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Introduction to Drug Development and Regulatory Decision-Making

Lawrence J.Lesko and Chandrahas Sahajwalla Food and Drug Administration Rockville, Maryland, U.S.A.

The science of contemporary drug development is a tremendously complex and costly process but it has successfully advanced our understanding of modern diseases and has improved public health significantly by providing society with many valuable drug treatments. A crucial step in the drug development process is the submission of nonclinical and clinical data and information in a New Drug Application (NDA) to the Food and Drug Administration (FDA) by a sponsor seeking marketing authorization. A typical new molecular entity (NME) that is the subject of a NDA has most likely been studied preclinically for 57 years and has been in clinical trials for 67 years. The average cost of bringing an NME to market is somewhere between 500 and 800 million dollars including the costs of lost opportunities and lead-compound failures [1]. With this investment of time and money, many scientists involved in drug development have explored various ways to make drug development as efficient, and yet informative, as possible [2].
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Lesko and Sahajwalla

Despite its successes, the drug development process, including regulatory decision-making based on benefit/risk assessments, can be improved in three areas. 1. Provide a greater understanding of human health and the causes of diseases at a genomic or molecular level. This would address the well-known heterogeneity of disease states that underlies the wide interindividual variation in efficacy observed with many common treatments. For example, incomplete or absence of response occurs in 3050% of eligible patients with hypercholesteremia who are treated with statins. With greater insights into health and disease, sponsors would be more likely to identify a target protein or receptor and to find the best NME to provide preventive, curative, or palliative treatment for patients. Improve the safety of medicines. Adverse drug reactions (ADRs) have had a major impact on morbidity, mortality, and health economics. In studies going back to 1974, up to the present time, approximately 1520% of hospitalized children and 2530% of hospitalized adults have experienced drug-related adverse events [3, 4]. The overall incidence of drug-induced adverse events in nonhospitalized patients is thought to be around 7% [5]. The economic cost of drug-related morbidity and mortality to society has been estimated to be almost 200 billion dollars [6]. While there are many reasons, some of them unknown, for the relatively high incidence of ADRs (e.g., medication errors, drug interactions), it is thought that the majority of the risks associated with drug therapy are known and most drug-related adverse events are preventable [7]. Optimize drug doses and dosing schedules. Approximately 70% of drug-related adverse events are due to extended pharmacological actions. Thus, there is growing evidence to suggest that drug doses approved for marketing may be higher than is necessary and may be contributing to the high frequency of serious drug side effects. A recent study that examined the doses of 354 prescription drugs recommended in the label and released between 1980 and 1999 found that approximately 17% of these drugs had a reduction in dose or a new restriction for use in special populations such as patients with renal or hepatic disease [8]. Furthermore, it has been reported that prescribers in their practice frequently use doses which are lower than the FDA-approved label dose [9]. In an informal survey, it was also found that doses approved in other countries, e.g., Japan, are

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Drug Development and Regulatory Decision-Making

lower than those approved in the United States and most often there are no apparent scientific rationale for these differences. These three areas of improvement should be viewed as a challenge to the scientific community in industry, academia, and the regulatory agencies to engage in dialogue and scientific collaboration to optimize the drug development process. This is especially important in light of the emergence of new genetic technologies and our understanding of the human genome that provides us new ways to ask important questions during the drug development process. Indeed, the promise of personalized or predictive medicine that stems from pharmacogenetics and pharmacogenomics means that the benefit/risk ratio of drugs is systematically optimized by identifying and selecting the right drug target, developing the right drug, and delivering the right dose to the right patient. ROLE OF CLINICAL PHARMACOLOGY At the core of the drug development process is a fundamental understanding of the clinical pharmacology of the drug substance. Clinical pharmacology can be thought of as a translational science in which basic information about the relationship between a drugs dose, local or systemic exposure and response (related to either efficacy or safety) is applied in the context of patient care. Knowledge of this relationship, which is a key to successful therapeutics, and how it is altered by the intrinsic (age, gender, renal function, etc.) and extrinsic (diet, drugs, life-style) factors of an individual patient is one of the major contributions of clinical pharmacology to drug development and regulatory decision-making. Once a lead compound with the intended pharmacological action is identified, the step-wise process to characterize and potentially optimize its pharmacokinetic (PK) properties (i.e., absorption, distribution, metabolism, and excretion), as well as to minimize its pharmacokinetic limitations (e.g., poor absorption), begins in humans as part of phase I human clinical trials. Soon after, other principles of clinical pharmacology [e.g., pharmacokinetic-pharmacodynamic (PD) relationships] become critical to the evaluation and selection of the most appropriate dosing regimen of the drug in a carefully selected target population enrolled in phase II clinical trials. These trials form the scientific rationale for subsequent dose selection in large-scale phase III clinical trials where the primary goal is to provide adequate evidence of efficacy and relative safety of the drug. Phase III trials are the most expensive and time-consuming component of the overall drug development process and many believe that paying careful attention to doing clinical pharmacology homework has

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Lesko and Sahajwalla

the greatest potential to reduce the failure rate of new drugs at this nearfinal stage of development. Often, in parallel with phase III clinical trials, a group of clinical pharmacology studies, such as those in special populations, are conducted in human volunteers to develop a knowledge database of factors influencing drug exposure. These data are crucial for an understanding of when, and how much, to adjust dosage regimens. Because these studies typically focus on changes in systemic exposure, as a surrogate marker for either efficacy or toxicity, the availability and the intelligent use of exposure (e.g., dose, PK measurements)-response (e.g., biomarkers, surrogate clinical endpoints, clinical outcomes, PD) relationships to interpret the results of these studies become critical to information for various sections of the product label. These studies can be broadly classified into two broad categories: (1) those dealing with patient-intrinsic factors that include gender, age, race, diseases states (primarily renal and/or hepatic impairment), and genetic (e.g., activity of cytochrome P450 enzymes) factors, and (2) those dealing with patientextrinsic factors that include drug-, herbal- and nutrient-drug interactions, environmental variables (e.g., smoking, diet), and lifestyle factors. ROLE OF BIOPHARMACEUTICS Related to the science of clinical pharmacology, biopharmaceutics can be thought of as the body of scientific principles applied to convert a wellcharacterized drug substance to an appropriate, and potentially optimized, drug product. At the heart of biopharmaceutics is a thorough understanding of the physical, chemical and biological properties of the drug substance related to absorption (e.g., solubility, stability and intestinal permeability) and how to utilize these data to decide on the best route of administration and to develop a successful dosage form. The development of an initial formulation for a drug substance entails the study of drug product dissolution under a variety of environmental conditions (e.g., pH), and linking the resulting rate and extent of dissolution to the subsequent rate and extent of absorption (i.e., bioavailability or BA). These so-called in vitro-in vivo correlations (IVIVC) are important to early optimization of formulation performance in order to achieve systemic plasma drug concentration-time profiles later in human clinical trials with the greatest chance for therapeutic success. Not infrequently, the final, to-be-marketed formulation of the active drug substance is different than the initial formulations used in either early or late clinical trial phases of development. Biopharmaceutics plays a critical role in linking the in vivo performance or BA of each of the early formulations (i.e., reference formulations) to the final (i.e., test formulations) formulations.

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Drug Development and Regulatory Decision-Making

The standard study to assess comparative BA of the test and reference formulations is the bioequivalence (BE) study. Often, the results of BE studies are expressed as measures of exposure, such as area under the plasma concentration-time curve (AUC) and peak or maximum plasma concentration (Cmax). The ratio of these in vivo measurements (test/ reference) are usually statistically reported as 90% confidence intervals (CI). BE is declared if the 90% CI is between 80 and 125% (goalposts). However, if the 90% CI is either partially or completely outside these goalposts, therapeutic equivalence is determined by integrating the clinical pharmacology information about exposure-response relationships into the regulatory decision-making process. REGULATORY REVIEW Within the Center for Drug Evaluation and Research (CDER) of the FDA, the regulatory review of clinical pharmacology and biopharmaceutics studies is the responsibility of the Office of Clinical Pharmacology and Biopharmaceutics (OCPB). The mission of OCPB has patient care and therapeutics as center stage, and this is reflected by the scientific goals of clinical pharmacology and biopharmaceutics, that is, to critically study, thoroughly understand, and successfully identify (1) the right dose, in (2) the right dosage form, for (3) the right patient. The final step is to responsibly translate this knowledge to the product label with appropriate information about the use of the drug/drug product in the clinical pharmacology, precautions, warnings, contraindications, and/or dosage and administration sections of the package insert. This is indeed a critical step in the review process, since labeling a drug for use in the manner that is intended for patients to use it (or not use it) is one of the most important ways of risk management for ADRs. OCPBs review process is based on a paradigm known as the QuestionBased Review, or QBR [10]. It recognizes that it would be unreasonable to expect that everything will be known about the clinical pharmacology (CP) and biopharmaceutics (BP) of a drug/drug product at the time of NDA submission. Accordingly, the QBR emphasizes the importance of the reviewers responsibility to ask the right questions related to the efficacy and safety of new medicines based on the clinical pharmacology and biopharmaceutics database provided by the sponsor in a NDA, and also to identify what is important but not known about the drug. The latter may be the basis for postmarketing studies (phase IV commitments). There are many critical principles in applying the QBR but two stick out the most when reviewing CP and BP studies: (1) analyzing study results and integrating knowledge thoughtfully across studies, and not just reviewing

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Lesko and Sahajwalla

studies in isolation from one another, or necessarily in the chronological order in which they were conducted, and (2) interpreting results of CP and BP studies in the overall context of what is also known from the nonclinical chemistry, pharmacology and toxicology data, and the clinical efficacy and safety information, and not just to focus on providing a narrow-focused CP/ BP report to medical officers. To meet these responsibilities, reviewers are strongly encouraged to act credibly and to communicate extensively with other professionals during the review process. VIEW TOWARD THE FUTURE Clinical pharmacologists and biopharmaceutical scientists have an opportunity, as much as any professional, to lead the pharmaceutical industry and regulatory agencies in leveraging their science and technology for achieving future breakthroughs in therapeutics. The process of marrying comprehensive biopharmaceutical information to clinical pharmacology data, and integrating that knowledge into what is known about drug efficacy and safety, will bring the drug development enterprise a step closer to realizing the dream of individualized medicine. Part of this process will be leveraging several existing fundamental technologies and new scientific discoveries to a greater extent. Pharmacogenetics (PGt) and Pharmacogenomics (PGx) While no consensus on definitions is at hand, for the purpose of this chapter PGt can be thought of as the study of the genetic variability in PK among individuals, affecting liver enzymes that metabolize drugs and transporters that determine BA and drug distribution. PGx, closely related to PGt, may be defined as the study of genetic variability, including that of drug receptors (PD), among individuals, affecting the rest of the genome that regulates drug response. Many believe that PGt and PGx are at the core of future drug development processes with applications ranging from new knowledge about the molecular basis of diseases to identification of new genes or gene products (e.g., protein) that serve as novel drug targets. There are several significant industry examples of the impact of PGt and PGx. These include (1) the comarketing of trastuzumab (Herceptin, Genentech) and a diagnostic test (HercepTest) for patients with breast cancer whose tumors have overexpressed HER 2 activity [11], (2) a gene-based diagnostic marker that has the potential to identify at-risk patients with HIV for hypersensitivity to abacavir (Ziagen, GSK), (3) haplotypes that have the potential to be used as diagnostic tests to optimize the selection of approved HMG Co-A reductase inhibitors (statins) in patients with

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Drug Development and Regulatory Decision-Making

hypercholesteremia, and (4) potential genetic markers to identify patients with rheumatoid arthritis who are responders to IL-1 and TNF-inhibitors. A regulatory perspective on PGt and PGx has recently been published and regulatory agencies worldwide generally are optimistic that these sciences will, in time, profoundly transform the drug development and regulatory review processes [12]. However, closer attention needs to be paid to what is already known about PGt with an eye toward how this information can be integrated into current standards of patient care to reduce the incidence of ADRs. For example, it has been reported that of the top 27 drugs frequently cited in ADR reports, 59% are metabolized by at least one enzyme having poor metabolizer (PM) genotype. Eleven of the 27 drugs (38%), mainly used for cardiovascular and CNS diseases, are metabolized specifically by cytochrome P450 (CYP) 2D6 [13]. Despite the strong suggestion that knowing a patients CYP 2D6 genotype (or phenotype), and adjusting doses downwards or upwards depending on the genotype, would positively influence benefit/risk of therapy, CYP 2D6 genotyping is not recommended in any package insert of approved products. There are a variety of reasons for this, but as genotyping tests for CYP enzyme activity become more widely available and cost-effective, clinical pharmacologists will have the responsibility to ask the right questions about genetic polymorphism and to act responsibly on the information during drug development and regulatory review. In the broad world of PGx, there will be greater reliance on global DNA sequencing and candidate gene studies to discover genes and genetic biomarkers that play a role in assessing disease progression and variability in drug response. Clinical pharmacologists will have opportunities to explore associations between gene variants, in the form of single nucleotide polymorphisms (SNPs) or combinations of SNPs (haplotypes), to better understand variability in drug response and dosage requirements. In addition, complementary PGx technologies, such as gene-chip microarrays and quantitative polymerase chain reaction (PCR), will provide additional insights into the genetic basis of disease and drug response which will impact clinical therapeutics in terms of measuring disease- and druginduced differences in expression profiles and providing multiple biomarker panels to associate with drug therapy. Assay Development It is well known that chemical assays of high quality (i.e., adequate sensitivity, selectivity, and reproducibility) are essential to obtaining credible data in clinical pharmacology studies (e.g., PK) and biopharmaceutics studies (e.g., BE). However, in the future, assay development that includes more sophisticated technologies and more attention to detail will be needed.

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For example, there are many pharmacological or physiological biomarkers of drug activity which are used in analyzing exposure-response relationships for the purpose of making decisions in drug development or regulatory review, where evidence of validation of the measurement of the response component is incomplete or missing. In addition, with the evolution of PGt and PGx, principles of validation of new technologies such as mass spectrometry (proteomics), high-throughput DNA sequencing, and expression profiling (microarrays) will need to be established to ensure credible interpretation and use of these data. Each of these newer technologies, in contrast to traditional technologies, will provide a tremendous amount of information about changes in gene expression and potentially useful biomarker panels. The bioinformatics software used to mine these data sets is not standardized at the moment, and as a result various association algorithms, cluster analyses, and SNP and haplotype identification methods are used from company to company. The potential for interlaboratory differences in interpretation is enormous and consensus on how to use these tools reliably will be important in clinical pharmacology and biopharmaceutics studies of the future. Modeling and Clinical Trial Simulation (CTS) Development and validation of models for exposure-response datasets have been widely used by clinical pharmacologists during drug development and regulatory review to understand the nature of dose-response and PK-PD relationships and to predict alternative clinical scenarios. There are many examples of the value of modeling in terms of improving drug development and regulatory review [14]. In the future, modeling of biological systems at the cellular level, disease progression models, and models for quantitative assessment of risk will take on greater importance in CP studies. More recently, CTS or computer assisted trial design (CATD) methodologies have been advanced as tools to use phase I and phase II exposure-response information to design phase III trials, predict trial outcomes in terms of efficacy and safety, and allow for more informed decisions on benefit/risk analysis and the economics of drug development programs [15]. CATD, while not routinely used in drug development and regulatory review, is likely to take on more importance as our understanding of the causes of disease, disease progression, molecular drug targets, and drug pharmacology/ toxicology increases through the co-evolution of genetics and genomics. Diagnostic Tests and Kits As PGt and PGx mature, it is highly likely that gene-based diagnostic tests and kits using genetic markers will significantly influence drug

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Drug Development and Regulatory Decision-Making

development and regulatory review. These tests and kits will not only be used on patient blood or tissue samples to diagnose diseases when they are present, but will also be able to (1) predict the probability of developingdiseases in the future, (2) identify patients who are most likely to be responders or nonresponders, (3) select the most appropriate dose for a given individual, and (4) select the best drug in a class once a decision is made to institute drug therapy. To date, there are relatively few diagnostic test kits approved by FDA, although in the future this would be desirable. HercepTest (Dako Corporation) and PathVysion Her-2 DNA FISH (Vysis) have been approved by FDA to measure HER 2 activity prior to making a medical decision to administer Herceptin to women in advanced stages of breast cancer, and HIV-1 TruGene Assay (Applied Sciences/Visible Genetics) has been approved to measure HIV resistance and to provide drug treatment options for patients with AIDS. FDA approval of genebased diagnostics would provide many advantages such as assuring high quality reagents, validated reference standards, standardized assay procedures and protocols, and greater acceptance of these tests by patients and physicians. Interpreting the test results for physicians, by bridging this information to package inserts, is likely to become an important responsibility of clinical pharmacologists in the future. Knowledge Management (KM) For the purposes of this chapter, KM is defined as the marriage of science, bioinformatics, and computer technology to more effectively assess and utilize the ever increasing amounts of clinical pharmacology and biopharmaceutics data arising from drug development. As an example, modern NDAs may contain more than 60 CP and BP studies, and each study contains many more pieces of data than ever before. In order to conduct a meaningful and thorough analyses of these data and to learn as much as possible about the drug/drug product, industry and regulatory scientists will need the capability that computer visualization and analysis software can offer. Applying web-based data management will enable endusers to (1) use information across studies better, (2) make more efficient and informed decisions about benefit/risk, and (3) create learning databases that can be effectively queried to compare CP and BP attributes across drugs and therapeutic areas. Visualization software is also a powerful way to communicate important CP and BP information to those in other disciplines in order to make maximum use of the scientific data at hand.

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SUMMARY The current mission and goals of clinical pharmacology and biopharmaceutics is highly likely to expand and be transformed in the future as the new tools, technologies, and expectations (as described above and in the following chapters) become reality. Many of the questions about efficacy, safety, benefit/risk, drug dosing, and drug product performance will be tailor made for the scientists in CP and BP. These scientists will have to integrate their knowledge with other disciplines more broadly to take a leading role in drug development and regulatory decision-making. The efforts of clinical pharmacologists and biopharmaceuticists, if future challenges are accepted by the profession, will have the potential to introduce innovation and ultimately impact the standards of medical care. How CP and BP data is interpreted and applied in the future will affect risk assessment, risk management plans, and drug development and regulatory decisions. The quality of CP information in drug product labels and the setting of standards and specifications based on BP data to assure consistent drug product performance over time in the marketplace will likely impact the effectiveness and, perhaps most importantly, the safety of new medicines. This is, without a doubt, a common and meritorious goal shared by clinical pharmacologists and biopharmaceuticists whether they practise in industry or in regulatory agencies. REFERENCES
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