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The first golden era of cancer drug development was initiated in the 1940s and gave rise to the cytotoxic agents that dominate current cancer medicine. The second golden era is now underway in which cancer genomics will direct drug development.
As addressed by the recent Food and Drug Administration Critical Path Initiative, tools are urgently needed to increase the speed, efficiency, and cost-effectiveness of drug development for cancer and other diseases. Molecular imaging probes developed based on recent scientific advances have great potential as oncologic drug development tools. Basic science studies using molecular imaging probes can help to identify and characterize disease-specific targets for oncologic drug therapy. Imaging end points, based on these disease-specific biomarkers, hold great promise to better define, stratify, and enrich study groups and to provide direct biological measures of response. Imaging-based biomarkers also have promise for speeding drug evaluation by supplementing or replacing preclinical and clinical pharmacokinetic and pharmacodynamic evaluations, including target interaction and modulation. Such analyses may be particularly valuable in early comparative studies among candidates designed to interact with the same molecular target. Finally, as response biomarkers, imaging end points that characterize tumor vitality, growth, or apoptosis can also serve as early surrogates of therapy success. This article outlines the scientific basis of oncology imaging probes and presents examples of probes that could facilitate progress. The current regulatory opportunities for new and existing probe development and testing are also reviewed, with a focus on recent Food and Drug Administration guidance to facilitate early clinical development of promising probes.
Chemoprevention drug development has the goal of identifying safe and effective chemopreventive agents for clinical use. Several distinctive strategies are pursued in developing chemopreventive agents: (a) identifying and validating predysplastic and early dysplastic lesions that can be used instead of cancers as endpoints for measuring chemopreventive activity; (b) identifying and testing candidate agents based on considerations of mechanisms of action; (c) evaluating combinations of agents with potential for maximizing efficacy and minimizing toxicity; and (d) applying a systematic methodology for identifying and ranking candidate agents at each stage of development to ensure discovery of the best agents and most effective use of available resources. This article discusses 22 drugs and three drug combinations which have reached an advanced stage of development as chemopreventive agents. The first generation of drugs are the most advanced, now being in Phase II and Phase III clinical trials. These drugs include several retinoids [vitamin A, 13-cis-retinoic acid, all-trans-N-(4-hydroxyphenyl)retinamide], calcium, beta-carotene, tamoxifen, and finasteride. The second generation drugs are those in Phase I clinical trials. From most to least advanced, these drugs are 2-difluoromethylornithine, sulindac, piroxicam, oltipraz, N-acetyl-I-cysteine, aspirin, ibuprofen, carbenoxolone, 18 beta-glycyrrhetinic acid, and the combination of 2-difluoromethylornithine with piroxicam. The third generation includes agents with significant evidence of chemopreventive activity in animal models. These agents are now in preclinical toxicity testing. They are S-allyl-I-cysteine, phenhexyl isothiocyanate, curcumin, ellagic acid, fumaric acid, fluasterone, and the combinations of all-trans-N-(4-hydroxyphenyl)retinamide with oltipraz and all-trans-N-(4-hydroxyphenyl) retinamide with tamoxifen.
The idea of model-based drug development championed by Lewis Sheiner, in which pharmacostatistical models of drug efficacy and safety are developed from preclinical and available clinical data, offers a quantitative approach to improving drug development and development decision-making. Examples are presented that support this paradigm. The first example describes a preclinical model of behavioral activity to predict potency and time-course of response in humans and assess the potential for differentiation between compounds. This example illustrates how modeling procedures expounded by Lewis Sheiner provided the means to differentiate potency and the lag time between drug exposure and response and allow for rapid decision making and dose selection. The second example involves planning a Phase 2a dose-ranging and proof of concept trial in Alzheimer's disease (AD). The issue was how to proceed with the study and what criteria to use for a go/no go decision. The combined knowledge of AD disease progression, and preclinical and clinical information about the drug were used to simulate various clinical trial scenarios to identify an efficient and effective Phase 2 study. A design was selected and carried out resulting in a number of important learning experiences as well as extensive financial savings. The motivation for this case in point was the "Learn-Confirm" paradigm described by Lewis Sheiner. The final example describes the use of Pharmacokinetic and Pharmacodynamic (PK/PD) modeling and simulation to confirm efficacy across doses. In the New Drug Application for gabapentin, data from two adequate and well-controlled clinical trials was submitted to the Food and Drug Administration (FDA) in support of the approval of the indication for the treatment of post-herpetic neuralgia. The clinical trial data was not replicated for each of the sought dose levels in the drug application presenting a regulatory dilemma. Exposure response analysis submitted in the New Drug Application was applied to confirm the evidence of efficacy across these dose levels. Modeling and simulation analyses showed that the two studies corroborate each other with respect to the pain relief profiles. The use of PK/PD information confirmed evidence of efficacy across the three studied doses, eliminating the need for additional clinical trials and thus supporting the approval of the product. It can be speculated that the work by Lewis Sheiner reflected in the FDA document titled "Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products" made this scientific approach to the drug approval process possible.
Drug development in anaesthesia poses specific challenges. Describing the development of remifentanil highlights some of these. A new drug in anaesthesia must achieve its clinical goals in all patients and significant levels of toxicity are unacceptable. Rather than asking, "What new drugs does the anaesthetist need?" it may be more relevant to pose the question, "How can we design drugs to do things better?". Recent trends in anaesthesia have led to the development of short acting agents--one of these agents, remifentanil, has been designed to provide a mu-opioid receptor agonist with a rapid and predictable offset of action. The insertion of an alkyl ester group into this 4-anilidopiperidine molecule has resulted in a compound which, whilst retaining the desired mu-opioid receptor pharmacology, is susceptible to metabolism by non-specific esterases in the blood and tissues. The rapid onset and offset of action means that the anaesthetist can deliver high doses of opioid resulting in stable anaesthesia and the lack of accumulation ensures that even after prolonged infusion remifentanil does not compromise recovery. This ability to control the anaesthetic process has relevance in both short and long procedures and the unique characteristics of remifentanil may also in the future prove to have utility in the intensive care setting.
The Global Alliance for TB Drug Development is dedicated to closing the R&D gaps. However, advances cannot be made without investment by national and international health organizations, private sector pharmaceutical and biotechnology firms, foundations, and others. Their support is needed to develop a broad portfolio of promising candidates with a special emphasis on developing fast-track and/or sterilizing drugs. Funding agencies and research organizations must devote significant resources in the short term to close the gaps in the R&D value chain and to leverage the strengths available. Fortunately, the need, the expertise, and the enthusiasm exist. By combining resources into R&D efforts to discover and develop a broad portfolio of promising candidates, the Global Alliance and its sponsors can make a vitally important contribution to improved control and the eventual elimination of tuberculosis from every country of the world.
Positron-emission tomography (PET) provides potential in neuropsychiatric drug development by expanding knowledge of drug action in the living human brain and reducing time consumption and costs. The 5-hydroxytryptamine(1A) (5-HT(1A)) receptor is of central interest as a target for the treatment of anxiety, depression, and schizophrenia. Research on the clinical significance of the 5-HT(1A) receptor now benefits from the highly selective radioligand [carbonyl-(11)C]WAY-100635 (WAY) for quantitative determination of 5-HT(1A) receptors in the primate and human brain in vivo using PET. In this paper, three studies are reviewed to demonstrate the suitability of WAY as radioligand for quantification of central 5-HT(1A) receptors in brain and as an applicable tool for drug development. In the first study a monkey model was used to characterize WAY binding. It was confirmed that the reference ligand 8-OH-DPAT and psychoactive drugs such as buspirone and pindolol occupies 5-HT(1A) receptors in the primate brain. Pindolol is an beta-adrenoreceptor antagonist with a high affinity to 5-HT(1A) receptors. This drug has been suggested in combination with selective serotonin reuptake inhibitors for the treatment of depression and was given to healthy males in the second study. Pindolol induced a marked inhibition of central 5-HT(1A) receptors as calculated by the ratio-analysis method and simplified reference tissue model, 2 h after administration of 10 mg as a single oral dose. This observation suggests that pindolol may have a role for the suggested potentiation of selective serotonin reuptake inhibitor treatment of depression. The third study was on robalzotan (NAD-299), a recently developed 5-HT(1A) receptor antagonist and putative drug with implications for the treatment of depression. In the cynomolgus monkey brain, robalzotan in the dose range 2-100 microg/kg IV occupied 5-HT(1A) receptors in a dose-dependent and saturable manner with a maximal calculated occupancy of 70-80%. The relationship between robalzotan plasma concentration and 5-HT(1A) receptor occupancy could be described by a hyperbolic function that was used to guide the selection of appropriate doses in man. In a subsequent PET study of robalzotan binding to 5-HT(1A) receptors in the living human brain, similar results have been replicated recently. These studies reviewed here illustrate and corroborate that quantitative neuroimaging of receptor binding has potential for the evaluation and dose finding of new central nervous system drugs.
Rational drug therapy requires knowledge about the ratio of risk (adverse drug reaction) to benefit (therapeutic efficacy) for all drugs to be used in humans. However, with newly marketed drugs, the risk/benefit ratio is usually not sufficiently known. Safety is often less well defined than efficacy. This is the result of the present mode of drug development. Premarketing studies are conducted in comparatively small, homogenous populations over relatively short time intervals and under standardized conditions. Only after marketing are larger, more diversified populations exposed over prolonged times, often under uncontrolled conditions. Adverse drug reactions (ADRs) are the result of either overdosage, or allergic or idiosyncratic reactions. They can be life-threatening or mild. Some of the ADRs are common (greater than 1:10); others are very rare (less than 1:1000). The overall rate of ADR occurrence in ambulatory and hospitalized patients is high enough to have significant socioeconomic consequences. Some of the risk populations can be suspected a priori: elderly, multimorbid patients and patients with compromised drug elimination who may be overdosed if the regimens are not appropriately modified. Some problem drugs may be recognized if they display one or more of the following characteristics: narrow therapeutic index, steep dose-effect relationship, nonlinear kinetics, variable bioavailability, and pharmacogenetically determined kinetics. Other individuals at risk, however, may not be readily identifiable. They develop allergic and idiosyncratic reactions after drug exposure without exhibiting easily recognizable predisposing factors. In order to determine the number of individuals so affected, and the associated drugs as quickly as possible during the developmental process, specific ADR surveillance measures are taken.(ABSTRACT TRUNCATED AT 250 WORDS)
Pharmacogenetics examines the genetic characteristics of individuals to understand variations in response to therapeutics. This approach has the potential to significantly affect the development of new medicines. The application of pharmacogenetic principles could yield significant time and resource savings within the drug development process. In preclinical drug development, pharmacogenetics could be applied to compound screening and identifying potential side effects before entering full clinical testing. Subpopulations of patients with different drug responses and underlying genetic markers could be stratified in clinical trials by analyzing their genotype. These data can improve clinical trial design and offer the possibility of optimized drug prescription based on patient genotype. Pharmacogenetics can guide the development of therapeutic interventions by identifying nonresponder patient groups. Advances in high-throughput genotyping technologies have added potential by facilitating the technical hurdles and improving drug development strategies, clinical trial design, and postmarket pharmaco-vigilance. Pharmacogenetics, thus, impacts all phases of drug development and will fundamentally change the practice of medicine in the near future.
In a health care environment dominated by the growth of managed care organizations, generic competition, therapeutic substitution and drug utilization review, drug development is an extremely risky proposition. Consequently, it is imperative to incorporate a mechanistic approach to drug development that combines a thorough understanding of a drug at the molecular/cellular level with a rigorous preclinical, and clinical pharmacology program. This should enable the sponsor to evaluate multiple hypotheses during the early "learning" phases of clinical development (Phases I and IIA) and to eliminate nonpromising candidates early on while drug development costs are low. Clinical research done properly in the early stages of drug development will also set the stage for designing and conducting optimal "confirming" registrational Phase IIB/III studies for promising drug candidates. Pharmacokinetics (PK) and pharmacodynamics (PD) modeling and simulation are crucial components of a mechanistic approach to optimal drug development and their application has significant impact in both early and late development efforts. This communication describes several applications of pharmacokinetics and pharmacodynamics modeling and simulation that were important in guiding, optimizing and ensuring the success of development efforts for drug candidates in the therapeutic areas of cardiology and oncology. These examples are used to illustrate and discuss the use of the current state-of-the-art in pharmacokinetics and pharmacodynamics modeling and simulation at numerous stages in the development cycle and to postulate on future directions in this area.
The Food and Drug Administration has issued new guidance intended to assist sponsors in the clinical development of drugs for the treatment of HIV infection.
Although several new oncology drugs have reached the market, more than 80% of drugs for all indications entering clinical development do not get marketing approval, with many failing late in development often in Phase III trials, because of unexpected safety issues or difficulty determining efficacy, including confounded outcomes. These factors contribute to the high costs of oncology drug development and clearly show the need for faster, more cost-effective strategies for evaluating oncology drugs and better definition of patients who will benefit from treatment. Remarkable advances in the understanding of neoplastic progression at the cellular and molecular levels have spurred the discovery of molecularly targeted drugs. This progress along with advances in imaging and bioassay technologies are the basis for describing and evaluating new biomarker endpoints as well as for defining other biomarkers for identifying patient populations, potential toxicity, and providing evidence of drug effect and efficacy. Definitions and classifications of these biomarkers for use in oncology drug development are presented in this paper. Science-based and practical criteria for validating biomarkers have been developed including considerations of mechanistic plausibility, available methods and technology, and clinical feasibility. New promising tools for measuring biomarkers have also been developed and are based on genomics and proteomics, direct visualisation by microscopy (e.g., confocal microscopy and computer-assisted image analysis of cellular features), nanotechnologies, and direct and remote imaging (e.g., fluorescence endoscopy and anatomical, functional and molecular imaging techniques). The identification and evaluation of potential surrogate endpoints and other biomarkers require access to and analysis of large amounts of data, new technologies and extensive research resources. Further, there is a requirement for a convergence of research, regulatory and drug developer thinking - an effort that will not be accomplished by individual scientists or research institutions. Research collaborations are needed to foster development of these new endpoints and other biomarkers and, in the United States (US), include ongoing efforts among the Food and Drug Administration (FDA), National Cancer Institute (NCI), academia, and industry.
BACKGROUND: Continued scepticism about the benefits of population pharmacokinetics and/or population pharmacodynamics, here referred to collectively as the population approach, hampers its widespread application in drug development. At the same time the sources of this scepticism have not been clearly defined. In an attempt to capture and clearly define these concerns and to help communicate the value of the population approach in drug development at Parke-Davis we conducted a survey of customers within the company. The results of this survey are presented here. METHODS: All drug development programmes conducted over the past 10 years that included a population approach in data analysis and interpretation were identified. A brief description of the population analysis was prepared together with a brief description of how the resulting information was used in each drug development programme. These synopses were forwarded to relevant members of each drug development team together with a survey designed to solicit opinions as to the relevance and impact of these analyses. RESULTS: The most frequent use of information derived from population-based analysis was in labelling. In all cases of drugs making to New Drug Application (NDA) submission the analyses resulted in information that was included in approved or proposed labelling. In almost half of the cases summarised here (5 of 12), population-based analysis was perceived to have resulted in information that influenced the direction of individual development programmes. In many of these cases the information was serendipitous. It is also noted that most of these analyses were not the result of clearly defined objectives and prospective analysis plans. CONCLUSIONS: Use of the population approach, even when applied retrospectively, may have value in complementing or supporting interpretation of other data collected during the course of a trial. Atypical systemic exposure is quickly and easily assessed for correlation with adverse events or exceptional efficacy in retrospective or ad hoc evaluation. Although we know of no direct evidence, it is possible that such use of population pharmacokinetic data has facilitated NDA review and approval by providing insight into the role of atypical systemic drug exposure in otherwise spurious events.
Traditional biomarkers have played an important role in drug development as well as patient care. A single traditional biomarker or surrogate endpoint is unlikely to either characterize the complete pathophysiology of a complex disease or capture all the therapeutic benefits or potential adverse effects that a drug will have in a diverse patient population. Transciptome analysis, on the other hand, can provide a large-scale survey of gene expression associated with the etiology of a human disease or pharmacological responses to a therapeutic intervention. The quantitative and qualitative readouts can provide increased power to identify novel drug targets or biomarkers indicative of drug safety or efficacy. Transcriptomics has positively impacted drug development and will continue to improve the medicines of the future. Here, we describe the increasingly important roles that traditional biomarkers and transcriptome analysis have played in various phases of drug discovery and development as well as the opportunities and challenges that they present to the pharmaceutical industry.
The potential applications in drug development of pharmacokinetic-pharmacodynamic modeling are numerous: optimal medication regimen, design of galenic forms, identification of specific effects of metabolites and enantiomers. Nevertheless, this methodology is presently under-used, as appears from an analysis of the literature. We examine this point as well as progress in both non-invasive pharmacodynamic measurement and specific experimental design that could lead to a future extension of PK-PD in toxicology and phase I drug development.
The history of antipsychotic drug development has had a long and torturous course, often based on chance findings that bear little relationship to the intellectual background driving observations. In 1891, Paul Ehrlich observed the antimalarial effects of methylene blue, a phenothiazine derivative. Later, the phenothiazines were developed for their antihistaminergic properties. In 1951, Laborit and Huguenard administered the aliphatic phenothiazine, chlorpromazine, to patients for its potential anesthetic effects during surgery. Shortly thereafter, Hamon et al. and Delay et al. extended the use of this treatment in psychiatric patients and serendipitously uncovered its antipsychotic activity. Between 1954 and 1975, about 15 antipsychotic drugs were introduced in the United States and about 40 throughout the world. Thereafter, there was a hiatus in the development of antipsychotics until the introduction of clozapine treatment in the United States in 1990 opened the era of "atypical" antipsychotic drugs, which show a reduced potential to induce extrapyramidal symptoms (EPS), an increased efficacy for the negative symptoms of schizophrenia, no elevation of prolactin after chronic use (except risperidone), and, at least for clozapine, effectiveness in some patients previously regarded as treatment-refractory. This review describes the available atypical antipsychotic drugs and their characteristics, and concludes by highlighting those in the pharmaceutical "pipeline."
Drug 'developability' assessment has become an increasingly important addition to traditional drug efficacy and toxicity evaluations, as pharmaceutical scientists strive to accelerate drug discovery and development processes in a time- and cost-effective manner. The fraction of drug absorbed and the maximum absorbable dose (MAD) can be estimated from in vivo clinical pharmacokinetics, mass balance studies or in vivo drug permeability in humans by different calculation methods. Unfortunately, in vivo data are usually unavailable at the early stages of drug discovery and development, and in vitro screening for the permeability, solubility, activity and toxicity of a drug has become a routine measurement in drug discovery and development. These in vitro data could be used to predict drug 'developability' with different calculation methods before selecting candidates for clinical evaluation. The fraction of drug absorbed in human could be predicted by in vivo human permeability or in vitro Caco2 permeability. For example, if drug permeability in Caco2 cells reaches 13.3 to 18.1 x 10(-6) cm/s, its predicted in vivo permeability in humans would reach 2 x 10(-4) cm/s, and its predicted fraction of drug absorbed would be > 90%, which is defined as highly permeable. The MAD could also be predicted with in vitro permeability, or calculated absorption rate constant. In addition, in vitro solubility and permeability data can also be used for the biopharmaceutics classification system (BCS) and, subsequently, to direct formulation optimization strategies. If drug 'developability' becomes an obstacle for drug delivery based on these in vitro data and predictions at the early stages of drug discovery and development, options such as prodrug approaches could be explored to enhance drug 'developability', in addition to different formulation methods. Therefore, in vitro absorption testing is a highly valuable tool in the decision-making process to select candidates for in vivo clinical studies at early-stage drug discovery and development.
Drug development for functional gastrointestinal disorders is complex. These conditions involve central and peripheral physiological changes, together with psychological factors. Methodological problems have included a poor appreciation of the physiological and psychological correlates of patients' symptoms, a lack of animal models of proven relevance, and safety issues. Government, patient pressure groups and the Internet can also influence a drug's success. Most recent interest has focused on the serotonin (5-HT) modifying drugs. Cisapride has been withdrawn in some countries because of concerns related to QT prolongation and cardiac arrhythmias. The 5-HT3 antagonists, developed to modify visceral sensation, have caused constipation; alosetron, also withdrawn, caused ischaemic colitis. The 5-HT4 agonists induce peristalsis; tegaserod and prucalopride, both delayed in their development due to issues of safety and efficacy, benefit patients with 'constipation-predominant' irritable bowel syndrome or idiopathic constipation. 5-HT1 agonists improve impaired gastric accommodation and symptoms in patients with functional dyspepsia. Antidepressants also affect serotonin metabolism. Previous examples of success in this area involved drugs targeted at peripheral receptors mediating motor function or secretion. Modification of sensory function is a much more challenging objective. The experience with serotonin modifying drugs has been mixed, and some important lessons are there to be learnt.