Development of FDA-Regulated Medical Products: A Translational Approach

List of Figures and Tables

Figure 1.1 Pharmaceutical industry R&D spending.

Table 1.1 New molecular entities: applications and approvals.

Figure 1.2 Drug development pathway.

Figure 1.3 Preapproval capitalized cost per approved NME.

Figure 1.4 Some definitions of translational research.

Figure 1.5 Sources of funding and support for translational research and development.

Table 1.2 Three dimensions of the critical path.

Figure 1.6 Sampling of schools with programs related to medical product development.

Figure 2.1 Product development planning is an integrative approach.

Figure 2.2 Product development planning.

Table 3.1 Chronology of significant regulations relevant to healthcare product development.

Figure 3.1 Examples of recent FDA initiatives affecting product development.

Table 4.1 Not all products of biological source are regulated by CBER.

Figure 4.1 Definition of a drug.

Figure 4.2a Minimum information included in an IND.

Figure 4.2b Clinical trial testing phases.

Figure 4.3 Definition of a biological product.

Figure 4.4 Definition of a medical device.

Figure 4.5 Minimum information included in an IDE.

Figure 4.6 Definition of a combination product.

Table 4.2 Number of original drug and biologics applications filed with CDER and CBER.

Table 4.3 Major medical device submissions received by CDRH.

Table 4.4 Examples of NMEs approved in 2011.

Table 4.5 Some recent biologics approvals.

Table 4.6 Recent medical device approvals and clearances.

Table 5.1 Examples of U.S. national class action product liability settlements.

Figure 5.1 Establishing product defects for product liability.

Figure 5.2 Responsibilities of product development planning in minimizing future product liability problems.

Figure 5.3 Primary considerations for product development planning.

Figure 6.1 Phases of clinical testing.

Figure 6.2 Mean time (months) from receipt to approval of priority NDA/BLA submissions.

Figure 6.3 Medical device classification panels.

Figure 6.4 Examples of reserved Class I devices.

Figure 7.1 The 1-10-100 rule.

Figure 7.2 Class I devices subject to design controls.

Figure 7.3 Examples of items to include in a design controls checklist.

Figure 8.1 Examples of potential interactions of risk elements.

Figure 8.2 Objectives of risk assessment and management.

Figure 8.3 Example of FMECA matrix.

Table 9.1 Examples of safety-based withdrawals of product approvals.

Figure 9.1 CDER recall statistics.

Figure 9.2 CDRH recall statistics.

Figure 9.3 CBER recall statistics.

Table 10.1 Outline of device HFE/UE report.

Figure 10.1 CDRH comments on human factors.

Figure 10.2 Examples of FDA publications on the topic of human factors.

Table 10.2 Examples of easily confused drug names.

Figure 10.3 Examples of general questions relative to demography and products.

Table 11.1 Initial evaluation tests for consideration: biological evaluation of medical devices.

Table 11.2 Supplementary evaluation tests for consideration: biological evaluation of medical devices.

Figure 11.1 Principles of ICH GCP.

Figure 11.2 Drug development pathway.

Figure 11.3 Diagrammatic representation of the ICH Common Technical Document.

Table 12.1 Common pharmacoeconomic methods.

Table 12.2 Examples of quality-of-life domains.

Figure 12.1 Questions applicable to CER.

Figure 13.1 Stylized new product development funnel.

Figure 13.2 Internal impediments to medical product development that can be controlled or influenced by a product development organization (salmon swimming upstream analogy).

Figure 13.3 Internal impediments to medical product development that are not usually controlled or significantly influenced by a product development organization (salmon swimming upstream analogy).

Figure 13.4 External impediments to medical product development that can be controlled or influenced by a product development organization (salmon swimming upstream analogy).

Figure 13.5 External impediments to medical product development that are not usually controlled or influenced by a product development organization (salmon swimming upstream analogy).

Figure 13.6 What a product development organization requires.

Figure 14.1 The product development process is an integral component of product development planning.

Table 14.1 Six-step healthcare product development process.

Figure 14.2 The product development process.

Figure 14.3 Questions to consider when evaluating ideas.

Figure 14.4 Examples of idea evaluation criteria.

Figure 15.1 Development portfolio management is an integral component of product development planning.

Table 15.1 Framework for basic assessment of ideas, projects, and future opportunities.

Figure 15.2 A simple portfolio map matrix.

Table 15.2 Additional characteristics for project mapping.

Figure 15.3 An example of a technology portfolio matrix.

Figure 15.4 Portfolio map matrix showing types of projects.

Figure 15.5 A project map for a fictitious company: is it good or bad?

Figure 15.6 Signs that a project should be killed.

Figure 16.1 Technology assessment is an integral component of product development planning.

Figure 16.2 Considerations in technology assessment.

Figure 16.3 Examples of critical skills and knowledge base for informed technology assessment.

Table 16.1 Framework for basic assessment of ideas, projects, and future opportunities.

Figure 16.4 Additional issues relevant to technology assessment.

Figure 17.1 Technology forecasting is an integral component of product development planning.

Figure 17.2 The relationship between science, technology, and market.

Figure 17.3 Some factors contributing to the emergence of new diseases and the reemergence of previously controlled diseases.

Figure 17.4 Considerations for technology forecasting.

Figure 17.5 Some areas of interest at FDA for the twenty-first century.

Figure 18.1 A non-comprehensive alphabetical list of risks.

Table 18.1 Types of intellectual property.

Figure 18.2 Important factors influencing IP value in medical product development planning.

Table 18.2 Some basic costs associated with obtaining a U.S. patent.

Table 18.3 FY 2012 FDA user fees.

Figure 18.3 The customer/quality continuum.

Acronyms and Abbreviations

BLA—Biologics License Application

CBER—Center for Biologics Evaluation and Research

CDC—Centers for Disease Control and Prevention

CDER—Center for Drug Evaluation and Research

CDRH—Center for Devices and Radiological Health

CEA—cost-effectiveness analysis

CER—comparative effectiveness research

CPI—critical path initiative

CRO—contract research organization

FDA FD&C Act—Food, Drug, and Cosmetic Act

FDAMA—Food and Drug Administration Modernization Act

510(k)—Premarket Notification application

FMECA—failure mode effects and criticality analysis

FTA—fault tree analysis

GCP—good clinical practice

GLP—good laboratory practice

GMP—good manufacturing practice

HFE—human factors engineering

ICH—International Conference on Harmonization

IDE—Investigational Device Exemption

IND—Investigational New Drug application

IP—intellectual property

ISO—International Organization for Standardization

MDUFMA—Medical Device User Fee and Modernization Act

NDA—New Drug Application

NIH—National Institutes of Health

NME—new molecular entity

NSF—National Science Foundation

OCP—Office of Combination Products

PDUFA—Prescription Drug User Fee Act

PHS Act—Public Health Service Act

PMA—Premarket Approval

QFD—quality function deployment

QOL—quality of life

SMDA—Safe Medical Devices Act

TQM—total quality management

Preface

The years since the publication of the previous edition of this book have seen profound changes in the actions and attitudes of patients, insurers, manufacturers, and the Food and Drug Administration regarding the streamlining of medical product development and approval. What those years have not seen is a concomitant increase in innovative treatments with profound benefits to patients.

Over the past decade, the path to the development of new drugs, biologics, and medical devices in the United States has become increasingly inefficient, costly, and strewn with formidable obstacles. Despite enormous investments in research by both private and public sources and a surge in scientific and technological advances, new medical products barely trickle into the marketplace. For a variety of reasons, applied sciences necessary for medical product development are not keeping pace with the tremendous advances in basic sciences.

Not surprisingly, industry and academia are under substantial pressure to transform discoveries and innovations from the laboratory into safe and effective medical products to benefit patients and improve health. This evolution—from bench to bedside—has become known as translational research and development.

Translating promising discoveries and innovations into useful, marketable medical products demands a robust process to guide nascent products through a tangle of scientific, clinical, regulatory, economic, social, and legal challenges. There are so many human and environmental elements involved in shepherding medical advances from lab to launch that the field of medical product development has been referred to as an ecosystem. The purpose of this book is to help provide a shared foundation from which cross-functional participants in that ecosystem can negotiate the product development labyrinth and accomplish the goal of providing both groundbreaking and iterative new medical products. This book is intended for anyone in industry, the public sector, or academia—regardless of functional specialty, workplace, or seniority—who is interested in medical product development.

Part I: Unique Challenges in Medical Product Development

Chapter 1: Pushing the Pipeline

Translational Research and Product Development

How wonderful that we have met with a paradox. Now we have some hope of making progress.—Niels Bohr

The U.S. healthcare product pipeline needs major plumbing repair.

There is no lack of innovation or shortage of important scientific discoveries in this country, but our ability to transform scientific advances into new and effective medical products has been disappointing. Despite a steady increase in the amount of money invested in research and development, there is a serious gap in making the transition from the research lab to the patient. Novelty and innovation are the goals of academic and corporate research funding and honors. But to have an impact on healthcare, innovations must be shepherded through challenging stages subject to rigorous Food and Drug Administration (FDA) requirements, as well as through business development–related scrutiny. It is not an easy or intuitively obvious road from lab to launch, and productivity in terms of the introduction of new, innovative drugs, biologics, and medical devices has not kept pace with opportunities or expectations. The pipeline needs a big push.

Productivity Gap

Although the productivity gap certainly exists for biological products and medical devices, as well as prescription drugs, for the sake of simplicity, let us examine U.S. industry expenditure on research and development of pharmaceuticals relative to the number of new, innovative drugs that have been approved by FDA during the same time period. To dissect innovation from elaboration or imitation, only new molecular entities (NMEs) will be examined. The distinction between NMEs and other traditional drugs is summarized below:

• Innovation = NMEs, which are defined as active ingredients that have never before been marketed in the United States in any form. This is the category that comprises truly new therapeutic products.

• Elaboration = Non-NME new drugs, which include incremental modifications of existing drugs, such as changes in formulation or new indications (additional health conditions for which an existing drug can be prescribed). Although clinical trials are required to gain FDA approval, since the initial discovery and preclinical and clinical safety testing of the active drug component have already been done, the development costs and regulatory review times are usually substantially lower than for NMEs.

• Imitation = Generic drugs, which are the same as a brand-name drug in dosage, safety, strength, administration, quality, performance, and intended use. FDA requires specific scientific data on the therapeutic equivalence of generic drugs to the branded drug, but does not require clinical trials. Consequently, development costs are not even in the same league as for NMEs or non-NME new drugs.

According to the U.S. Congressional Budget Office, the pharmaceutical industry is one of the most research-intensive industries in the United States.1 Pharmaceutical firms invest as much as five times more in research and development (R&D), relative to their sales, than the average U.S. manufacturing firm. Government-funded research institutes and agencies such as National Institutes of Health (NIH), NSF, and the Centers for Disease Control and Prevention (CDC) have ramped up R&D spending. Publicly and privately funded academic R&D activity at universities and hospitals is continuing at a pace commensurate with funding. Despite this, the rate at which U.S. innovators have been able to bring new drugs from the research pipeline into the market has slowed considerably over the past decade.

Figure 1.1 shows the estimated amount of money spent on R&D by the private pharmaceutical sector. In Table 1.1, we see that the number of NME approvals has essentially stagnated. Furthermore, applications for NME approvals are not increasing, and candidate products did not appear to be any more likely to advance to the stage of final FDA review in 2011 than in 2000. Some new therapeutic biological products are considered to be NMEs, and are included here in the discussions of NMEs.

A myriad of explanations can be presented. Blame has been placed on outdated clinical trial models and inefficient regulatory review and approval processes. Costs are often cited as an impediment. Indeed, costs are a significant problem, but if investments are being made with dwindling numbers of deliverables, blame also must be directed to the way the money is being spent. While individual elements do contribute to failure, the most egregious problem lies within the product development process itself.

It is estimated that development of a therapeutic new molecular entity to the point of approval takes up to 15 years (see Figure 1.2). Recent estimates place the cost of developing a commercialized NME at over $1.3 billion (Figure 1.3).2 The numbers in Figure 1.3 include costs associated with R&D and the costs of failed projects, which are capitalized and time adjusted. These are disheartening figures, and the associated productivity gap has become a concern to industry, academia, FDA and other government agencies, lawmakers, public and private funding sources, and patient advocacy groups. Of course, there are the concerned patients themselves, who hear or read reports on a daily basis about exciting discoveries that hold promise for diagnosis, treatment, cure, or prevention of diseases—but who rarely get to hear about, or benefit from, the availability of any breakthrough products.

Because of the great diversity within medical devices, and because there are different regulatory pathways for various types of devices, estimates of product development time and costs are less readily analyzed, but the overall trend holds true. A recent report says that taking a medium-risk medical device cleared for marketing through the Premarket Notification 510(k) process requires $31 million on average, and that bringing a high-risk device approved for marketing through the more rigorous premarket approval (PMA) process burns up about $94 million.3 About three-quarters of those costs are related to stages linked to FDA. The devices in the report are likely to be innovative new medical technologies requiring clinical data, rather than simply extensions or products demonstrated to be substantially equivalent to low or intermediate risk devices.

From a regulatory perspective, biologics may function as either drugs—including but not limited to NMEs—or medical devices, and are similarly affected by the productivity gap. Distinctions in drug, medical device, and biologic product categorization and classification are discussed elsewhere in this book.

Translational R&D

Moving a scientific idea, discovery, or design from the research stage, through the product development process, to a viable and marketable medical product can be a formidable challenge. Surmounting the obstacles calls for a revision in attitudes and processes related to medical product development. Enter translational research. Translational research—also frequently called translational science or translational development—refers to concepts and practices intended to advance scientific discoveries from the lab to the patient. The approach is typically described as bench to bedside.

As a relatively new and evolving discipline, translational research and development has somewhat different meanings depending on the particular institution or interest group engaged in its applications to medical products or healthcare practices. Examples of these definitions are shown in Figure 1.4. For the purposes of this book, with its focus on the development of marketable prescription drugs, biologics, medical devices, and combinations thereof, the definition of translational research proposed by the Coulter Foundation seems most suitable:

• It is driven primarily by considerations of use and practical applications of the research results, as opposed to basic research, which is driven primarily by a quest for knowledge.

• It envisions the development of a practical solution that addresses a particular clinical problem or unmet clinical need.

• It often envisions as an endpoint the development of a particular product.

• The research results generally include intellectual property that can be protected by patents.

• It involves clinical application as a goal, and therefore requires a transition (a translation) of the research from the research laboratory to the clinic (bench to bedside).

• It involves commercialization as a goal, and therefore requires a transition (a translation) of the technology (technology transfer) from the academic institution to a commercial entity for final product development, manufacturing, and sales.4

In addition to the existence of diverse definitions of translational research, there are other complicating terminology factors. Translational research is sometimes divided into two stages or phases, sometimes into three, and sometimes into four. In the most general sense, the first stage (T1) is the advancement of research laboratory discoveries to clinical studies, and the second (T2) is focused on moving knowledge gained from clinical trials into the community