Drug-device Combinations for Chronic Diseases

SuPing Lyu, Ronald Siegel

• Publisher: Wiley
• Year: 2015
• Print ISBN:
  9781118120002
• Edition: 1
• eBook ISBN:
  9781119002970
• Topic: Technology & Engineering
• Subtopic: Materials Science
• Index: Technology & Engineering

This book covers two areas, the first detailing the concepts and technologies of drug-device combination products. The second area includes case studies of important products that either significantly shape our technologies and thinking, or contribute to current healthcare practice.

The book:

• Discusses where drugs and devices work, where they fail, and when they need to work with each other
• Reviews interactions between human bodies and the drug-device combination products the measurements of these interactions
• Covers  how a drug-device combination product is developed, tested, and regulated
• Includes case studies of steroid releasing leads, AOA treated tissue heart valves, intrathecal drug delivery pumps, infuse bone grafts, drug eluting stents, and antimicrobial meshes

Part I
Backgrounds

1
Addressing Medical Device Challenges With Drug–Device Combinations

Mahender N. Avula¹ and David W. Grainger^1,2

¹Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA

²Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112-5820, USA

1.1 Introduction

Implanted medical devices (IMDs) comprising synthetic biomaterials have seen exponential growth in their applications and clinical use over the past five decades [1]. The scope and fields of use for IMDs have increased multifold with the advent of new technologies, innovation, and improved understanding of human physiology and its underlying problems. Increasing rates of medical device adoption can be attributed to various factors, including aging median populations worldwide [2], innovations in design and function that increase performance and reliability, rising standards of living among patients in developing nations, and noted improvements in patient quality of life offered by the devices. New IMDs continue to offer improved treatment alternatives for cardiovascular, orthopedic, oncologic, and many other diseases [3]. Given these factors, the global medical device market is expected to continue growing, reaching approximately US$302 billion in 2017 with an annual growth rate of ∼6% over the next 6 years (2011–2017) [4]. Tens of millions of people in the United States alone have some kind of IMD in their body. Despite enhanced safety and efficacy, new device design strategies are required to understand and address complex human factors affecting device performance in vivo. Innovations in design, biomaterials, surface modifications and biocompatible coatings, and device-based onboard drug delivery mechanisms are among strategies employed to improve clinical IMD performance.

1.1.1 Combination Medical Devices

Drug–device combination medical products are innovative biomedical implants with enhancements to device function provided by the onboard formulation and local pharmacology of selected drugs at the implant site [5]. Combination devices couple a drug loading and releasing mechanism onto an approved prosthetic implant. Together, these seek to provide several improvements to the in vivo performance and lifetime of implantable medical devices in various classes and capacities, including cardiovascular, ophthalmic, orthopedic, diabetes, and cancer applications. Drug–device combination products represent relatively new device class among implantable medical devices, one that is drawing increasing attention from both the pharmaceutical and device manufacturing industries and the clinicians to address several long-standing problems associated with IMDs. In 2003, the Food and Drug Administration (FDA) approved a coronary drug-eluting stent (DES) (Cordis CYPHER™, Johnson and Johnson, USA) opening the market to similar officially designated “drug–device combination products” in the United States [6]. Several notable medical devices with locally delivered drugs had earlier precedent, namely, steroid-releasing pacemaker leads, hormone-releasing intrauterine devices, antibiotic-impregnated catheters, aerosolized drug inhalers, drug-infused condoms, and several other precedents. Additionally, several combination products also existed earlier in Europe than elsewhere, for example, antibiotic-releasing bone cements, drug-eluting stents, heparin-coated catheters, and others (approved with the CE mark). FDA's Office of Combination Products (OCP) was established in 2002 to provide a pathway for assigning principal FDA oversite and review policies to drug–biologic–device combinations that could otherwise be confused or compromised by traditional FDA review file assignments [7]. The objective was to provide a streamlined and consistent process for assigning these new products to FDA Centers based on claimed primary modes of action (i.e., device or drug). The OCP defines a “combination device” under 21 CFR 3.2(e) as “A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity; or two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products.” Table 1.1 summarizes this classification system. Most combination devices add a drug bioactivity adjunct to an already-approved implanted device to counteract challenges faced by the device in the context of the local host tissue environment. This can include inflammation, fibrosis, coagulation, and infection, improving performance in several conditions. One prominent example is the use of the drug-eluting stent, where local release of micrograms of drug to the vascular bed has reduced the need for surgical intervention by 40–70% over bare metal stents [8–10]. However, combination products are often optimized into an integrated system from separate drug and device products: They were never designed de novo to complement each other in structure and function, that is, controlled drug delivery is often an add-on feature to an existing FDA-approved medical device design that is suboptimally adapted to the structural, mechanical, or electronic function of the device [6]. New strategies and new technologies that combine drugs, devices, and biologics de novo as coordinated, unified new designs are expected to provide a new generation of combination products, more intelligently incorporating and merging new technologies, changes, and refinements of both existing drug delivery mechanisms and medical device functions, shifts from traditional devices and drugs, while remaining compliant with regulations [6].

TABLE 1.1 Diversity of Combination Medical Products Used in Physical or Chemical Combinations, or Copackaged as a Kit, or as Separate Cross-Labeled Products

Combination Product Type	Clinical Examples
Drug and device	Drug-eluting stents, antimicrobial catheters, tibial nail, and sutures
Drug and biologic	Autologous platelet concentrate delivery of gentamycin to an open fracture; demineralized bone matrix delivery of statins to bone defect
Biologic and device	Heparin-coated vascular grafts, insulin infusion pumps, spinal cages with rhBMP-2
Drug and biologic and device	No precedents approved; fictional example: adenoviral NfκB transgene delivery from Taxol-eluting vascular stent

Diverse classes of drugs are used in combination devices to enhance medical device and implant performance. Anti-inflammatory, antifibrotic, antiproliferative, antithrombotic, and antibiotic drugs are primary classes of pharmaceutical agents often combined with a controlled delivery mechanism suited to the application. Site- and implant-specific drug interventions before, during, and after medical device implantation can be used to alleviate several adverse host responses, providing a local therapeutic strategy when a device design or systemic drug delivery alone is insufficient. For example, anticoagulants are applied to cardiovascular and intravascular implants to reduce device-based thrombosis, while antifibrotic, anti-inflammatory, and antiproliferative drugs are used for soft tissue implants and endovascular stents susceptible to fibrous tissue in-growth and smooth muscle proliferation. Antibiotics are released from orthopedic implants, shunts, and percutaneous and urinary catheters that exhibit high infection incidence.

Conventional therapeutics are administered in different ways, including nasal, oral, parenteral (intravascular, intramuscular, subcutaneous, and intraperitoneal), topical, transdermal, and other administrative routes [11]. A...

Table of contents

• Cover
• Wiley – Society for Biomaterials Series
• Title Page
• Copyright
• Foreword
• Preface
• Part I: Backgrounds
• Part II: Products
• Index
• End User License Agreement