Early Drug Development: Strategies and Routes to First-in-Human Trials

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Library of Congress Cataloging-in-Publication Data:

Early drug development : strategies and routes to first-in-human trials / edited by Mitchell

N. Cayen.

p. ; cm.

Includes bibliographical references.

ISBN 978-0-470-17086-1 (cloth)

1. Drug development. I. Cayen, Mitchell N.

[DNLM: 1. Drug Discovery-methods. 2. Clinical Trials, Phase I as Topic. 3. Drug Approval-organization & administration. 4. Drugs, Investigational-therapeutic use. 5. Research Design. QV 744 E12 2010]

RM301.25.E27 2010

615′.19–dc22

2009045882

Contributors

Örn Almarsson, Alkermes, Inc., Waltham, Massachusetts

Mark Ammann, United BioSource Corporation, Ann Arbor, Michigan

Laura P. Andrews, Genzyme Corporation, Framingham, Massachusetts

Judith Atkins, Paraxel International Inc., Waltham, Massachusetts

Hugh E. Black, Hugh E. Black & Associates, Inc., Sparta, New Jersey

Lorrene A. Buckley, Eli Lilly and Company, Indianapolis, Indiana

Peter L. Bullock, Paul P. Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin

John Caldwell, University of Liverpool, Liverpool, United Kingdom

Mitchell N. Cayen, Cayen Pharmaceutical Consulting, LLC, Bedminster, New Jersey

Gary Eichenbaum, Johnson & Johnson Pharmaceutical Research and Development, Raritan, New Jersey

Kathryn Hackett-Fields, Pfizer Global Research and Development, Groton, Connecticut

Duane B. Lakings, DSE Consulting, Inc., Elgin, Texas

Ronald W. Moch, Hugh E. Black & Associates, Inc., Rockville, Maryland

Stephen B. Montgomer, Hugh E. Black & Associates, Inc., Alpharetta, Georgia

Amin A. Nomeir, Schering-Plough Research Institute, Kenilworth, New Jersey

Shari L. Perlstein, Pfizer Global Research and Development, Groton, Connecticut

Rafael A. Ponce, ZymoGenetics, Seattle, Washington; presently at: Amgen Inc., Seattle, Washington

Stanley A. Roberts, CoxX Research LLC, San Diego, California

Mary M. Sommer, Pfizer Global Research and Development, Groton, Connecticut

Vangala Subrahmanyam, Sai Advantium Pharma Ltd., Hinjewadi, Pune, India

Alfred P. Tonelli, Johnson & Johnson Pharmaceutical Research and Development, Raritan, New Jersey

Keith Wilner, Pfizer Global Research and Development, La Jolla, California

Foreword

From 1950 to the late 1990s, the global pharmaceutical industry was responsible for a series of advances that addressed major disease areas and led to significant improvements in public health and quality of life. In no particular order, these treatments may be exemplified by drugs (a) controlling blood pressure, and latter, blood cholesterol; (b) controlling gastric acid secretion; (c) controlling female fertility; and (d) progressively addressing major cancers, so that many tumor types are now treated as chronic diseases rather than terminal illnesses. The reader will be able to add many other examples to this list. Although these years were also marked by instances of patients harmed by drug treatments, most notably thalidomide in the early 1960s, the introduction of new therapies has revolutionized medical care for many people, created new personal freedoms, and is a major factor in the increase in life expectancy achieved in many countries over the past 50 or more years.

In recent years, the ability of the pharmaceutical industry to sustain this remarkable contribution has been challenged. Although we have seen a huge growth both in scientific understanding in the biomedical sciences and in the technical feasibility of many aspects of drug research and development, these advances have not been accompanied by corresponding increases in research productivity: put very simply, the research and development pipeline of new medicines has gotten blocked, so that fewer and fewer new agents reach the market each year. The reasons for this are many and varied. Making new compounds with interesting and therapeutically relevant biological activity is a challenge, but those that are produced lack other key features of usable drugs. In recent years it has proved very difficult indeed to develop such active compounds into novel medicines. The business model used by many pharmaceutical companies is not capable of infinite replication. The development of more blockbuster drugs, which have underpinned much of the growth seen from the mid-1970s onward, is now less and less likely in times when science seeks to stratify drug development and medicine seeks individualized therapies. The protection of intellectual property and the maximization of marketing exclusivity are now more important than ever and come under pressure from health care providers, who emphasize the need for low-cost generic prescribing as one means to address the escalation of costs. The regulatory environment in the early twenty-first century is both sophisticated and questioning in all jurisdictions and is supported by the very high expectations of the public in terms of both the efficacy and safety of new therapies. It is to be hoped that recent developments in this area, such as the U.S. Food and Drug Administration's Critical Path and the European Union's Innovative Medicines Initiative, will bear fruit, but there have been few successes thus far.

Against this background, this new volume provides an invaluable guide to the earliest and most critical stages of drug development, getting promising new chemicals into humans quickly, effectively, and safely, to provide information of maximum benefit for critical decision making. The Editor, who has a lifetime of experience in exactly this arena, has identified a series of key topics and matched them to well-qualified authors, resulting in an extremely helpful handbook to guide the experienced investigator and novice alike through what can all too easily be a mine field.

Drug development is simultaneously an art and a science. It depends on excellent science in all of the various chemical, biological, and clinical disciplines that contribute, but at present at least the coordination of the management of all of the resources required as well as critical and fully informed decision making is best regarded as an art. It is my view that this new volume represents a substantial contribution by providing an integrated approach to an area that has suffered from excessive fragmentation.

John Caldwell

Pro-Vice-Chancellor and Dean of the Faculty of Medicine

University of Liverpool, United Kingdom

August 2009

Preface

During my career in the pharmaceutical industry in Canada and the United States, initially as a bench scientist and subsequently in managing departments in big pharma companies, and now as an industry consultant, I have never ceased to view the drug discovery and development paradigm with a combination of excitement, awe, wonder, and caution. There are many reasons for this mix of emotions. First, the discovery and development of successful medicines represent hugely complex challenges, with what seems to be a constantly shifting end zone. Our learning curve about the etiology and treatment of disease, coupled with the numerous changes in regulatory climate, help contribute, in my view, to make successful pharmaceutical development one of the most difficult of business enterprises. The second and probably more fundamental reason for these feelings is that the more I have learned over the years about how foreign compounds interface with living organisms, the more I realize that there is so much that I will never learn or understand. This is a sobering thought. Those of us who are in the business of developing medicines to treat human disease are doing the best we can to assure that we do not put patients at risk and that there is a high likelihood of therapeutic success. Given the complexity of the human body, the best we can hope for, based on all our advances over several millennia, is that successful therapeutics continue to morph from hit-and-miss to higher odds of positive outcomes in larger percentages of the target population. We still have a long way to go. It continues to amaze me that in most therapeutic areas, we have only reached the stage where we are merely alleviating disease symptoms rather than curing the actual disease.

It is therefore not surprising that the road to successful drug development has many twists, turns, and intersections, and that many travelers take different routes. It is critical to note that the path must eventually lead not to the submission of a new drug application (NDA), but to the attainment of an approvable NDA. The primary goal of this book is to describe those routes that have the greatest likelihood of a successful journey during the initial stages of the voyage [i.e., up to the first-in-human (FIH) trial]. The authors who provide these perspectives have had decades of experience in both big and small pharma companies, biotechnology companies, contract research organizations, regulatory affairs, and various aspects of consulting. Each chapter focuses on a specific discipline that contributes to the late discovery and early development of new candidate drugs, and is designed to describe the state-of-the-science, challenges, strategies, and how to regarding study designs and data interpretation. Many basic concepts are described and explained. The text can be used as a primer for new investigators as well as a resource for the experienced. It should be noted that each author is presenting the topic from his or her viewpoint and perspectives and that for the most part, no one size fits all. Indeed, given the fact that no single discipline can stand on its own, there is some overlap between chapters, and the reader may therefore obtain different viewpoints on similar topics (e.g., safety assessment of metabolites in Chapters 2, 3, 8, and 9; the TGN1412 monoclonal antibody human toxicity issue in Chapters 10 and 12). For example, approaches will vary based on such factors as:

Small-molecule versus biotherapeutic drug

Route of drug administration

Frequency of drug administration

Target disease

Corporate resources, goals, portfolio management, and competitive landscape

We decided early where on the drug development path to end this book, and that was in the planning (but not implementation) of an FIH study. However, the more difficult decision was deciding where to begin. For various reasons, including the fact that there are numerous excellent published treatises on the discovery process, we decided arbitrarily to start at the point where a new chemical entity (NCE) has been shown to possess pharmacological activity in an initial screen (hit-to-lead), and then proceed to the next step toward the process of selection as a candidate drug (lead optimization). Accordingly, there is extensive discussion of those disciplines and activities necessary to demonstrate that the FIH trial will have a high likelihood of success; these disciplines include toxicology, safety pharmacology, CMC (chemistry, manufacturing, and controls), ADME (absorption, distribution, metabolism, and excretion), pharmacokinetics and toxicokinetics, GLPs (good laboratory practices), bioanalysis, regulatory submissions, and related activities. It is emphasized that there is no such thing as the perfect drug candidate, whether from the efficacy or safety viewpoint; as Sir Harold Macmillan pointed out: To be alive at all involves some risk.

One of my personal challenges when I begin consultation with a pharmaceutical company is to learn the lexicon which is the in-house language but which may not be readily transparent to new visitors. We have tried to be consistent within and have decided arbitrarily to use such terms as FIH [rather than FTIM (first time in man)], NCE [rather than NME (new molecular entity) or NCD (new candidate drug)], and nonclinical (rather than preclinical, though both will be found).

I would like to thank Jonathan Rose at John Wiley & Sons for inviting me to put this book together and for his guidance during the process. I am very grateful to the authors of the various chapters for their dedication and patience, and for providing this project with their vast array of experience and expertise.

It is my joy to dedicate this book to my wife, Judy, who was instrumental in encouraging me to take on this project and whose love and support were absolutely invaluable during its course.

Mitchell N. Cayen

Bedminster, New Jersey

September 2009

Part I

INTRODUCTION

1

Drug Discovery and Early Drug Development

Mitchell N. Cayen

1.1 The Drug Discovery and Development Scene

1.1.1 Pharmaceutical Research and Development Challenges

Although it is common practice to envisage the launching of a therapeutic as a linear paradigm comprising a drug discovery phase gradually bridging into a development phase, it should be noted that such a process is rarely so straightforward. There are many potential intersecting paths to a successful new therapy, often involving a mixture of successive or concurrent intellectual, scientific, practical, commercial, regulatory, and other considerations among academia, industry, and government. However, for the purposes of the focus of this book, the road to therapeutic success is being presented generally as a linear continuum starting with drug discovery, continuing to drug development, then submission to regulatory agencies and approval, and ending with what is hopefully a high-quality medication that exhibits optimal safety and efficacy in the target population.

Given the achievements in the past several decades in our understanding of the underlying mechanisms of disease, huge technological advances, and the goal of optimizing monetary, staff, and time resources, it would be expected that in the ideal world, in recent years we should have been witnessing an increase in the availability of new and improved medicinal products. However, anyone involved in health care delivery is well aware that this is not the case. The past five years have witnessed a dramatic decline in the number of new drugs approved by the U.S. Food and Drug Administration (FDA) compared to a decade ago. Compared to the highs of 53 in 1996 and 39 in 1997, the numbers of new drugs approved by the FDA was 21 in 2003, a decade high of 36 in 2004, 20 in 2005, 22 in 2006, 19 in 2007 (the fewest in 24 years), 25 in 2008, and 26 in 2009. Concurrently, the costs to discover, develop, and register an approvable new drug is compelling, and has been escalating from about $800 million in 2001 [1] to $900 million in 2004 [2] to about $1.3 billion today (comprising approximately $425 million for nonclinical and $850 for clinical development, although such estimates do vary, depending on the source material and analyses techniques), and the time from discovery to commercialization ranges from 10 to 15 years. The good news is that the average time for FDA approval has declined to an average of 1.1 years in 2005–2007 from around 2 years previously. With patent protection lasting for 20 years, at least in the United States, the time frame for profitability remains relatively narrow, although a patent-protected drug is generally highly profitable during this protected period. Following are some of the contemporary perspectives, challenges, and pressures inherent in the pharmaceutical industry that affect the timely availability of novel therapeutics.

Research and Development Challenges

Research and development productivity has been declining.

Late-stage pipelines have become relatively thin.

Industry is tackling diseases of greater complexity [e.g., oncology and central nervous system (CNS) malfunctions such as Alzheimer's disease, Parkinson's disease, schizophrenia, and bipolar disease], necessitating complex clinical design protocols.

No drug is perfectly safe or spectacularly efficacious at all doses.

The concept of risk/benefit ratio is changing with the realization that the balance may not only be determined by dose, but that different patients may be more likely to gain the benefit, whereas others may be more prone to risk.

Marketing pressures within pharmaceutical companies may be at odds with research and development goals, including risk/benefit analyses.

Many companies are pulling potentially good drugs out of the pipeline because of regulatory agencies' diminished tolerance for side effects.

Business Perspectives

Industry is struggling with greater scrutiny, patent expirations, major mergers, poor stock performance, thousands of layoffs, and thinning pipelines.

Generic competition will eliminate $67 billion annual revenues for U.S. pharmaceutical sales between 2007 and 2012; more than three dozen drugs will lose patent protection during this interval.

Accordingly, the first annual revenue decline in four decades will occur between 2011 and 2012.

New blockbusters are lacking to replace old ones such as Lipitor and Plavix. There remains a mindset by many organizations that only blockbusters are worth developing.

However, blockbuster mentality restricts research direction and diversification.

To remain competitive, drug companies must adjust to shifting market conditions (including enhanced standard of care), which may become altered during the course of drug development.

1.1.2 Attrition During Discovery and Development

It is thus well known that the odds of a new chemical entity (NCE) finding its way to becoming a successful therapeutic agent are extremely low. Only one in 5000 to 10,000 NCEs are approved and, in both the United States and Europe, approximately one in nine compounds that enter clinical development end up as approved products. Emerging data seem to indicate that the approval rate is somewhat higher for biopharmaceuticals than for small-molecule drugs. In the early 1990s, one of the main causes of this high attrition was pharmacokinetics and bioavailability (including problematic clinical drug–drug interactions); however, with the recent focus on the very early assessment of such characteristics (Chapter 2), these properties can be identified to a great extent prior to the first-in-human (FIH) study, resulting in early elimination of compounds unlikely to elicit undesirable absorption, distribution, metabolism, and excretion characteristics in patients. In the past several years, the principal reasons for attrition are generally in the following order: clinical efficacy > nonclinical toxicology > commercial > clinical safety > pharmacokinetics/bioavailability > cost of goods > formulation [2]. Success rates can vary with the therapeutic area: For those NCEs entering an FIH trial, the percentages that end up as marketed drugs are approximately 20% for cardiovascular, 16% for arthritis/pain and infectious diseases, and 5 to 8% for oncology and CNS malfunctions.

The chapters in this book are designed to aid in the determination of the most efficient and effective path to the FIH trial with NCEs that have a high likelihood of morphing into successful therapeutics. It should be noted that the mindset of reducing attrition in clinical development should be in place from the earliest stages of discovery, given that research, development (nonclinical and clinical), and marketing personnel should be aligned as early as possible in the discovery process. In this manner, all relevant disciplines can help create the animal pharmacology models best predictive of clinical efficacy, and later to design a proof-of-concept endpoint in the FIH study to provide evidence that the molecular target is being hit and that hitting such a target will elicit the anticipated physiological response [the exploratory investigational new drug (IND) approach to rapid attainment of such information is discussed in Chapter 11]. Early coordination among disciplines can also help reduce attrition by the early elimination of compounds with poor pharmaceutical properties (e.g., solubility; permeability), insufficient chemical and metabolic stability, low bioavailability, potent enzyme inhibition or induction, mechanism-based toxicity, and other characteristics that would affect the clinical safety and efficacy of an NCE. Whether within a big pharma company, a smaller pharma/biotech organization, or a virtual company, strategic planning at all stages of discovery and development are critical, and can make or break a company (Chapter 13).

1.1.3 Corporate Strategy Perspectives

Given the extraordinary challenges and extensive commitment of time, financial, and human resources necessary to achieve marketing of a successful drug, the end result is usually a relatively profitable enterprise for the pharmaceutical company compared with many other industries. Such profitability is important, as it enables the industry to reinvest in research and development for those debilitating diseases that require improved therapies. The pharmaceutical industry has witnessed more major changes in the past century than, arguably, has any other major industry. This is probably because as we learn more about the causes and etiology of disease, which continue to remain elusive because of the complexities of normal and abnormal biological systems, adjustments must be made continuously based on our emerging understanding of the continuum between efficacy and safety. The basic principle of pharmacology (i.e., that no drug is perfectly safe and that safety is dose dependent), is sometimes overlooked by those intricately involved in the process. Despite all the knowledge we have accumulated, most contemporary therapies still alleviate disease symptoms rather than resulting in a cure of the target disease.

Although discrete pharmaceutical companies have been developing drugs for well more than a century, no optimal business model has emerged that would be predictive of success. With the numerous scientific, medical, marketing, financial, and regulatory pressures and challenges of recent years, some companies prescribe to the bigger is better philosophy, such as the recent megamergers of Pfizer and Wyeth, Merck and Schering-Plough, and Roche and Genentech; whether such consolidation results in industry stabilization remains to be determined. Other big pharma companies have been establishing relatively independent small research units that seem to mimic those in smaller biotech companies. Small to midsized pharmaceutical companies, virtual companies, and smaller biotech companies often try to develop new drug candidates through to successful proof of principle in humans, and then attempt to partner with a larger organization with more extensive clinical development and marketing muscle. The smaller the company, the more likely it is to exit product development early. Virtually all companies—small and large—utilize the services of contract research organizations (CROs) to supplement their programs, and this resource is discussed later in the chapter.

For companies of all sizes, it is critical to have a portfolio management strategy which is dependent on such considerations as the inherent size, research/development/marketing staff skills, tolerance for risk, geography, corporate culture, and unfortunately, internal politics. Once a decision is made to embark on the development of an NCE, a plan is put in place that incorporates time lines through to the anticipated new drug application (NDA). There are numerous strategies that can comprise such a plan. One approach, which can be extremely useful, in particular for staff scientists within specific disciplines who may not be privy to the big picture, is to write the outline of the drug label first. Although this may seem to be counterintuitive, focusing on and writing the target therapeutic qualities of a medicinal product can help in the design of specific studies that will determine whether the NCE meets those qualities.

The development plan should comprise several go/no go decision points (e.g., proof of principle), which will help determine whether a program should continue to progress through several gates. Often, however, other problematic data may emerge that are outside the formal decision points. One of the most difficult decisions is the timing regarding when a development program should be terminated, based on emerging problematic safety, efficacy, and/or pharmacokinetic data. A development program will typically have one or more champions and several stakeholders from numerous disciplines who may rationalize why the drug candidate should continue along the development path instead of intaking the difficult decision to terminate the program. The basic paradigm will continue to comprise intense planning, strategic decision making, extensive research, long-term nonclinical safety, and clinical safety and efficacy studies, comprehensive data collection and statistical analyses, and relevant support programs. Whatever the strategy, it is ultimately the drug that speaks, and it is incumbent upon all those within large or small organizations and all contributing disciplines to conduct the most appropriate studies that will enable all relevant aspects of efficacy and safety to be uncovered. Small and large studies in all disciplines must be conducted based on sound scientific disciplines, to avoid garbage in–garbage out results with equivocal interpretation. One cannot force a drug candidate to exhibit properties that it does not possess.

In light of the perspectives noted above, a primary goal of the chapters that follow is to help guide those involved in the exciting field of pharmaceutical discovery and development to plan and conduct those studies beginning with lead optimization (discovery support), to early development, through to the FIH trial. The goal is to evaluate NCEs that have the greatest likelihood of leading to valuable therapeutics, and to develop strategies that will optimize what are often limited monetary, time, and human resources. Moving forward, it will be important to adjust the focus of the various disciplines as new advances in biomedical and genomic technologies emerge, and to determine which of these technologies are really useful in predicting human safety and efficacy, thereby affecting the drug development process. It must always be kept in mind that the ultimate goal in drug development is not the NDA submission process but the attainment of an approved NDA.

1.2 Drug Discovery

1.2.1 Target Identification

Drug discovery is a process whereby potential therapeutics are designed and identified. Historically, most drugs have been discovered either by isolating the active ingredients from natural sources such as plants, animals, or minerals, or by empirical approaches that capitalized on enlightened serendipity (such as the discovery of penicillin in a dirty petri dish in Alexander Fleming's laboratory, or the invention of aspirin—still the most widely used drug worldwide). Indeed, in developed nations, herbal remedies have become more popular. With rapid advances beginning in the twentieth century in the understanding of the origins and pathology of human disease, modern drug discovery typically focuses on studying the metabolic pathways related to a disease state or pathogen, and manipulating these pathways using medicinal chemistry, biochemistry, physiology, microbiology, and/or molecular biology. Genetic and genomic information also offers great promise in drug discovery and therapeutic success [3].

The first step in the process is target identification, and it is this critical step that necessitates a true understanding of the pathogenesis of the disease. Target identification for numerous serious diseases is being pursued aggressively by laboratories in the pharmaceutical industry, universities, and government institutions worldwide. The ideal target is generally a clearly identified molecular entity (such as an enzyme or a receptor) known to be directly associated with the disease pathophysiology. Certain targets are considered to be more likely than others to be amenable to changes that the medicinal chemist can target with compounds that might ultimately lead to a successful medicine. The term druggability of a given target (druggable target) is being used to indicate the likelihood of being able to modulate a target with a small-molecule drug or antibody, and it is important to predict the potential druggability of a novel target. Parameters that influence druggability include cellular location, specificity, development of resistance, transport mechanisms, side effects, and toxicity. Some target classes, such as protein kinases or the large family of transmembrane receptors such as the G-protein-coupled receptors (GPCRs) have been targeted successfully, and a large number of approved drugs, such as many biogenic amines, eicosanoids, lipid-signaling molecules, and numerous peptide and protein ligands, exhibit their mechanism of action by interfacing with GPCR receptors. The many serious diseases that remain poorly treated may witness breakthroughs due to the exploitation of many unexplored targets.

However, many safe and effective drugs have been and continue to be discovered and developed without a true understanding of the actual target; that is, the mode of action may be known, but the mechanism of action may not be uncovered until later, or not at all. With their longer history, small-molecule drugs currently tend to be focused on the better established targets, while extensive research has been ongoing on new targets for biotherapeutics (i.e., biotechnology-derived drugs such as therapeutic proteins, peptides, oligosaccharides, and monoclonal antibodies). Also, the concept of druglike properties is used by medicinal chemists as a guide to the likelihood of an NCE becoming a successful drug [4]. Such characteristics include physicochemical properties such as lipophilicity, as well as optimal absorption, distribution, metabolism, and excretion (ADME) profiles (Chapter 2), which enable the compound to exhibit targeted efficacy for a sufficient length of time. Indeed, it appears that lipophilicity has emerged as the single best physicochemical characteristic that is predictive of the druglike property of a chemical regarding potency, efficacy, ADME, and toxicity [4]. This is exemplified by the Lipinski rule of five [5, 6], which is a rule of thumb describing the molecular properties of a drug that can predict the high absorption and permeability of small-molecule drugs, although the rule does not predict if a compound is pharmacologically active. The rule states that, in general, an orally active drug should not violate more than one of the following four criteria:

1. No more than five hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms)

2. No more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms)

3. Molecular weight below 500 Da

4. Calculated octanol–water partition coefficient (c log P) below 5

The Lipinski rule is only applicable for those compounds that are not substrates for active transporters (Chapter 2). An analysis of databases of the past decade of NCE hits and leads have shown that advanced lead compounds and early clinical candidates that have undergone attrition tend to differ in the desirable physicochemical properties described above, and that the undesirable phenomena were traced back to the nature of the high-throughput screening tests and hit-to-lead optimization practices [7]; this reinforces the value of studying druglike properties as early as feasible.

1.2.2 Hit-to-Lead Identification

Following target identification, and for small-molecule chemicals, the medicinal chemist is charged with the responsibility of compound synthesis (e.g., combinatorial chemistry, high-throughput chemistry, classical organic chemistry synthesis, compound libraries) based on numerous strategies and considerations [8]. This is followed by appropriate in vitro [usually by actual or virtual (using computer-generated models) high-throughput screening] and in vivo screens of the new compounds for potential potency and selectivity, and an evaluation of how NCEs with the appropriate characteristics are selected for specific targets of interest. Novel pharmacophores can also emerge by drug design, which involves the prediction of which NCEs might fit into an active site based on the biological and physical properties of the target. Thus, these initial evaluations focus on efficacy and potency rather than on potential safety. High-potency drugs are associated with low-efficacious doses, and in general, the lower the efficacious dose, the less the likelihood of toxicity and side effects.

It is rare that a perfect drug candidate will emerge from these early screens. Typically, several compounds will be uncovered with some degree of activity, and if these compounds share common chemical features, one or more pharmacophores can then be developed. Collaboration between biology and medicinal chemistry is critical such that medicinal chemists can attempt to use structure–activity relationships (SARs) to improve the characteristics of the lead compound(s) [e.g., increase activity against the target selected (potency)], decrease activity against unrelated targets (selectivity), and/or improve druglike properties (e.g., lipophilicity, as described above; metabolic stability). The goal is to improve the properties of the NCEs to allow the most favorable compounds to move forward to later-stage testing (e.g., disease models) in discovery and to enter the early stages of development. This process of drug discovery is discussed in detail in other treatises [e.g., 9,10] and is beyond the scope of this book. A variety of terms are used to define the major consecutive steps of the discovery and early development process following target identification: hit identification, hit confirmation, hit to lead, lead identification, lead characterization, lead optimization, and bridging from discovery to development. Realistically, these are not discrete stages of the discovery/early development process but should be viewed as a continuum as an NCE gradually morphs into a candidate drug. These terms are used only rarely in this book; instead, pre-FIH drug discovery implies those activities that occur, starting with lead optimization: that is, those studies that begin to define whether an NCE emerging from discovery is a realistic candidate to enter human trials.

As a general rule, pharmaceutical companies prefer to develop orally active small-molecule drugs, which can be administered conveniently to the patient, ideally once a day. However, many life-threatening diseases have not been attacked successfully by small molecules, and the evolution of biotherapeutics such as therapeutic proteins and peptides, monoclonal antibodies, oligosaccharides, and nucleic acids has revolutionized the industry. These macromolecular drugs pose specific challenges in terms of production, drug delivery, interpretation of animal toxicity studies, and administration to patients (Chapter 12).

1.2.3 Lead Optimization Strategies

To this point we have provided a brief overview of some of the early aspects of the discovery process. As stated, discovery and development can be considered a continuum; where one ends and the other begins—indeed, whether such a sharp distinction exists—varies among drug sponsors. For purposes of the discussions in subsequent chapters, the development phase is considered to begin when a decision is made to select an NCE for nonclinical development and the initial good laboratory practices (GLP) toxicity studies are planned. The chapters herein describe those discovery support activities, development programs, and support functions, starting when one or more NCEs emerge from in vitro and in vivo pharmacological testing as potentially efficacious new candidate drugs through to the recommended plan for the dosage regimen for the FIH trial.

The key challenge in drug development institutions, whether small or large organizations, is to establish a strategy whereby as many of the key properties of NCEs emerging from pharmacological testing as possible are evaluated in the most efficient and effective manner. There is, of course, no ideal drug, but some of the characteristics that can be considered important in the decision as to which of several compounds will be selected for pre-FIH development are listed in Table 1.1. This list should not be considered a boiler plate compendium, as the common thread throughout the pharmaceutical industry is that no two companies would have identical strategies as to what should be included in, or excluded from, this list. For example, protein binding has not been included, as it is not considered by this author to be a key variable in the early decision-making process, although other investigators may view its importance as greater in the discovery paradigm. However, most drug sponsors would want to assure that most of these key properties have been studied prior to recommendation for pre-FIH development. In the chapters that follow, the assumption is made that the first seven properties—potency, selectivity, biology, chemical stability, chirality, patent status, and physicochemistry—have been studied appropriately such that the emerging NCEs can proceed through the gate for evaluation. Discussions are presented on the lead optimization and pre-FIH development programs principally for orally administered small-molecule drugs and systemically administered biotherapeutics, along with the regulatory expectations and various planning strategies for the critically important FIH trial.

Table 1.1 Some Optimal Characteristics Evaluated During the Discovery Phase for Orally Administered Drugs

1.3 Pre-FIH Drug Development

1.3.1 Introduction

Drug development refers to the activities undertaken after an NCE has been identified as a potential drug candidate to evaluate its suitability as a medication. In the context of this book, NCEs are considered to be compounds that emerge from the drug discovery process based on promising activity against a biological target(s) thought to be important in the target disease, and have been selected for GLP toxicity trials based on optimal lipophilicity, in vitro metabolism, nonclinical pharmacokinetics/bioavailability, and possibly preliminary safety pharmacology and/or in vitro toxicity tests. In the next few sections of this chapter we present some general perspectives of pre-FIH development and the FIH trial, most of which are covered in detail in subsequent chapters.

1.3.2 Pre-FIH Toxicology

Once an NCE has been selected as a feasible drug candidate, in vitro and in vivo studies are initiated to evaluate the drug's toxicity (Chapter 7). Acute toxicity involves harmful effects in an organism through a single or short-term administration, although its utility in the overall toxicology program may be waning. Chronic toxicity is the ability of a drug candidate to cause untoward effects after multiple administrations over an extended period of time. The goals are to identify organs targeted by the drug, effects on mammalian reproduction, and for drugs to be administered chronically, whether there are any long-term carcinogenic effects. These nonclinical safety evaluations are conducted according to strict regulatory procedures called good laboratory practices (GLPs) (Chapter 9). Toxicity evaluations are among the first development studies to be conducted on a candidate drug, and will continue concurrently through the course of the clinical development phases. The interpretation of toxicity findings is often different for small-molecule drugs than for biopharmaceutics; for some biologics, there are issues with superpharmacology, wherein there is too much of a desired response being responsible for the adverse effects observed.

During the pre-FIH phase, the in vivo studies typically conducted are limited to a 2-week to 3-month duration (depending on the duration of use in humans) in a rodent and nonrodent species, whose choice is based on which is believed most closely correlated to humans. Species differences in gastrointestinal tract physiology, intrinsic enzyme activities, circulatory system, bioavailability, or metabolic profiles will render some species more appropriate than others. Also, certain classes of drugs may not be relevant in some species; for example, rodents are poor models for antibiotic drugs because the resulting alteration to their intestinal flora can cause significant adverse events that are not relevant for humans. Some species are used for similarity to specific human organ systems (e.g., swine for dermatological products, dogs for gastric studies). Species selection for pre-FIH toxicity studies should be made very carefully in light of the delays and additional expense that might occur (e.g., for new dose-ranging studies; see Chapter 7) should it be considered advisable to change the species at later stages of development.

The promising young field of toxicogenomics is emerging as a possible alternative to animal toxicology testing. These cell-based assays offer a compelling strategy for the evaluation of specific potential toxicity (e.g., the effect on gene expression in hepatocytes) with the hope that this discipline can be employed to reduce the use of whole animals. The dilemma is whether such in vitro models or toxicity biomarkers can be roughly equivalent to the classically used in vivo models and whether cell-based screens can ever replace animal testing. Perhaps toxicogenomics may best be employed at the early screening stages as a predictive toxicology tool to eliminate NCEs in the discovery phase. There is a critical need to develop and validate toxicogenomic high-throughput assays and other models which can at least partially replace current resource-intensive animal testing. Of course, all whole-animal models themselves have shortcomings in predicting human safety, although some modified animals, such as genetic knockouts, knock-ins, or transgenic models, can be used for specific purposes. In the meantime, it appears that the classical testing of a rodent and a nonrodent species for toxicity properties will remain the gold standard for the foreseeable future.

1.3.3 Formulation and Drug Delivery

The formulation and delivery of drugs into the human body forms an integral part of the drug discovery and development process (Chapter 5). Indeed, formulation issues can influence the design of the lead molecules and feed back into the iterative lead optimization cycle as well as nonclinical and clinical evaluations. The goals of formulating drug substances into drug products is to assure optimal stability and absorption for oral products (e.g., by enhancing absorption through their interaction with the cell membrane of the gastrointestinal tract) and solubility for systemically administered drugs. Indeed, a significant number of drug discovery and development programs center around new ways of formulating known or marketed drugs in order to improve on their pharmacokinetic profiles, thereby enhancing their safety and/or efficacy characteristics, or improving on the dose regimen (dose level or dose frequency). Components of formulation substances that are not generally regarded as safe (GRAS) become part of the nonclinical safety assessment program (i.e., they must be qualified). Sometimes side effects such as local irritation or allergic reactions are attributable to drug formulation rather than the active pharmaceutical ingredient (API).

One of the key logistical challenges in the initiation of pre-FIH toxicity studies is the timely availability of drug substance (or drug product, if formulation is required). It is not uncommon, upon deciding that a lead candidate is to become a candidate drug to undergo toxicity testing, for a drug sponsor to experience the frustration of delays in the synthesis and testing of sufficient amounts of drug required for the animal studies. In most instances, the synthetic route used to generate milligram (or low-gram) quantities of the drug in support of discovery and early development is not feasible for scale-up to the high-gram or possibly kilogram amounts needed for rodent and nonrodent toxicity evaluations. Accessibility of cost-effective starting material can become an issue. There is a catch-22 element to such delays, in that resources should not be devoted to scale-up synthesis of compounds which may not become candidate drugs, yet once a decision is made to proceed to humans, it is desirable to schedule the toxicity studies as rapidly as possible with sufficient amounts of high-quality drug. It is thus important that representatives of the various disciplines that comprise the project team (Chapter 13) work closely together so as to minimize such inherent delays in the early development process.

1.3.4 Pre-FIH Drug Metabolism and Pharmacokinetics

As with the other major disciplines that comprise the nonclinical and clinical evaluations of candidate drugs [toxicity testing; CMC (chemistry, manufacturing, and controls)], evaluation of the ADME and pharmacokinetic properties of a drug candidate (Chapter 2) is a continuum beginning with support of discovery through to the NDA. This also applies to bioanalytical support of the discovery and development programs (Chapter 4) and the toxicokinetic evaluations (Chapter 8) required to demonstrate that there is a correlation between dose regimen in the toxicity studies with systemic exposure to relevant drug-derived material [parent drug and/or metabolite(s)].

As stated previously, the reason that pharmacokinetic (PK) and ADME characteristics are no longer the principal cause of attrition during drug development or of drug withdrawals postmarketing due to untoward drug–drug interactions (e.g., withdrawals of Posicor in 1998 or Hismanal in 1999) is that technologies are now being utilized during the discovery phase to weed out those NCEs that have poor such characteristics. Within the armamentarium of available rapid ADME, bioavailability, and bioanalytical testing procedures and laboratory equipment, the discovery unit must decide what to do when and with what; that is, medicinal chemists can rapidly generate numerous compounds which, with high-throughput techniques, can rapidly be evaluated for biological activity. Thus, discovery support ADME groups can become flooded with numerous NCEs and be asked to tell us which compounds have good ADME/PK properties.

Strategic planning is critical in determining which studies should be done early and which can be deferred until later. Certainly, it is desirable to have an early assessment in vitro in human preparations of metabolic stability and cytochrome P450–mediated enzyme inhibition, as well as some indication of oral bioavailability in laboratory animals (pharmacology and/or putative toxicity species) (Table 1.1). Other possible discovery support tests are decided on a case-by-case basis; for example, although it is necessary to evaluate plasma protein binding of a drug undergoing clinical development, it is probably not necessary to have this information as part of the go/no go decision package during discovery or during pre-FIH development. Permeability and transporter assays are readily available to characterize drug uptake into, or efflux from, the target organ(s), and depending on the emerging properties of the NCEs being examined, the project team will decide if this assay is also relevant in compound selection. As most drugs undergo at least some biotransformation, a strategy is recommended regarding how much metabolism work should be conducted at this stage, as metabolites may also contribute to pharmacological activity, or with in vitro tests that do not involve metabolic activation [e.g., cardiac hERG (human ether-a-go-go related gene) channel assay; Table 1.1], a negative finding is valid for a parent drug but not for putative metabolite(s).

Once the decision is made to proceed to conduct pre-FIH toxicity studies, it is necessary to develop and fully validate the bioanalytical assay for the drug in plasma of the animal species selected (Chapter 4), to analyze the plasma samples, and to perform the toxicokinetic analyses to assess systemic exposure (Chapter 8). During this stage it is also advisable to time the validation of the bioanalytical assay for human plasma such that there will be no delay in such analyses once the FIH trial is initiated. The only regulatory ADME/PK requirements or expectations for ADME/PK in IND submissions are typically comparative in vitro data on metabolism across species (toxicity species and humans) and toxicokinetic support of the pre-FIH toxicity trials. Often, however, it is in the interest of the sponsor and for investigational review boards to have additional information that can help support predictions of safety and efficacy in initial human studies.

1.4 The FIH Trial

The first administration of a drug candidate to human subjects is arguably the most exciting moment on the development path and the time that probably generates the highest anxiety, for this study represents the culmination of all the pre-FIH activities and results in the generation of initial data on the safety and possibly pharmacokinetics of the candidate drug in the target species. Up to this point, all of the information available has been based on in vitro and nonclinical pharmacology, toxicology, and ADME models, some of which may or may not be reliable indicators of human response. Also, this stage often involves change from a nonclinical champion of the NCE to a clinical champion on the development team.

It is critical that the FIH trial be designed appropriately so as to address its primary purpose: that is, to characterize the safety, tolerability, and pharmacokinetics of the NCE, including an evaluation of its maximum tolerated dose. Efficacy is rarely a primary goal of the FIH trial, as they are generally insufficiently powered to assess a relevant pharmacodynamic endpoint and the studies are typically conducted in healthy volunteers rather than in patients. However, it could be extremely useful if some biomarker of pharmacodynamic activity were available to be included in the FIH trial.

There are several challenges in the design and implementation of an FIH trial. The primary challenge is selection of the starting dose, the dose escalation strategy, and the stopping dose (Chapter 10), based generally on the totality of safety and plasma exposure data emerging from the pre-FIH toxicity studies (Chapter 7) as well as the results from the safety pharmacology studies (Chapter 6). The second challenge is to assure that all resources are available in a timely manner (e.g., sufficient appropriately tested drug product and fully validated bioanalytical assay). Thus, it is important that representatives from all the various disciplines involved in generating the relevant data—nonclinical pharmacology, toxicology, safety pharmacology, drug metabolism and pharmacokinetics, formulation development—contribute to the important decision regarding the starting dose and study design of the FIH trial.

1.5 The Regulatory Landscape

Drug development is different from other high-tech ventures in that it is highly regulated, although some outside the industry would argue that it is not regulated enough. There is no doubt that the tough new regulatory landscape is altering drug development strategies. It is important that the pharmaceutical industry appreciate that regulatory authorities in the United States [11], Europe [12], and elsewhere have become more demanding regarding the adequacy of benefit/risk assessments, particularly in the wake of high-profile withdrawals by the FDA of drugs such as Vioxx. Industry commentators have suggested that the increased risk aversion by regulatory agencies, resulting in larger clinical trials, is a contributor to the recent decreases in new drug approvals. On the other hand, regulatory authorities tend to argue that fewer drugs are being approved because pharma has filed fewer NDAs, due to faltering research efforts. More clarity is being sought by drug sponsors as to the regulatory tolerance for risk, which hopefully will not be a moving target given the myriad medical, scientific, political, and business interests that are interacting with government officials. Also, uncertainty exists as to how the some 200 new provisions in the FDA Amendments Act of 2007 will affect agency requirements. Although some drugs still reach the market without adequate assessment of efficacy, it is important to note that marketed drugs are rarely withdrawn due to poor quality or efficacy, and that the percentage of marketed actually drugs withdrawn due to patient risk is quite low. The latter include:

2007: aprotinin (Trasylol)—increased complications or death

2007: tegaserod (Xelnorm)—heart attack and stroke

2007: pergolide (Permax)—risk of heart valve damage; still available outside the United States.

2006: ximelagatran (Exantia)—increased hepatotoxicity

2005: pemoline (Cylert)—increased hepatotoxicity

2004: rofecoxib (Vioxx)—risk of myocardial infarction (the most publicized withdrawal in recent years)

Although marketing of approved therapeutics is generally targeted worldwide, our heterogeneous world results in regional differences, such as varying standards of care, population dynamics such as ethnic and metabolic features, and emerging markets (Asia-Pacific; Latin America; Eastern Europe; Middle East/Africa) with different regulatory challenges and opportunities (Chapters 14 and 15). Historically, three main regulatory bodies have dominated the global oversight of drug approvals:

1. The U.S. Food and Drug Administration (FDA)

2. The European Medicines Agency (EMEA)

3. The Japanese Ministry of Health, Labor, and Welfare (MHLW)

A gigantic step in attempts to globalize and harmonize regulatory guidelines was the establishment in 1992 of the International Conference of Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH), which brought together representatives from the FDA, EMEA, and MHLW, together with their industry counterparts from the U.S. Pharmaceutical Research and Manufacturers Association (PhRMA), the European Committee for Proprietary Medicinal Products (EC-CPMP/EFPIA), and the Japanese Pharmaceutical Manufacturers Association. Representatives from other countries, including Canada (Health Canada) and Australia (Therapeutic Goods Administration), also participated. The goal was to attempt to develop an international consensus on the scientific, technical, and regulatory aspects of drug development and product registration, and to make the regulatory processes more transparent with the generation of harmonized guidelines that would be applicable worldwide (www.fda.gov/cber/ich/ichguid.htm). These common requirements agreed upon by the major regulatory bodies have simplified at least some of the drug development processes, have reduced duplication due to regional regulatory differences, although regional guideline documents that remain still take precedent within the respective geographical areas. Regarding IND submissions, one of the major benefits that emerged from ICH is the ability to submit INDs electronically worldwide using the common technical document format (eCTD). The ICH process is a growing initiative which continues today, and the FDA, EMEA, and MHLW continue to harmonize their policies on a broad range of regulatory issues, much of which is discussed in later chapters.

In addition to the sections that describe the common technical document (CTD) (with prefix letter M) format for submission of marketing applications to regulatory agencies (Chapter 15), the ICH guidance documents, some of which are relevant to pre-FIH development studies, are divided into three general categories:

1. Safety. These guidances, designated with the prefix letter S, refer to nonclinical safety, but not clinical safety, and describe the short- and long-term toxicity studies for small-molecule drugs and biopharmaceutics. Included are genotoxicity tests, reproductive toxicology, immuntoxicity evaluations, and carcinogenicity studies. Also included in this category are support functions such as toxicokinetics, safety pharmacology (including QT-interval prolongation), and tissue distribution studies.

2. Quality. These documents, designated with the prefix letter Q, fall under the general category of chemistry, manufacturing, and controls (CMC) for small-molecule drugs and biopharmaceutics. Included are stability testing procedures, validation of analytical methodologies for drug substance and impurities, dissolution testing, good manufacturing practices (GMPs), and other relevant guidances.

3. Efficacy. These documents, designated with the prefix letter E, describe various aspects of efficacy as well as safety evaluations conducted in human subjects. Included are good clinical practices (GCPs), dose–response approaches, special populations (e.g., pediatrics and geriatrics), statistical principles, data management, structure and content of clinical study reports, acceptability of foreign clinical data, and other clinical support documents.

Regulatory authorities continue to issue guidances or guidelines independent of ICH. It should be noted that although a regulation is legally binding (such as GLP regulations, Chapter 9; GMPs; GCPs), guidances are technically just a recommendation and are nonbinding. As stated in the preamble to the FDA guidance Web page (www.fda.gov/CDER/GUIDANCE), Guidance documents represent the agency's current thinking on a particular subject. However, it is wise for sponsors to consider the contents of regulatory guidances as expectations, and any planned deviations should be subject for discussions with the FDA or other relevant agencies (Chapter 14).

1.6 Contract Research Organizations

One of the most valuable resources available for sponsors to support discovery and development programs is the wide variety of institutions known as contract research organizations (CROs). The use of such organizations is mentioned in passing in several chapters of this book. The term CRO originally referred to clinical research organization, as initially, in the early 1980s, such discrete institutions were involved solely in phase III clinical trials. At that time, various government entities were outsourcing clinical testing under grants and contracts. Throughout the past three decades, CRO functions have expanded to encompass a wide array of discovery and development functions (Table 1.2), to include both nonclinical and clinical activities, and to support functions such as CMC (for contract formulation and testing) and analytical/bioanalytical assay development, validation, and sample analyses. The advent of liquid chromatography-mass spectrometry (LC-MS/MS) as a sensitive and specific bioanalytical tool led to an explosion of new specialty CROs in the early 1990s. Today it is possible to outsource virtually all components of drug discovery and development. The role of the CRO is to provide complementary capabilities for a sponsor company's in-house operations. At the other end of the scale, the range of expertise of CROs can enable virtual companies to develop and register drug candidates with no internal resources with the exception of management personnel in collaboration with outside scientific, clinical, and regulatory consultants.

Table 1.2 Some Contract Research Organization Functions and Activities

The availability of CROs enables drug research and development institutions to develop strategies that combine internal and external resources in the most efficient possible manner. This is certainly the case when considering the use of nonclinical CROs that specialize in discovery support and nonclinical development. In the ideal world, drug sponsors would conduct all studies in-house; in this manner, resources (time/staff/cost) and flexibility are under the direct control of the sponsor company. However, even big pharma companies find the need to utilize the services of CROs for those studies for which expertise is not available internally, or it is deemed more efficient to outsource. Indeed, given the growing number of available services and the attraction for high-quality scientists to become part of the CRO industry, it is often advisable to outsource to CROs even though studies could be set up and performed in-house. Such considerations are company specific.

CROs come in all shapes and sizes: from the multinational one-stop shopping (or so they say) organizations to smaller specialty laboratories, some of which are associated with academic institutions; there are currently some 500 CROs worldwide competing for business [13]. When a sponsor firm decides to outsource to a nonclinical CRO or contract formulator for their pre-FIH programs, many considerations must be taken into account. Although too numerous to include, some of those considerations, many of which also apply to clinical CROs, include the following:

1. Choose the CRO carefully. There is nothing more wasteful in the drug discovery and development business than to conduct poor quality studies which generate equivocal answers (i.e., garbage in–garbage out). This will often occur if a sponsor uses cost as the primary variable in CRO selection. Although it is important to generate competitive bids for study conduct from two or more CROs, those companies selected to submit bids should be high-quality organizations with an established positive reputation. CRO providers can be located by attending relevant scientific meetings. Sponsors should make independent inquiries about the CRO and/or to arrange for qualified personnel to visit the CRO site for a due-diligence evaluation. Some key criteria for CRO selection include, but are not limited to, the following:

Quality of the scientific staff (especially the study director) and equipment

Problem-solving abilities and data interpretation capabilities

Company and staff stability (e.g., whether economics has resulted in recent staff reductions or changes that may affect their operations)

Experience in specific study and/or therapeutic area

Operational efficiency and flexibility

Relations with regulatory agencies (including results of recent FDA inspections and severity of FD-483 citations, which should be requested for review)

Record keeping (including sample-handling procedures) and documentation [including standard operating procedures (SOPs)]

Management oversight of operations

Quality and efficiency of quality assurance oversight of operations and review of data (if applicable)

Quality of written documentation

If overall quality, experience, and level of service are deemed to be similar, cost and other variables, such as turnaround time, should affect the selection. When bids are received, the sponsor should assure that they understand the rationale for the cost of each line item and should