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PubMed2004

The convergence of cancer prevention and therapy in early-phase clinical drug development.

After decades of separate but not equal drug development, prevention and therapy are beginning to converge at the level of early-phase clinical testing. This highly beneficial convergence is due to spectacular molecular advances in our understanding of neoplasia (both cancer and precancer), cancer risk and prognosis, and the mechanisms by which novel drugs with less toxicity and more cytostatic activity profiles target specific molecular events to suppress malignant and premalignant cells. The future full convergence of prevention-therapy drug development (aided by technological advances, such as in molecular imaging) promises to hasten the progress of oncology in reducing the public health impact of the major cancers.

Antineoplastic Agents↗

PubMed1998

Exploratory studies: implications for drug development in Alzheimer's disease.

The process of drug development involves cycles of learning and confirming. In the learning phase of the cycle, data from studies are used to generate hypotheses; later studies are designed specifically to confirm these hypotheses. There is a growing realization that exploratory studies early in drug development are critical for the design of large confimatory clinical trials. For example, patients often differ from healthy volunteers in their tolerance of CNS compounds, so investigators should determine the maximum tolerated dose (MTD) in the patient population though a "bridging study" prior to designing Phase II efficacy trials. By performing well-controlled safety/tolerability studies with a small number of patients on an inpatient basis, researchers can avoid exposing large numbers of study participants to the wrong dose. Bridging studies also provide information on the approximate frequencies of various types of adverse events, which is very helpful in designing outpatient trials to confirm the safety profile. A second type of exploratory study, a "dynabridge study", is an early pharmacokinetic/pharmacodynamic (PK/PD) study in patients to measure drug concentrations and activities in the central compartment (assessed by sampling the CSF). Dynabridge studies can be used to optimize the dosing regimen, to confirm that the drug is affecting the targeted receptor, and to measure correlations between drug activity and proposed surrogate markers.

Alzheimer Disease↗

PubMed1998

Stable isotope techniques in early drug development: an economic evaluation.

Stable isotope labeled (SIL) drug methods are compared with standard methods for performing early (phases I and IIa) drug development studies (mass balance, bioavailability, single-dose volunteer and patient, multiple-dose volunteer and patient). SIL methods offer considerable reduction in the cost (> 50%) and number of subjects (67%) required for bioavailability and multiple-dose patient studies. Moreover, a complete early drug development program is described for optimally combining SIL and standard studies, which can reduce cost by 23% and number of subjects by 36% compared with a program using standard methods. These reductions should result in development time savings of at least one year.

Clinical Trials, Phase I as Topic↗

PubMed1998

Drug interactions at the renal level. Implications for drug development.

The kidney plays a major role in the elimination of drugs. The purpose of this paper is to: (i) review the mechanisms of renal elimination; (ii) identify potential mechanisms for renal drug interactions; (iii) review in vitro and in vivo animal models for studying renal elimination mechanisms and identifying potential drug-drug interactions; (iv) review experimental designs used in identifying drug-drug interactions in humans with an emphasis on gaining information regarding the mechanism of the interaction; and (v) make recommendations regarding the potential for renal drug interactions in drug development. It is concluded that clinically significant drug interactions resulting in toxicity because of some mechanism at the renal level appear to be relatively rare and that in vitro screening should not be done on all drugs during drug development. Five potential mechanisms exist for drug interactions at the renal level: (i) a displacement of bound drug resulting in an increase in drug excretion via an increase in glomerular filtration; (ii) competition at a tubular secretion site resulting in a decrease in drug excretion; (iii) competition at the tubular reabsorption site resulting in an increase in drug excretion; (iv) a change in urinary pH and/or flow that may increase or decrease drug excretion depending on the pKa of the drug; and (v) inhibition of renal drug metabolism. The most well known renal drug interaction is competitive inhibition of tubular secretion, ultimately leading to an increase in plasma drug concentration. Only when renal clearance is a major contributor to the total clearance (> 30%) and plasma concentrations are greater than the Michaelis-Menten transport constant does the potential exist for clinically significant renal drug-drug interactions because only then does nonlinear pharmacokinetics become evident. The potential for drug interactions is small when renal clearance is less than 20 to 30% of the total clearance and/or when plasma concentrations are less than the Michaelis-Menten transport constant, unless the drug has a narrow therapeutic window.

Animals↗

PubMed2005

A call to restructure the drug development process: government over-regulation and non-innovative late stage (Phase III) clinical trials are major obstacles to advances in health care.

The history of drug/vaccine development has included major advances guided primarily by risk/benefit analyses concerning the innovative agent, not by evidence-based clinical trials (Phase I-IV). Because the approval for new drugs is hindered under the present process, the system requires restructuring. The Phase I/II study period should be more flexible, using the "environment of knowledge" about the new agent, plus risk/benefit assessments. Phase III, as presently constructed, does not add new adverse events data, it provides a narrower profile of drug efficacy than properly done Phase II studies, and placebo-controlled trials continue to raise unresolved ethical and social issues. Phase III studies should be abandoned for most drugs, and substituted with properly powered Phase II dose-ranging studies plus careful post-marketing surveillance. Phase III should be a penalty for poor drug development, not a regulatory requirement. To accomplish efficient drug development, greater cooperation between pharmaceutical companies and governments in developing clinical trials is needed rather than over-regulation. These changes will synchronize the drug development and regulatory process with the current rapid drug discovery process, reduce drug development time and cost, and improve patient care.

Animals↗

PubMed2004

Membrane transporter/receptor-targeted prodrug design: strategies for human and veterinary drug development.

The bioavailability of drugs is often severely limited due to the presence of biological barriers in the form of epithelial tight junctions, efflux proteins and enzymatic degradation. Physicochemical properties, such as lipophilicity, molecular weight, charge, etc., also play key roles in determining the permeation properties of drug candidates. As a result, many potential drug candidates may be dropped from the initial screening portfolio. Prodrug derivatization targeting transporters and receptors expressed on mammalian cells holds tremendous potential. Enhanced cellular delivery can significantly improve drug absorption. Such approaches of drug targeting and delivery have been the subject of intense research. Various prodrugs have been designed that demonstrate enhanced bioavailability and tissue specificity. This approach is equally applicable to human and veterinary pharmaceuticals since most of the transporters and receptors expressed by human tissues are also expressed in animals. This review highlights studies conducted on the use of transporters and receptors in an effort to improve drug bioavailability and to develop targeted drug delivery systems.

Animals↗

PubMed2007

The applications of biomarkers in early clinical drug development to improve decision-making processes.

Selecting and evaluating biomarkers in drug discovery and early drug development can substantially shorten clinical development time or the time to reach a critical decision point in exploratory drug development. Critical decisions such as candidate selection, early proof of concept/principle, dose ranging, development risks, and patient stratification are based on the appropriate measurements of biomarkers that are biologically and/or clinically validated. The use of biomarkers helps to streamline clinical development by determining whether the drug is reaching and affecting the molecular target in humans, delivering findings that are comparable to preclinical data, and by providing a measurable endpoint that predicts desired or undesired clinical effects and will increase the success rate in the confirmatory stage of clinical development. Appropriateness of biomarkers depends on the stage of development, development strategy, and the nature of the medical indication. Even if a biomarker fails in the validation process there may be still a benefit of having used it. More knowledge about pathophysiology of the disease and the drug has been obtained. Different levels of validation exist at different development phases. Biomarkers are perhaps most useful in the early phase of clinical development when measurement of clinical endpoints may be too time-consuming or cumbersome to provide timely proof of concept or dose-ranging information. Examples of biomarkers are illustrated for the development of new drugs in variant cardiovascular, pulmonary, and CNS diseases.

Animals↗

PubMed2004

Challenges in bringing the bench to bedside in drug development for SLE.

It is now widely accepted that the current standard of care for systemic lupus erythematosus (SLE) patients is inadequate. There has not been a new medication approved for this disease in thirty years. Attempts to develop and test new drugs have been ongoing since the mid-1990s, but have encountered formidable obstacles. Current models for lupus pathogenesis have provided a theoretical framework for understanding how heterogeneous genetic defects might combine in various ways to increase susceptibility to SLE in different individuals, and could have important implications for new drug development. With the current burst of drug discovery and increased public awareness of SLE, the impetus to overcome these obstacles has never been greater.

Animals↗

PubMed1998

[Development of anti-cancer drugs under new renewed GCP--from the viewpoint of drug development company developer].

During the past 7 years since the enforcement of Japan's first GCP in October 1990, various standards and guidelines have been introduced in Japan. On the other hand, the harmonization of GCP has been the subject of major discussion at ICH in order to allow the mutual acceptance of clinical data from different countries. In order to further improve the reliability and consistency of clinical data and the ethics of clinical trials in Japan, the new GCP was enforced in April 1997. A clinical study is conducted by the sponsor, but will only be successful with the collaboration of trial subjects, medical institutions, heads of medical institutions, investigators, subinvestigators, pharmacists, nurses, laboratory technicians, and other assisting staff. Before the full enforcement of the new GCP, we, as sponsors of clinical trials, carried out a survey of the current status of clinical trials centering on the reactions of medical institutions to the new GCP, future of clinical trials on anti-cancer drugs in Japan, and differences in time from clinical trials to registration in Japan, the United State and Europe. We sent a questionnaire by facsimile to 21 pharmaceutical companies which have developed or are developing anti-cancer drugs and obtained replies from 20 companies (95%) from August 25 to 30, 1997. This paper reports issues concerning clinical trials on anti-cancer drugs based on the results of our survey.

Antineoplastic Agents↗

PubMed2000

Gene targeted agents: new opportunities for rational drug development.

In addition to traditional drug development methods designed to modulate the activity of protein targets, knowledge of disease gene DNA sequences provides an opportunity for the highly rational design of therapeutic agents that act at the DNA level through sequence-specific interactions. Among the ligands capable of binding DNA in a precise, sequence-specific manner are oligonucleotides, peptide nucleic acids and polyamides. Various strategies employing these agents to either transiently or permanently alter gene expression have been investigated over the past decade. During the past two to three years, important steps have been taken to illustrate the therapeutic potential of these ligands. Triple-helix (triplex) forming oligonucleotides have been particularly effective DNA-targeting agents with a wide range of applications, including the positive and negative transcriptional regulation of target genes, as well as the controlled delivery of site-specific mutations. This review will focus upon recent advances involving the use of sequence-specific DNA-binding ligands to modify gene expression and/or structure, with particular emphasis on the use of triplex-forming oligonucleotides in these roles.

Animals↗

PubMed2001

Scale and scope in drug development: unpacking the advantages of size in pharmaceutical research.

Drug development performance is examined using data on clinical research projects of 10 pharmaceutical companies. In contrast to previous work on the discovery phase of pharmaceutical R&D we find a strong correlation between the diversity of firms' development efforts and the success probability of individual projects, but no effect of scale per se. Large firms' superior performance in drug development appears to be driven by returns to scope rather than returns to scale. Scope is confounded with firm fixed effects, however, suggesting an important role for inter-firm differences in the organization and management of the development function.

Clinical Trials as Topic↗

PubMed2005

Pharmacokinetics/Pharmacodynamics and the stages of drug development: role of modeling and simulation.

Pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation (M&S) are well-recognized powerful tools that enable effective implementation of the learn-and-confirm paradigm in drug development. The impact of PK/PD M&S on decision making and drug development risk management is dependent on the question being asked and on the availability and quality of data accessible at a particular stage of drug development. For instance, M&S methodologies can be used to capture uncertainty and use the expected variability in PK/PD data generated in preclinical species for projection of the plausible range of clinical dose; clinical trial simulation can be used to forecast the probability of achieving a target response in patients based on information obtained in early phases of development. Framing the right question and capturing the key assumptions are critical components of the "learn-and-confirm" paradigm in the drug development process and are essential to delivering high-value PK/PD M&S results. Selected works of PK/PD modeling and simulation from preclinical to phase III are presented as case examples in this article.

Clinical Trials as Topic↗

PubMed1992

The decline in new drug development.

The future depends on innovation, not imitation. New drug development can be encouraged in a number of ways (Table 4), and the rewards are great. Who knows what dramatic drug discoveries remain to be found in a new synthetic compound, a fresh soil sample, or a plant obtained from some pristine forest? In any event, let us all hope that the molecular roulette that has governed drug development in the past will be replaced by a more rational, and less empirical, approach.

Chemistry, Pharmaceutical↗

PubMed1999

Frontiers of drug development. 26-28 July 1999, Pasadena, CA, USA.

This conference on the Frontiers of Drug Development was co-sponsored by the University of Southern California (USC) and three Japanese universities: Tokyo University of Pharmacy & Life Science (TUPLS), Nagoya City University (NCU), and Meijo University (MU). A major focus of the meeting was to present research activities from these four universities in the area of drug development in conventional, as well as in complementary, therapy. Speakers were also invited from universities other than the sponsoring institutions. The intention was to present a comprehensive coverage of drug development processes, from molecular design to pharmacoeconomic considerations.

Journal Article↗

PubMed2002

Drug development process for a product with a primary pediatric indication.

This article reviews the drug development process in the United States, focusing on practical issues and new U.S. Food and Drug Administration (FDA) regulations and guidance for developing a drug with a primary pediatric indication. Atomoxetine, a novel treatment for attention-deficit/ hyperactivity disorder (ADHD), is used to illustrate how the modern drug development process works and to highlight changes in the development of ADHD treatments since the introduction of the stimulants over 50 years ago. In addition to dealing with unique regulatory requirements and guidance, developing a drug for use in a pediatric population poses novel challenges in diverse areas including biomedical ethics, developmental pharmacology, and clinical trial design and implementation.

Antidepressive Agents↗

PubMed2005

Opinion: anticipating change in drug development: the emerging era of translational medicine and therapeutics.

Despite the large investments made in drug discovery in the past decade, there is still a dearth of new drugs. This highlights the persistence of a model of drug development that has not adapted to changes in science, public perception of drug companies or the marketplace. A high profit margin in the United States has shielded drug development from the usual economic pressures that would ordinarily drive reform. The strategy of merger, pursued by many companies to compensate for the failure to develop new drugs, has, in most cases, compounded the problem, imposing geographic and cultural segregation on an already inefficient process.

Biomedical Research↗

PubMed2006

Drug development and hormesis: changing conceptual understanding of the dose response creates new challenges and opportunities for more effective drugs.

This review proposes that the emerging acceptance of the hormetic dose-response model in toxicology and pharmacology has the potential to significantly change important aspects of drug development. Two situations where the hormesis concept may affect drug development are considered: one in which low-dose stimulation may represent an adverse/unwanted effect (eg, stimulation of tumor cell proliferation by antitumor drugs), the other in which low-dose stimulation defines the therapeutic zone (ie, a beneficial or intended effect; eg, cognition enhancement in Alzheimer's disease treatment). Examples are used to demonstrate that the hormetic dose-response model has implications for the definition of an ideal candidate for a therapeutic agent, as well as implications for study designs needed to assess the quantitative features of the dose-response relationship.

Animals↗

PubMed1999

8th Annual International Conference on Obesity and Non-Insulin Dependent Diabetes Mellitus: novel drug developments.

The 8th Obesity & Non-Insulin Dependent Diabetes Mellitus and Novel Drug Developments Conference organised by International Business Communication, Inc. was held on 19th - 20th, April 1999 in London, followed by an one-day symposium on Novel Drug Developments for NIDDM & Insulin Resistance. More than 100 delegates from both academic and industrial institutes attended the two meetings. The presentations provided insights into the understanding of mechanisms and developments of novel drugs for treatments of obesity and Type 2 diabetes. This review offers a general overview of the fields in appetite suppression, thermogenesis and insulin sensitisation. Discussions focused on several emerging therapeutic areas, including novel compound developments and target identification of receptors, proteins and viruses with the use of conventional methods and recently emerged technologies, such as bioinformatics and invertebrate modelling of human systems.

Journal Article↗