Tissue Repair
- US General Surgery: Market Opportunities
- Global Electronic Ambulatory Infusion Devices
- Global Markets for Hyaluronic Acid-Based Medical Devices
This reference work is both important and unique. Its uniqueness is that it ties together the commercial aspects of the performance of major biomedical devices available today on the global market, with the technological development of these devices that is the core of the research efforts in the field. The information presented here is indeed extremely difficult to find in other available sources and yet it is critical not only for business people who need to stay abreast of the market trends or for government agencies who need to know the current status and the future prospects in biomedical industries and R&D, but also to researchers themselves. Indeed, the information provided in this reference would be key for researchers who would be able to have a glimpse on the “other” side of the results of their research; that is, the commercial viability side. In other words, having this reference would allow researchers to determine as to whether the final result of the subject of their research in the field of biomedical device applications is a success or a failure in the actual marketplace. For example, are the imaging devices, one of the “symbols” of modern technological and scientific applications in today's biomedical device field, ultimately making it in the marketplace or not? If they are, then what makes them successful? If they are not, what makes them a failure? How do they fair in, for example, Japan? In the European community? In North America? Globally? Finally, very important for researchers—does the market success of specific devices mean more funding for research in their respective field of biomedical device research? Further, if so, then where geographically and from what national government source, could such funding possibly be expected? Indeed, as today's researchers evaluate realistic prospects of continuous and increased funding in the specific R&D areas of bio-medical device technology, the information as provided in this Reference, especially if periodically updated, will be essential and could well prove this Reference an indispensable source.
Overall, medical devices is a growing $80-billion-a-year business. Some 20 million Americans now walk around embedded with high-tech gear: artificial hips and knee joints, pacemakers, heart defibrillators, et cetera. Most of the 80,000 devices now in use—and most of the 4,000 new ones approved every year—are safe and effective. Because of this impressive growth rate, there has been a very substantial push for mergers and acquisitions in the commercial world of medical devices.
[Page xii]Correspondingly, the research, development, output, and investment in today's biomedical device sectors are enormous and growing. Take, just as an example, the orthopedic industry, which is today the largest sector in medical devices. It has the most revenues—$17 billion versus the No. 2 cardiology sector's $14 billion. It has the most companies (1,500 vs. cardiology's 500), and it addresses three of the larger chronic diseases: arthritis, osteoporosis, and back pain. To put that in perspective, those three diseases encompass roughly 75 million patients in the US—three times the number addressed by the cardiovascular market—and roughly 25% of the country's population. A number of elements will combine over the next decade to create an even greater opportunity for the sector, including an overall increased life expectancy, increased technological innovation, an increasingly favorable regulatory and reimbursement environment, and attractive industry economics and profitability. Combined, these elements will cause the industry to grow more than fourfold from $15 billion per year to $65 billion in the coming decade resulting in as much as $80 billion of potential investor profits. In 2007, the number of patients requesting treatment for arthritis, osteoporosis, back pain, sports, or other trauma will rise an estimated 2.3% to 150 million people worldwide. Approximately 77% of this growth will be attributable to an aging population in the US, Europe, and Japan. Several technologies to watch include
- alternate bearing components (i.e., ceramic on ceramic hips, oxinium knees), minimally invasive surgical hip and knee techniques,
- signaling factors (bone morphogenic proteins such as infuse and the Peptides),
- anti-adhesion gels,
- mobile bearing knee,
- increasing use of external fixation (i.e., therapeutic bracing) to deliver specific pain therapy or to accelerate tissue repair.
Not less important, from the standpoint of expected growth, investment, and R&D output is the cardiovascular area, coronary artery disease being the world's leading killer. On the drug front, Pfizer has risen to the top of the pharmaceutical industry largely on the strength of Lipitor which, along with its rivals, became one of the world's best-selling class of medicines in the past two decades. Its ability to lower bad artery-clogging cholesterol, known as LDL, has led to substantial reductions in heart attacks and death, transforming cardiology in the process. As many as half of heart attack victims have LDL levels that are considered normal. As it turned out, many of these patients also had low levels of HDL or good cholesterol which helps clear arteries of the bad kind. More than 50 million Americans, about 25% of the population, have low HDL, according to the American Heart Association. Pfizer's effort to develop an HDL-raising drug began in 1990 after a paper was published in the New England Journal of Medicine showing no evidence of early heart disease among a dozen Japanese families with high HDL. Pfizer's decision to develop Torcetrapib, a drug to produce [Page xiii]higher HDL, was one result. Early results have been promising and Pfizer plans to invest almost $1 billion in its development.
In the meantime, as the problem of dealing with heart attacks remains an important issue, biomedical devices such as stents, which are wire-mesh scaffolds to prop open blood vessels, offer quick relief of symptoms. Bypass surgery is the most invasive procedure that involves cracking open the chest. But for especially serious disease, it may be the best solution. The stent's roots go back to 1977 when legendary cardiologist Andreas Gruentzig, using a device fashioned in his own kitchen, performed the first coronary balloon angioplasty procedure in Zurich. The event heralded the age of interventional cardiology, offering the promise that patients could get diseased arteries fixed without open heart surgery. This is the promise of stents. It soon emerged, however, that stents had a problem of their own: the tendency to promote the formation of scar tissue that often re-clogged the artery triggering a recurrence of chest pain. The problem was called restenosis, and in 15% to 25% of cases it required a repeat procedure, usually within 6 months of the first one. Today stents are big business. Cardiologists who implant them have largely supplanted heart surgeons as the generals in the fight against heart disease. The devices have provided vital profit-making for Johnson and Johnson and Boston Scientific Corp., which dominate the $6 billion global market. Further, to deal with the problem of restenosis, drug-eluting stents (DES) have proven to be effective, and there are a number of DES products on the market or coming to the market.
The FDA looked at tightening medical device rules in the early 1990s. In 1993, the FDA issued a report on how the burgeoning device industry could conduct more rigorous clinical trials. That faded in 1997 when Congress passed a law dictating that new devices must be approved by the “least burdensome” method possible.
By that time the industry had gotten a big boost with the first metal stent for clogged arteries. Doctors were doing 300,000 balloon angioplasties annually in the US, but in upward of 40% of cases the artery re-clogged (restenosis) to combat this. J&J in 1994 introduced the first stent to prop the artery open; this cut restenosis to 15% of cases. Angioplasties soared to 80,000 a year by 2002. Then came J&J's drug-coated stent, which reduced the re-clogging problem to fewer than 5% of patients, and angios increased to more than a million a year.
The high level of commercial interest in stents has further generated both significant investments and a very significant R&D output aimed at improving their performance. For example, at this time, the FDA has been using panels of experts to weigh the safety of DES medical devices as, just recently, concerns have developed that DES stents may cause potentially fatal blood clots. Unlike drugs, medical devices that have been approved by federal regulators are generally protected from personal-injury lawsuits, as a result of the Congressional law passed in 1997. Currently, there are almost 5 million patients worldwide who have the DES devices in their chests—on average, about 1.5 each.
[Page xiv]Today, there are many greatly significant classes of medical devices, all of which are the results of extensive scientific research and further industrial development. While this Reference deals primarily with commercial/business aspects of these devices, it is nevertheless interesting and important to recall how it all started and to look at the technological/scientific background of at least some of them. For that purpose, let's consider briefly one of the most exciting and technologically (and commercially) promising examples—medical imaging systems and techniques. One of the more widely known among those is the X-ray imaging device.
X-rays enable researchers and doctors to look for the first time into the human body to examine internal structure without cutting open the body. The discoverer of X-rays, Wilhelm Conrad Roentgen, made a radiograph of his wife's hand in 1895. He won the first Nobel Prize in Physics 6 years later for the break-through work.
The art of imaging with X-rays has come a long way since then. Significant improvements have resulted from the availability of intense synchrotron radiation, from the use of phase contrast and related contrast means (besides the original absorption contrast), and from the invention of computer-assisted tomography (CAT) that moved projections from two dimensions (2D) to a full understanding of three dimensions (3D). Allan Cormack and Godfrey Hounsfield received the 1979 Nobel Prize in Physiology or Medicine for developing the CAT scan.
American Paul Lauterbur and Briton Sir Peter Mansfield won the Nobel Prize for Medicine in 2003 for discoveries leading to a technique that reveals images of the body's inner organs. Magnetic resonance imaging, or MRI, has become a routine method for medical diagnosis and treatment. It is used to examine almost all organs without need for surgery, but is especially valuable for detailed examination of the brain and spinal cord as well as other areas. Lauterbur, of the Biomedical Magnetic Resonance Laboratory at the University of Illinois in Urbana, discovered the possibility of creating a two-dimensional picture by producing variations in a magnetic field. Mansfield, of the University of Nottingham in Britain, showed how signals the body emits in response to the magnetic field could be mathematically analyzed, which made it possible to develop a useful imaging technique. Mansfield also showed how extremely fast imaging could be achievable. This became technically possible within medicine a decade later. MRI images have had an enormous impact on health care in the developed part of the world today. Worldwide, more than 60 million investigations with MRI are performed each year. MRI represents a major breakthrough in medical diagnostics and research.
The next major area in medical imaging is PET/CT. Positron emission tomography (PET) and Computerized Tomography (CT) are both standard imaging tools that allow physicians to pinpoint the location of cancer within the body before making treatment recommendations. The highly sensitive PET scan detects the metabolic signal of actively growing cancer cells in the body and the CT scan [Page xv]provides a detailed picture of the internal anatomy that reveals the location, size, and shape of abnormal cancerous growths. Alone, each imaging test has particular benefits and limitations, but when the results of PET and CT scans are “fused” together, the combined image provides complete information on the cancer location and metabolism.
While a CT scan provides anatomical detail (size and location of the tumor, mass, etc.), a PET scan provides metabolic detail (cellular activity of the tumor, mass, etc.). Combined PET/CT is more accurate than PET and CT alone. Anatomical: CT scanners send X-rays through the body, which are then measured by detectors in the CT scanner. A computer algorithm then processes those measurements to produce pictures of the body's internal structures. Metabolic: PET images begin with an injection of FDG, an analog of glucose that is tagged to the radionuclide F18. Metabolically active organs or tumors consume sugar at high rates, and as the tagged sugar starts to decay, it emits positrons. These positrons then collide with electrons, giving off gamma rays, and a computer converts the gamma rays into images. These images indicate metabolic “hot spots,” often indicating rapidly growing tumors (because cancerous cells generally consume more sugar/energy than other organs or tumors).
A PET/CT scan allows physicians to measure the body's abnormal molecular cell activity to detect
- cancer (such as breast cancer, lung cancer, colorectal cancer, lymphoma, melanoma, and other skin cancers),
- brain disorders (such as Alzeheimer's Disease, Parkinson's Disease, and epilepsy), and
- heart disease (such as coronary artery disease).
PET/CT scans are simple, painless, and fast, offering patients and their families life-saving information that helps physicians detect and diagnose diseases early and quickly begin treatment. There are over 600 scanners installed worldwide in such leading institutions as
- M.D. Anderson,
- US Oncology,
- Hammersmith Hospital,
- University of Munich,
- Thompson Cancer Center, and
- Washington University School of Medicine.
[Page xvi]Depending on the type of cancer, it can be treated by surgery, chemotherapy, or X-ray treatment. Without PET/CT technology it would virtually be impossible to treat squamous cell cancer tumors in the body by chemotherapy. In this instance, chemotherapy might involve chemotherapy one day a week for 6 weeks. Then the patient has 2 weeks off; during the 2 weeks off the patient has a PET/CT scan to determine the reduction in the size of the cancerous tumors which typically might be in several places in the body. The reduction in the size of the tumors is noted and a second 6-week round of chemotherapy is conducted followed by 2 weeks off during which a second PET/CT scan is conducted and so on until the tumors have been eradicated. With the constant advances in chemotherapy drugs, Avastin, for example, the chemotherapy might require 4 rounds before remission. Without PET/CT scans, the oncologists would be “flying blind.”
The next advance in medical imaging that should be mentioned here is represented by “full body scans.” Time was when our best medical minds thought peptic ulcers were a “lifestyle disease,” the result of too much stress, too much spicy food, or some combination thereof. For treatment, doctorly prescriptions included time off from work, chewing your food thoroughly, popping antacids, and drinking quantities of milk. In severe cases, patients went under the knife to have their stomach linings removed. So it is not altogether surprising that when Australian physician Barry Marshall suggested, at a Brussels conference in 1983, that peptic ulcers might have a bacterial cause, his findings were dismissed by colleagues as “the most preposterous thing ever heard,” according to his entry in the Biography Yearbook for 2005. Far from being deterred, however, Dr. Marshall pursued his line of inquiry into a bacterium named Helicobacter pylori, which had been discovered by his Australian collaborator Robin Warren and which seemed to be closely associated with gastric inflammation. Dr. Marshall even went so far as to make himself a research guinea pig by drinking a microbial stew which caused him to become ill but which further confirmed the validity of their hypothesis. Today, the milk-and-rest cure is a thing of the past, surgeries are rare, and a disease that affects some 4 million Americans annually can usually be treated successfully within a few weeks with an antibiotic cocktail. For their findings, Drs. Marshall and Warren shared the 2005 Nobel Prize in Medicine. It's an inspired choice—and a useful reminder that just because there is a scientific “consensus,” that doesn't mean it is true. In the US, 30% of the adult population is infected. In countries with poor sanitation, 90% of the adult population can be infected. In the US, diagnosis can be carried by endoscopic examination, which can also be used for the diagnosis of hemorrhoids, for example. In any event, it is a fact that many patients prefer to have a full body scan rather then endure the discomfort of an endoscopic examination. The full body scan is also referred to as a virtual endoscopic exam. The full body scan is a procedure preferred by many patients for general reasons. Specifically, for example, a full body scan can reveal the presence of a previously undiagnosed cancer, in some rare cases as much as a fourth-stage cancer.
[Page xvii]There are other modalities that are continuously developed, but passing on to the next generation of health care information systems, these will consist of a vast network of heterogeneous, autonomous, and distributed imaging scanners, image acquisition systems, databases, information systems, knowledge intensive applications, and large quantities of multimedia medical data. The diffusion of multimedia information management will enable the development of tools available for effective decision making and open up many opportunities in health care services. To transmit and link patient information, however, presumes the existence of an infrastructure. Currently most medical information management systems, such as hospital information systems and radiology information systems, handle only textual patient information and lack the computing mechanisms and networking resources to handle different kinds of digital modalities. The Picture-Archival and Communication Systems (PACS), which are evolving, lack the intelligence and flexibility in accessing, processing, and manipulating image information as the current Data Base Management Systems (DBMS) for managing textual data can. A key challenge facing system researchers and builders is to provide a new technological framework to integrate the current distributed, multimedia information resources into what appears to the users as a uniform and logical conglomerate of databases supporting diverse image-assisted medical applications. Research and development in the core technologies are being pursued with a view toward the development of a framework for multimodality imaging base management (MIBM). This framework can serve as a blueprint for developing digital radiology departments and integration of radiology with other departments for hospitals of the future. The implementation of the MIBM framework is a bottom-up endeavor, with the foundation of a comprehensive infrastructure for multimedia file management, archival and communication in place before developing sophisticated image database management and applications development in MIBM is evolutionary. In open systems connectivity and object interfaces support the incremental integration with standardized information systems as well as legacy systems of other hospital departments.
The hierarchical information framework consists of three components: a picture archiving and communication system (PACS), a medical image database system (MIDS), and a set of image-assisted medical applications. The value-added middle-ware, MIDS, enables the user to access multimedia images and text of the underlying heterogeneous distributed systems as if they are stored in a single database. In addition, the MIDS server also provides image processing, security measures, and workflow management for various medical applications; the MIDS serves as a framework to contain the comprehensive set of core functionality for image management. The workflow management system is used to adapt the functionality for the distinct processes of each health care organization. Modules interfacing to external systems seamlessly integrate with the image management framework, such that new applications can be developed to tailor the needs of the health care unit, yet minimizing the engineering and maintenance costs.
[Page xviii]An important result of this concept is improved patient services, while reducing cost expenses of the health care provider. Another important point is the need for integration with advances in medical and biotechnology research. Efforts are underway to image various levels of the human brain and to map the complete set of human genes. The tremendous amount of data that will be generated by such projects will need to be stored in distributed databases. New clinical information systems will be developed to provide a structured model for such databases, and standards need to be established. After the standards are in place, the integration of these next-generation clinical applications with the existing image-management framework will be crucial. Such integrated computerized medical records, containing the core functionality of PACS, RIS, and HIS, along with the next generation of clinical application components, will play a vital role in shaping health care practice of the future. With a means to present this wealth of information, health care providers will be able to make accurate diagnosis within a short time span, and plan more effective therapies and preventive measures.
As to the future and the approval process of new medical devices, new medical devices don't need the large-scale exhaustive trials of the drug industry, because it is easier to predict the behavior of a machine than it is to track the chemical interactions of a new drug in the body. But the FDA vows to pursue sweeping changes in how it monitors device performance after approval, creating a massive database to track all adverse events, far faster than today's paperwork reporting process can. According to Daniel Schultz, the FDA's chief device regulator, “We are talking about fundamental changes.” He emphasizes that the benefits of medical devices “far out-weigh any risk.”
And this translates to a bright future for medical devices. Just look at the incredible commercial success of many of them as so vividly illustrated in this very useful Reference!
Introduction[Page xix]Biomedical Devices: Intersection of Science, Technology, and Business
This reference covers an important area of the commercial performance of major existing biomedical devices in today's global markets. This is a subject of great interest in itself. While analyzing the performance of current devices, it is useful to researchers to consider the broad picture of expected developments of these devices, emerging technologies and trends in global health care, and a broad vision of the future of the industry.
The global trend for the medical device industry can be linked to the rising demand for health care worldwide. Increased life expectancy is creating a new population of people that are seeking novel technologies that will effectively enhance their quality of life and life span. Also, the financial strength of developing counties such as China, India, Brazil, and Russia are creating a new population of people who are gaining access to modern health care. Analysts predict the medical device global market growth of 7.2% per year over the next 4 years;1 a prediction that estimates a total market size close to $300 billion by 2010! Which technologies will provide the driving force to fulfill this market forecast, and more importantly, which medical device sector will emerge the market driver? The corporate anticipation to the outcome to these questions will be apparent in future merger and acquisition activities within the already highly consolidated medical device industry.
Prior to elucidating potential medical device frontrunners, first a definition of a “medical device” must be cast. The Food and Drug Administration's (FDA) description will be utilized out of respect to the regulatory compliance agency of the US, the global leader in production and consumption of medical device goods. This exercise, although appearing slightly academic, is being executed with the intention to demonstrate the spectrum of products that fall within the category of medical devices. Although it is unlikely that the bedpan or tongue depressor sectors of the industry will be future newspaper headliners of tomor-row's business section, but a next generation disposable proteomic screening tool for cancer, or perhaps an exogenously activated thermal ablating kidney stone targeting nanoparticle, might be the “next-big-thing.” The point is, the medical [Page xx]device industry is incredibly diverse and therefore choosing the market drivers of tomorrow, let it be the actual device or the corporations that manufacture them, involves a bit of foresight, some understanding of the current states of technologies, and an incredible amount of serendipity.
The FDA Definition of a Medical Device
A medical device is an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part or accessory, which is
- recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them;
- intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animal; or
- intended to affect the structure or any function of the body of man or animals, and which does not achieve any of its primary intended purposes through chemical action within or on the body of man or animal and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.
Which emerging technologies of today have the potential of becoming the future blockbuster medical devices of tomorrow? It would be too presumptuous to simply create a list of specific devices; however defining technology sectors that may elicit significant future clinical impact can provide utility. It is this author's humble opinion that the technology areas of interest that may offer future medical device promise include early detection of disease, regenerative medicine, digital health, drug delivery, and personalized medicine.Early Detection of Disease
The ability to minimize the duration between the onset of disease and detection greatly improves patient survival, especially in regards to cardiovascular disease (CVD) and cancer. An incredible amount of research dollars have been spent on treating advanced diseases since many patients seek diagnosis once they become symptomatic, a time point often associated with the later stages of disease [Page xxi]progression. There is no question that education, proper access to health care, and improved therapy can offer tremendous clinical impact for managing advanced disease; however, a cost-effective, safe, and accurate diagnostic/screening device has the potential of revolutionizing clinical medicine. If a tumor can be located and removed prior to metastases, or vulnerable plaque in a coronary artery can be identified and secured before impending myocardial infarction, then the administration of often-futile, highly invasive, toxic, and expensive late-stage treatment strategies can be avoided.
There are numerous early detection approaches under development; however, it will most likely require a combination of technology advancements to define the next generations of diagnostic and screening systems. Some critical design requirements of interest include: greater resolution, less exposure to harmful radiation, higher throughput, less cost, and innovative integration of the “-omic” technologies. The term “-omic technologies” was first coined by bioinformaticians and molecular biologists to describe the fields of study in biology ending in the suffix “-omic,” such as genomics, proteomics, metabolomics, and transcriptomics. The significance of the -omic technologies to the medical device industry can be distilled to the fundamental statement that the basic science of the -omics, coupled with advanced bioinformatics, provides the analysis of extremely complex biological interactions that are capable of identifying pathophysiologic relevant biomarkers. In other words, the -omics can assist with targeting and disrupting disease.
Genomics: the study of the function and interactions of all of the genes in the genome. Genomics aims to understand the structure of the genome, including the mapping of genes and sequencing the DNA. Genomics examines the molecular mechanisms and the interplay of genetic and environmental factors in disease.2
Proteomics: the characterization and quantification of proteins and protein systems. Proteomics methods allows for the comparison of patterns of proteins isolated from bodily fluids or cells, in normal and diseased subjects.3
Metabolomics: the identification, measurement, and interpretation of the complex time-related concentration, activity, and flux of endogenous metabolites in cells, tissues, and other biosamples: blood, urine, and saliva. Metabolites include small molecules that are the products and intermediates of metabolism, as well as carbohydrates, peptides, and lipids.4
Transcriptomics: The study of the transcriptome is the complete set of RNA transcripts produced by the genome at any given moment; affords information about the global mRNA expression of particular tissue-yielding information about the transcriptional differences between two or more disease states.5
[Page xxii]One of the most recognized technology sectors pertaining to early detection is medical imaging. The medical imaging global market (i.e., X-ray, magnetic resonance, nuclear, and ultrasound) was estimated to reach $19 billion by 2006.6 Although medical imaging can be considered the first line of defense against health care's leading killers, there is much room for technology advancement and sophistication. As long as patients are suffering from disease, there will always be a drive in the medical imaging field for higher image resolution. This can be effectively achieved through technology advances in imaging systems as well as the utilization of innovative contrast agents. This is where -omic technologies can offer elegant approaches for image enhancement. Molecular targeting moieties (i.e., antibodies, aptamers, ligands) can be “tagged” or conjugated to the surface of nanoparticulates and employed to seek and bind particles to the surface of diseased cells and tissues via specific biomarkers, or molecular targets that are indicative of disease. Nanoparticles containing gadolinium, for example, provide positive contrast for molecular magnetic resonance imaging (MRI) applications to identify tumors and atherosclerotic plaques. There are a number of similar approaches that utilize targeted contrast agents being developed for the other imaging modalities that can be found in human clinical trials today.
Beyond medical imaging, promising early detection devices will include novel diagnostic kits and screening tools. The general population would actively embrace new procedures that would reduce patient anxiety associated with routine doctor visits or “check-ups.” Less invasive and nonintrusive procedures relative to conventional bronchoscopy, colonoscopy, and mammography methods are being developed, however such devices have had little to moderate impact and clinical penetration. For example, the response to a wireless capsule endoscopy system has been relatively unremarkable due to its relatively high price for the disposable capsule and limited utility (e.g., recommended adjunctive technique to upper and lower endoscopy). Patient sentiment may change as future technology advancements may allow for more robust clinical applications and with decreased procedure costs.
The most promising approaches for future diagnostic/screening tests exploit the -omic technologies once again. The holy grail of early detection modalities involves a cost-efficient device that is capable of extracting clinically relevant information from bodily fluids or cells for definitive evaluation of health for a broad spectrum of diseases. The -omic technologies inherently offer such potential when coupled with current MEMS/NEMS technology and bioinformatic analysis. Semiconductor technology offers exquisite control over the fabrication of micro-/nanoscaled features. Although the actual mechanisms that drive the interactions between biologics and nanostructured surface modified semiconductor substrates have yet to be fully elucidated, compelling evidence suggests that important physiopathologically relevant information can be extracted from such bodily fluids as blood serum. One approach utilizes [Page xxiii]nanoporous silicon chips to capture low molecular weight (LMW) proteins from the blood. Animal studies have shown minute, but identifiable, differences in LMW protein mass spectroscopy profiles for animals at different time points of disease progression. Such technologies have the potential to provide identification of new biomarkers and early detection of disease from a drop of blood!Regenerative Medicine
The concept of regenerative medicine inspires visions of futuristic clinical scenarios where damaged or diseased tissues and organs are not treated with therapeutics, but surgically replaced! Such an approach would ideally suit the global phenomenon of increased life expectancies where significantly large patient populations are suffering from age-related “wear and tear” conditions, such as arthritis, osteoporosis, and cardiovascular disease. The role of regenerative medicine, also referred to as tissue engineering, in the medical device industry is somewhat confusing. The FDA classifies medical products as either biological, drug, or medical device; regenerative medicine products fall within the gray area between biologics and devices. For clarification, the FDA has designated commercially available Carticel® (autologous cultured chondrocytes) as “biological” since the cartilage repair product comprising living cells. With that being said, Apligraf® (living, bi-layered skin substitute) is classified as a “device” due to the perception that it functions as a type of “bandage” despite also being composed of living tissue. Most artificial organ strategies will be categorized as devices based upon their construction around synthetically engineered tissue scaffolds. For clarification, the prospect of stem cells will not be considered in this prospectus since the technology intuitively falls under the biological category, although future cross-over products that will function as devices is highly probable. The clinical and economic impact of stem cell research has yet to be elucidated due to the ethical and political implications that are inherent to this controversial technology.
The promise of regenerative medicine offers the potential to provide engineered organs and tissue that mimic natural biological systems without prejudice or with minimal response from a patient's immune system; obvious areas of interest include: organ transplants, improved joint and limb replacements, revascularization of veins and arteries, and cosmetic repair surgeries. More than 89,000 US patients are on the organ transplant waiting list; 17 of those die per day while waiting for available vital organs: hearts, livers, kidneys, pancreas, lung, or bone marrow.7 The emergence and growth of the industry in recent years serve as positive indications for the future outlook. Between 1985 and 2002, the [Page xxiv]number of regenerative medicine companies globally peaked at 90-plus with a cumulative revenue of $100 million to $150 million (USD).8 Since then, the number of companies has risen to 150-plus, generating a cumulative revenue of $300 million to $400 million.8 Although these figures do not provide great evidence of an explosive new sector of the medical device industry, one must consider the implications of developing products regulated under such extremely strict efficacy and safety guidelines.
Clinical medicine is joining the digital age to help deliver health care with improved efficiency and convenience. New mobile computer kiosks are becoming standard features on hospital floors, becoming indispensable tools for caregivers. From the patient's bedside, the attending physician has secured access to such pertinent patient information as high-resolution digital images, laboratory results, and medication history. Integration of monitoring devices offers real-time patient information easily accessible from any access point in the hospital and beyond. An accessible patient database may appear unremarkable; however, for the first time in history, real-time patient data can be collected, “mined,” and analyzed at a global scale for drug discovery applications. Data mining is the process of using statistical techniques to extract potentially useful information from subtle relationships between data items to construct valuable predictive models. Through data-mining strategies, appropriate therapies and treatments can be recommended based upon the clinical outcomes of patients with similar medical histories and conditions.
[Page xxv]Telemedicine may represent the next evolutionary step for digital health care, the delivery of medicine over a distance. The penetration of the Internet offers tremendous opportunity for patients to receive real-time treatment and monitoring without leaving the comforts of home. Medical devices specifically designed to relay instantaneous patient information to their care providers may offer new markets of expansion for existing medical device makers. Already devices such as networked glucose readers and digital thermometers are connecting patients to their clinicians. As information technology continues to advance, patients will be given the opportunity to self-monitor their chronic conditions and acquire feed-back from their care providers through online health consultation while enjoying the comfort and safety of being at home with their families and friends. Analysts estimate the US digital home health market generated $461 million in revenue in 2005 with the expectations that it will grow to a $2.1 billion market by 2010!9 The aging population and shortage of doctors and nurses may drive this lofty expectation to its fruition.
The ultimate technology achievement of digital health care and telemedicine is remote surgery. As broadband data transfer becomes more efficient and robust, remote surgical procedures utilizing robotic surgical systems may become a reality. Robotic systems like Intuitive Surgical's da Vinci® Surgical System, may revolutionize surgical procedures, offering surgeons the ability to extend their scalpel to any operating room in the world! The greatest obstacle to this technology is lag, or the delay of information transfer that is associated with networked systems. Once communication issues are solved, the skills and experience of the surgical elite can be applied across the globe and beyond; the applications are endless: outreach programs to third world countries, access to dangerous battlefield treatment centers, and perhaps locations that support our space exploration endeavors.Drug Delivery
The global drug delivery market earned $426.9 billion in 2005,10 a considerably larger industry than biomedical devices! However, the oral delivery sector alone accounts for $283.7 billion,10 which assists in putting in perspective the potential contribution of medical devices in this market. Drug delivery systems are conduits by which therapeutic agents are introduced to the body with the intention of interacting at a target site of action. New drug delivery strategies have successfully improved patients’ lives through providing convenience (transdermal patches, insulin pumps), more tolerable administration options (inhalation devices, implants), and improved efficacy for conventional therapies and procedures (drug-eluting stents, liposomes). Future breakthroughs in delivery could include long-term, autonomous devices, and next-generation localizing and targeting of chemotherapeutics.
Small-scale, in vivo drug delivery systems require the coupling of innovative device technology and advanced therapeutic agents. A compromise between device size and therapeutic payload must be optimized to avoid developing an ineffective delivery system that is too small and incapable of delivering the desired medications at the required doses of micro-liters or more. Reformulations of conventional therapeutics to produce higher potency drugs would assist maintaining the small scale of the devices; however, additional requirements such as improved stability and solubility may also present limitations to shelf life and deliverability. I have much confidence that the pharmaceutical industry will embrace efforts to meet the demands of future drug delivery technologies based on two motivations: (1) new and effective drug delivery modalities may increase therapeutic efficacy and reduce harmful side effects and, from a more pragmatic point of view, (2) “Big Pharma” is scrambling to find ways to prevent the demise [Page xxvi]of their blockbuster drugs through patent expiration. New drug delivery systems may provide “line extension” life preservers to the pharmaceutical industry which is expected to lose $80 billion11 to expiring patents in the next few years! Either way, it may be a win-win situation for patients since the future may hold both new innovative drug delivery systems and cheaper generic drugs; Big Pharma will not be able to save them all!
Disregarding the economic impact of new drug delivery systems, the future clinical prospects for delivery devices is truly exciting, especially if the integration of advanced electronics and sensors validate modulated, remote-controlled, and autonomous systems. The utility of such devices could be easily applied to civilian life, third world countries, the battlefield, and even the moon! Constant or modulated release may provide convenience for hormonal therapies such as leuprolide acetate, which is conventionally administered on a monthly basis for advanced prostate or ovarian cancer patients. The same release strategies would be critical for third world countries where health care resources are poorly accessible; the delivery of interferon alpha to hepatitis C patients is a perfect example since conventional treatments require daily injections, or at least three times a week, for a 16-week period. For such cases, these treatment regimes are not practical and require alternative discourse. Remote activation of morphine administration for soldiers wounded on the battlefield is a relevant application; this approach allows medics to remotely activate pain relief instantly and potentially from a safe distance if needed, and reduces opportunities for abuse. Missions to the moon and Mars may be perceived as outlandish and costly ventures; however, the enabling technology that will make these travels possible will have direct application to civilian life. Remote-controlled or autonomous drug delivery devices will allow scientists to essentially bring the hospital to the astronauts, where hospitals are not available. Autonomous delivery or the release of drugs, as the direct response to a physiologic change, has unlimited application potential for diseases that involve chemical imbalances.
An additional endeavor of future drug delivery devices is to target therapeutics to the site of disease, for example a cancer lesion. In principal, this can be achieved through a variety of strategies, such as physical, biological, or molecular targeting of pathologically relevant sites with a desired chemotherapeutic agent. Such targeting mechanisms are already employed in the clinic and are commercially available. However, no level of targeting sophistication will produce substantial benefits in the therapeutic index unless the agents of therapeutic action can reach the intended lesion sites at the right dose; which explains the reasoning why current treatment strategies have not been totally revolutionized by the advent of today's emerging targeted therapies.
The challenge to drug delivery is to overcome the deficiencies of typical therapeutic strategies. Conventional cancer chemotherapeutics gain access to the blood stream through intravenous (I.V.) administration and are required to [Page xxvii]penetrate the extravascular space and present at the tumor lesion at an adequate concentration such to inflict lethal toxicity. Unfortunately, only 1 out of 100,000 molecules of the drug successfully reaches the intended site,12 permitting the overwhelming majority of the highly toxic, nondiscriminating, systemically disbursed, poison to manifest in a number of cruel side effects associated with cancer chemotherapy. Unfortunately, intrinsic to the body defense system are several extremely effective obstacles (collectively termed biobarriers) that largely prevent injected chemicals, biomolecules, nanoparticles, and any other foreign agents of therapeutic action from reaching their intended destinations. Biobarriers are sequential in nature, and therefore the probability of reaching the therapeutic objective is the product of the individual probabilities of overcoming each one of them.13 A corollary is that any efficient delivery method must be provided with tools that allow it to overcome all of these barriers, because opening all of the doors is necessary, but opening only one along a single path will not suffice.13,14 Requiring a therapeutic agent to be provided with a sufficient collection of weaponry to conquer all barriers and still be small enough for safe vascular injection is a challenge uniquely suitable for nanotechnology.14 As definition, nanotechnology-based devices must be of the nanoscale or have nanoscaled features, be man-made, and offer properties or functions made possible only through its minute size. Injected, nanoscale drug delivery systems, or nanovectors, are the ideal candidates to the time-honored problem of optimizing the therapeutic index for treatment; that is, to maximize efficacy, while reducing health-adverse side effects.13,14
A multistage nanovector approach may provide an elegant solution for delivering today's drugs to the tumors of tomorrow. This strategy will require the integration of numerous particle technologies (i.e., liposome, carbon nanotube/buckeyball, metallic shells, dendrimers, etc.) and chemotherapeutics. A conceptual prototype may utilize a carrier or “mothership” particle that is capable of releasing different stages of particles that are nested within one another and designed to circumvent different biobarriers and/or targeted release functions. A first embodiment of the strategy, designed for intravascular injection, may be conceptualized as follows: Stage One vectors are designed to travel through tumor capillaries and target cancer lesion vasculature. They will have different recognition moieties on their surface, including biologicals (aptamers, antibodies) and will feature detection and optimized adhesion strategies based on physical properties and charge distribution. Upon lodging in the tumor vasculature, they release preferentially penetration enhancers, and nanoparticles of Stage Two. The penetration enhancers could be directed against the basement membrane and/or toxins against the tight-junction proteins (TJP). The Stage Two nanoparticles are then allowed to penetrate across the basement membrane without constraint and selectively direct their cytotoxic payload against tumor cells. A very large number of possible embodiments for multistage nanovectors (i.e., particle type, size, shape, drug payload) could easily be envisioned and [Page xxviii]tailored to the biology of the biobarriers of interest, and through this, to the specific clinical applications.Personalized Medicine
Coinciding with the substantial progress in the Human Genome Project in the late 1990s, a new term emerged as a prediction of the future of the pharmaceutical industry: personalized medicine. Personalized medicine reaffirms the confidence of the new predictive sciences, or -omic technologies, in regards to the tremendous clinical impact they will command. The theory of personalized medicine involves the collection and analysis of a patient's genotype as indication to predict disease pathogenesis, disease progression, patient response to medication/therapy, and possibly even recommendations for certain preventative measures. Pharmaceutical companies are then expected to provide chemotherapies synthesized specifically for the indicated patient population or perhaps single individuals.
This concept of personalized medicine is doomed by (1) the expectations of pharmaceutical companies to undergo such a dramatic paradigm shift from production of blockbuster drugs to tailor-made therapeutics and (2) the unavoidable inherent costs of the FDA regulatory compliance process (i.e., drug discovery, preclinical and clinical trials) that is currently estimated to be 8 to 12 years and $800 million–plus! Unfortunately, to invest such time and money to benefit such a small patient population or individual is not a reasonable proposition.
Other approaches to personalized medicine may have more potential for generating clinical success. As mentioned before, advancements in digital health may provide access to an incredible amount of raw patient data, through which global data-mining opportunities may offer extraction of trends with significant clinical relevance. Physicians may use computational algorithms to predict clinical outcomes for specific patients through the comparative analysis of enormous patient populations presenting with similar medical histories who have received different treatment strategies. Personalized medicine in this approach allows physicians to tailor make, or customize, medical treatment for patients based upon the successful administration of similar therapies given to representative patient populations. This theory of personalized medicine does not require pharmaceutical companies to dramatically alter their business models and also gives rise to a new sector of sophisticated data-mining medical device systems.
Advancements in biomedical nanotechnology may also influence future personalized medicine doctrine. A novel nanoinspired personalized medicine [Page xxix]approach could utilize computation mathematical models and imaging modalities to offer pathophysiologically relevant patient information regarding numerous physical features (i.e., vascular diameter and tortuosity, tumor vascular fenestration size, blood flow dynamics, etc.) for the development of nanotechnology drug delivery strategies. The multistage drug delivery strategy described previously is a perfect example. Rational design algorithms could be applied to predict the optimal design of particle vectors to control their ability to navigate within the microvasculature to seek diseased endothelial cells. A physiologic snapshot produced by contemporary medical imaging modalities could then provide the physical parameters to output personalized treatment options. The appropriate vectors could then be chosen from combinatorial libraries of FDA-approved vectors and drugs; assuming of course that at that time, numerous particle vectors and drugs are available.Biomedical Device Industry Challenges
The medical device market is susceptible to many threats and unforeseen events, as is common to all industries. I have provided several promising technology sectors that may offer growth and stability to the industry, however, there are numerous “to be determined” factors that may play a significant role. Three of such TBD factors involve regulatory classification, threatening innovative technologies, and industry barriers to entry.Nanotechnology and the FDA
How nanotechnology will impact the medical device industry has yet to be determined; pending on FDA perception, nanotechnologies may be designated as drugs or devices. The FDA is taking proactive measures on how to address this emerging field through informational sessions and workshops, due diligence, education, and outreach. Some may argue that nanotechnology is just a buzz word that is causing unnecessary attention; nanoscaled entities have been around forever! However, there is no argument that new sophisticated technologies are being developed with exquisite control exhibiting novel properties and functions because of their nanoscale. The classification debate is not trivial; regulatory compliance requirements differ for drugs and devices, and the differences between the two are significant. The approval process for devices has historically been less extensive. Since the range of biomedical nanotechnologies is [Page xxx]so broad, the FDA is having much difficulty defining their classification criteria; therefore customers are encouraged to engage the FDA early in the developmental process to help facilitate the approval process. Bottom line, a device classification may shorten product evaluation timelines and therefore reduce time to market and product development costs.Disruptive Technologies
Another wild card that may instill market volatility in the medical device industry is the threat of disruptive technologies. Clayton Christensen, professor of business administration at Harvard Business School clarifies disruptive technologies as follows: “disruptive innovations create an entirely new market through the introduction of a new kind of product or service, one that is actually worse, initially, as judged by the performance metrics that mainstream customers value.” Disruptive technologies have the potential of decimating industry giants upon failure to recognize potential markets that initially appear unsatisfactory in regards to gross margin analysis requirements set forth by their governing business model. One of the best examples of how a disruptive technology can affect an industry giant comes from the disk-drive computer hardware industry. Seagate Technology's fall from grace can be attributed to their reluctance to timely embrace and develop 3.5-inch disk drives. At the time, 5.25-inch drives could meet the storage requirements of their customers; a task that the emerging 3.5-inch drive technology could not deliver. The lack of storage capacity of the 3.5-inch drive dissuaded Seagate to develop the technology; however, once the 3.5-inch technology improved, the drives became tremendously successful serving the emerging market of portable computers. Eventually they evolved to even meet the storage demands of personal computers, the coveted drive market that initially convinced Seagate to dismiss 3.5-inch drive technology. The evolution of the 3.5-inch drive technology crushed Seagate and set them sufficiently behind such to relegate them to a second-tier supplier in the portable computer market, a position they still have yet to emerge, even after savvy acquisitions.
It is impossible to accurately predict future disruptive technologies that have the potential of demoting current medical device giants from their elite status. However, the consolidated nature of the medical device giants makes them susceptible to complacency and inflexibility to embrace new emerging technologies. Analysts will prove wise to remain suspect of the stability of large corporations and to be cognizant of innovative start-ups that are eager to topple their larger counterparts or to be offered as acquisition gold mines; both can prove to be very lucrative to savvy investors.[Page xxxi]Group Purchasing Organizations
The function of group purchasing organizations (GPOs) is to act as intermediaries for hospitals to assist in the negotiation of contracts with medical suppliers. The purported mission of the GPO is to leverage its buying power to purchase the best medical products for its member hospitals at the lowest prices, such to pass on the savings to the hospitals and patients. Hospital networks are estimated to annually purchase more than $270 billion worth of medical devices, office equipment, hospital supplies, and pharmaceuticals; about 72% of all purchases that hospitals make are done using GPO contracts.15 At its inception, GPOs were to charge an administration fee to cover their overhead costs and pass the savings onto the hospitals and their patients.
The obvious flaw of this process is that the GPOs are paid by the medical supply companies, and not by the client customers they represent, the hospitals. Under this mechanism, a medical device maker has the option to pay fees to the GPO to secure an exclusive contract to sell its product to the GPO's hospital network, thereby guaranteeing percentage-based sales commitments from the hospitals! Some GPOs even collect additional fees beyond their administrative fee receipts of 3% and collect marketing fees, licensing fees, stocking fees, switching fees, and growth fees! The anti-kickback statute of the Social Security Act makes it a criminal offense to knowingly and willingly offer, pay, solicit, or receive remuneration to induce referrals of items or services reimbursable by federal health care programs (42 U.S.C. §1320a–7b(b)). Convinced that the GPOs would reduce health care costs, Congress amended the Act in 1986 and exempted GPOs from receiving such payment from device manufacturers. Now it is estimated that GPOs are generating excess annual revenue in the range of $5 billion to $6 billion,16 a figure well over the overhead costs for GPOs in which the fees were initially intended to pay.
The abuse of such purchasing power is an immediate threat to the medical device industry, more specifically to the medium to small companies that are unable to compete with industry giants who are capable of paying GPO fees. The exclusionary and often anti-competitive nature of GPO purchasing contracts are presenting small business entrepreneurs with two unappealing options: (1) sell their company to a larger competitor with GPO ties, or (2) endure risk of financial ruin and attempt to compete. This is a serious issue since more than 98% of the medical technology industry is composed of small businesses.17 The most alarming outcome of this situation is that it may stunt the pipeline of emerging technologies that inherently come out of smaller companies, which will effectively deny doctor and patient access to potentially the best, most cost-efficient, and effective medical device technology due to unethical barriers to entry.[Page xxxii]Closing Remarks
The biomedical device industry will continue to grow, enabled by the momentum created by advancements in fundamental science and technology. Although it will not register the market impact and return of yesterday's dot-com era, it should remain a relatively stable market performer. The technology sectors discussed in this Introduction should provide valuable insight to the future and direction of the industry, and hopefully inspire excitement and hope for biomedical devices that are currently being developed at the lab bench, validated in clinical trials, and emerging from corporate pipelines.
Mauro Ferrari, Ph.D., Professor, Brown Institute of Molecular Medicine; Chairman, Department of Biomedical Engineering, The University of Texas Health Science Center; Professor of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Professor of Bioengineering, Rice University, Houston, TX; President, Alliance for NanoHealth, Houston, TX
Jason H. Sakamoto, Ph.D., Professor, The University of Texas Health Science Center; Chief Operating Officer, Alliance for NanoHealth, Houston, TXReferences1. AHC Media LLC. Medical Device Daily: State of the Industry Report 2007. AHC Media LLC, 2007.2. Genomic medicine—a primer. N Engl J Med, 2002; 347(19):1512–1520.http://dx.doi.org/10.1056/NEJMra012240:3. The case for early detection. Nat Rev Cancer(2003)3(4):243–252.http://dx.doi.org/10.1038/nrc1041, et al.:4. Office of Extramural Research: 2006 Thesaurus: Computer Retrieval of Information on Scientific Projects. (ed.)National Institute of Health, 2006.[Page xxxiii]5. The use of high-dimensional biology (genomics, transcriptomics, proteomics, and metabolomics) to understand the preterm parturition syndrome. Bjog, 2006; 113Suppl 3:118–135., et al.:6. Frost & Sullivan: Medical Imaging Industry. (ed.)Frost & Sullivan, 2006.7. National Kidney Foundation: 25 Facts About Organ Donation and Transplantation. (ed.)National Kidney Foundation, 2005.8. Regenerative Medicine 2.0. Future Medicine2007; 2(1):11–18.:9. Digital Home Health—A Primer, 2006.10. Datamonitor: Datamonitor's Drug Delivery: Global Industry Guide (ed.)BioPortfolio, 2007.11. Takeda Pacific: Drug Delivery Systems: US Market Outlook, Advances for Pharma, Biotech & Medical Devices. (ed.)Research and Markets, 2006.12. Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol: pharmacokinetics, tumor localization, and safety in patients with AIDS-related Kaposi's sarcoma. J Clin Pharmacol1996; 36(1):55–63., et al.:13. Nanovector therapeutics. Curr Opin Chem Biol2005; 9(4):343–346.http://dx.doi.org/10.1016/j.cbpa.2005.06.001:14. Cancer nanotechnology: opportunities and challenges. Nat Rev Cancer2005; 5(3):161–171.http://dx.doi.org/10.1038/nrc1566:15. Knowledge Source Inc.: Group Purchasing Organizations Market Overview—2006. (ed.)Research and Markets, 2006.16. Group Purchasing Organizations: An Evaluation of Their Effectiveness in Providing Services to Hospitals and Their Patients. (ed.) International Center for Corporate Accountability, 2006.:17. New Medical Device Act Needs Full Funding. (ed.)SPG Media Limited, 2005.: