Early Drug Development

Strategies and Routes to First-in-Human Trials

Mitchell N. Cayen, Mitchell N. Cayen

• Publisher: Wiley
• Year: 2011
• ISBN:
  9781118035207
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

The focus of early drug development has been the submission of an Investigational New Drug application to regulatory agencies. Early Drug Development: Strategies and Routes to First-in-Human Trials guides drug development organizations in preparing and submitting an Investigational New Drug (IND) application. By explaining the nuts and bolts of preclinical development activities and their interplay in effectively identifying successful clinical candidates, the book helps pharmaceutical scientists determine what types of discovery and preclinical research studies are needed in order to support a submission to regulatory agencies.

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 pharmaceut...