SEARCH · PubMed Health

Results for “Drug development”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 181 records · Page 10Linked to original sources

PubMed2007

Positron emission tomography imaging as a key enabling technology in drug development.

The use of positron emission tomography (PET) in drug development has become more common in the pharmaceutical industry in recent years. One of the biggest challenges to gaining acceptance of this technology is for project teams to understand when to use PET. This chapter reviews the usage of PET in drug development in the context of target, mechanism and efficacy biomarkers. Examples are drawn from a number of therapeutic areas, but we also show that the relative penetration of this technology beyond CNS and oncology applications has been relatively small. However, with the increasing availability of PET and development of novel radiotracers it is expected that the utilization will be much broader in future years, with the additional expectation that the use of PET as an efficacy biomarker will also become more evident.

Animals↗

PubMed2007

Economics of new oncology drug development.

PURPOSE: Review existing studies and provide new results on the development, regulatory, and market aspects of new oncology drug development. METHODS: We utilized data from the US Food and Drug Administration (FDA), company surveys, and publicly available commercial business intelligence databases on new oncology drugs approved in the United States and on investigational oncology drugs to estimate average development and regulatory approval times, clinical approval success rates, first-in-class status, and global market diffusion. RESULTS: We found that approved new oncology drugs to have a disproportionately high share of FDA priority review ratings, of orphan drug designations at approval, and of drugs that were granted inclusion in at least one of the FDA's expedited access programs. US regulatory approval times were shorter, on average, for oncology drugs (0.5 years), but US clinical development times were longer on average (1.5 years). Clinical approval success rates were similar for oncology and other drugs, but proportionately more of the oncology failures reached expensive late-stage clinical testing before being abandoned. In relation to other drugs, new oncology drug approvals were more often first-in-class and diffused more widely across important international markets. CONCLUSION: The market success of oncology drugs has induced a substantial amount of investment in oncology drug development in the last decade or so. However, given the great need for further progress, the extent to which efforts to develop new oncology drugs will grow depends on future public-sector investment in basic research, developments in translational medicine, and regulatory reforms that advance drug-development science.

Antineoplastic Agents↗

PubMedDate not supplied

Pharmacokinetic-pharmacodynamic relationships in phase I/phase II of drug development.

Early investigation of pharmacokinetic-pharmacodynamic relationships in Phase I/II may facilitate the further clinical development of a new drug. Although some pharmacology assessments in Phase I are often only surrogates for the therapeutic effect, PK-PD modelling of those effects provides in general crucial information on the drug's potency in vivo. A mathematical PK-PD expression allows explorative simulations on the rate of onset of drug action, on the intensity and duration of the effects for doses in future clinical trials, or in situations of altered drug kinetics. Furthermore, understanding of the PK-PD relationship early on in drug development may anticipate unnecessary exposure of human subjects to inappropriate drug doses or trials.

Animals↗

PubMed2003

Controlling type I error rate for fast track drug development programmes.

The U.S. Food and Drug Administration (FDA) Modernization Act of 1997 has a Section (No. 112) entitled 'Expediting Study and Approval of Fast Track Drugs' (the Act). In 1998, the FDA issued a 'Guidance for Industry: the Fast Track Drug Development Programs' (the FTDD programmes) to meet the requirement of the Act. The purpose of FTDD programmes is to 'facilitate the development and expedite the review of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs'. Since then many health products have reached patients who suffered from AIDS, cancer, osteoporosis, and many other diseases, sooner by utilizing the Fast Track Act and the FTDD programmes. In the meantime several scientific issues have also surfaced when following the FTDD programmes. In this paper we will discuss the concept of two kinds of type I errors, namely, the 'conditional approval' and the 'final approval' type I errors, and propose statistical methods for controlling them in a new drug submission process.

Clinical Trials, Phase III as Topic↗

PubMed2000

Current pharmacogenomic approaches to clinical drug development.

Pharmacogenomics has recently become an integral part of the drug development process. The pharmacogenomics revolution comes at a time when pharmaceutical companies are faced with mounting pressures to lower the cost of drugs despite the continued rise in research and development spending needed to bring new drugs to market. Pharmaceutical companies want to avoid late stage failures or drugs labelled for restricted use following approval. More than twenty years of pharmacogenetic studies have established many of the genetic traits responsible for interindividual differences in the way patients metabolise drugs. The genetic polymorphisms found in the major drug metabolising enzymes (DMEs) and their associated phenotypes are well established. These monogenetic traits have a predictable influence on the pharmacokinetic and pharmacological effects of a large number of commonly prescribed drugs. This knowledge has been used to develop affordable, robust, clinical genotyping methods that can be used by pharmaceutical companies to screen patients prior to drug therapy. Prospective screening of Phase I volunteers for DME polymorphisms is done routinely at a number of pharmaceutical companies. As the pharmacogenomic initiatives at these companies evolve, more and more patients enrolled in Phase II-III clinical trials are genotyped to correlate efficacy with genetic markers that predict pharmacodynamic effects. There are a number of pharmacogenomic markers that provide useful diagnostic tools to prospectively evaluate treatment regimens, including the genetics of the host, cancerous tumours or infectious agents. The incorporation of pharmacogenomics into clinical drug development offers the opportunity for pharmaceutical companies to evaluate drugs with a better understanding of the effect that specific genetic variants will have on drug response. Prospective testing can ensure the inclusion of important phenotypic subgroups, thus impacting the efficiency of drug development. Ultimately this approach will validate the utility of genotyping prior to prescription, thereby ensuring that patients receive the right drug at the right dose the first time.

Clinical Trials as Topic↗

PubMed2003

Antiepileptic drug development for "therapeutic orphans".

Epilepsy is the most common serious neurological disorder among children. Excluding the elderly, the incidence of epilepsy is highest among children. About half of children with epilepsy have epilepsy syndromes that have unique onset in childhood. Clinical drug trials of antiepileptic drugs (AEDs) among children have been primarily performed using drugs developed for the larger adult partial epilepsy market. The current AED drug development system essentially renders children with epilepsy "therapeutic orphans" who can only benefit from AED development if a drug developed for adult partial epilepsy happens to also be effective for a pediatric epilepsy syndrome. The rapid evolution of different seizure types and childhood epilepsy syndromes, and rapid changes in baseline neurological status, make distinguishing clinical changes due to study drugs in clinical trials and the natural history of the epilepsy syndrome difficult. Unique ethical issues (e.g., informed consent), practical and logistical issues (e.g., serum AED level monitoring with microassay methods), as well as major financial and regulatory disincentives for the pharmaceutical industry are additional barriers to need-based AED development for children. A government-funded pediatric epilepsy group or consortium to conduct clinical trials similar to the successful Children's Oncology Group (COG) and regulations plus financial incentives that encourage the pharmaceutical industry to develop AEDs specifically for children are needed.

Anticonvulsants↗

PubMed2003

Animal models of depression: challenges from a drug development perspective.

Clinically effective antidepressant drugs have been available for many years but our understanding of how these drugs bring about their therapeutic effects, and how to develop more diverse, better treatments has progressed little. At a time when informed choices need to be taken early on in drug development programs in order to exploit the opportunities for innovation created through genomics, this article considers the strengths and weaknesses of behavioral pharmacology assays and their various roles in the drug discovery process. In the past, a widespread lack of confidence in animal models of depression, combined with the high failure rate of clinical trials and escalating costs of drug development, has stifled a more entrepreneurial approach to drug discovery. In order to encourage greater confidence in discovery programs, the gap between exploratory preclinical and clinical studies needs to be bridged. Functional pharmacology markers need to be developed in patient populations, and in normal volunteers and preclinical species, so that selection of new drug targets can be made with greater confidence at earlier stages of discovery programs. The use of functional brain imaging to quantify drug actions in the human CNS is developing rapidly and may provide powerful new techniques to filter active new drugs of the future from those that are less promising.

Animals↗

PubMed2005

An overview of drug development with special emphasis on the role of visual electrophysiological testing.

Visual electrophysiological techniques, such as electroretinography (ERG) and visual evoked potentials (VEP) can provide useful information on the safety, efficacy, and proper dosing of chemical entities under development as new drug therapies. During post-marketing safety surveillance, a variety of visual electrophysiological measures can be used to objectively assess and document individual patient response to ophthalmic drugs and ocular or visual system side effects of non-ophthalmic drugs. In this paper, the discovery, exploratory development, full-development and post-marketing stages of drug development are briefly outlined. The potential role of visual electrophysiological techniques in each of these stages is described and discussed.

Animals↗

PubMedDate not supplied

NIH-FDA Analgesic Drug Development Workshop: translating scientific advances into improved pain relief.

Analgesic drug development as currently undertaken is limited by a number of factors that contribute to the paucity of new analgesics introduced into clinical practice despite marked advances in delineating of the molecular-genetic mechanisms contributing to acute and chronic pain. The participants in this workshop explored the unmet need in analgesia and recommended strategies for enhancing analgesic drug development in the future. The workshop concluded that translating scientific advances into improved pain relief will require new thinking and a cooperative effort among the pharmaceutical industry, regulatory agencies, funding agencies, the biomedical research community, professional societies and clinicians. The workshop also recommended that a better understanding of the epidemiology of pain could contribute to improvement in clinical trial methodology and outcome measures.

Analgesics↗

PubMedDate not supplied

LC/MS applications in drug development.

The combination of high-performance liquid chromatography and mass spectrometry (LC/MS) has had a significant impact on drug development over the past decade. Continual improvements in LC/MS interface technologies combined with powerful features for structure analysis, qualitative and quantitative, have resulted in a widened scope of application. These improvements coincided with breakthroughs in combinatorial chemistry, molecular biology, and an overall industry trend of accelerated development. New technologies have created a situation where the rate of sample generation far exceeds the rate of sample analysis. As a result, new paradigms for the analysis of drugs and related substances have been developed. The growth in LC/MS applications has been extensive, with retention time and molecular weight emerging as essential analytical features from drug target to product. LC/MS-based methodologies that involve automation, predictive or surrogate models, and open access systems have become a permanent fixture in the drug development landscape. An iterative cycle of "what is it?" and "how much is there?" continues to fuel the tremendous growth of LC/MS in the pharmaceutical industry. During this time, LC/MS has become widely accepted as an integral part of the drug development process. This review describes the utility of LC/MS techniques for accelerated drug development and provides a perspective on the significant changes in strategies for pharmaceutical analysis. Future applications of LC/MS technologies for accelerated drug development and emerging industry trends are also discussed.

Amino Acid Sequence↗

PubMed2001

Use of bromine-76 and iodine-123 radiohalogenated tracers in the drug development process.

The only bromine and iodine radioisotopes worth using in PET or SPECT in vivo investigations during the development of a new drug are 76Br and 123I. It is most of the time impossible to isotopically label a drug with 76Br or 123I since the occurrence of drugs having a bromine or an iodine atom within their chemical structure is quite limited. However, by using specific radiobrominated or radioiodinated probes, it is possible to study in vivo the potential interaction of a drug with biochemical processes such as blood flow, glucose consumption, protein synthesis or cell proliferation and neurotransmission. Radiobrominated and radioiodinated probes have been described mainly for assessing cell proliferation. For imaging various classes of specific binding sites involved in neuronal or hormonal transmission, a great number of radiohalogenated ligands have been proposed and validated. The two-steps strategy consists of performing an "in vivo assay" by using first of all, one of these specific radio-brominated/-iodinated ligands (or probes) for targeting specific binding sites (receptor, transporter, enzymes) and in a second step by assessing the interaction of the cold drug on the binding of these probes. This indirect observation of drug-receptor (transporter, enzyme) occupancy allows predicting response, optimum dose and optimum scheduling. The most important radiobrominated and radioiodinated ligands specific for dopaminergic, serotoninergic, cholinergic and gabaergic binding sites and their application in drug development processes are reviewed.

Animals↗

PubMed1980

m-AMSA: an exciting new drug in the National Cancer Institute Drug Development Program.

m-AMSA is a new drug in the National Cancer Institute Drug Development Program. The drug has moderate but tolerable toxicity and has demonstrated tumor activity in acute leukemia and breast cancer. Numerous phase II studies are completed or in progress and phase III trials will soon begin. We review the preclinical and phase I clinical information on this drug. We then enumerate the present ongoing studies and make some suggestions for future studies that will allow a rapid and orderly assessment of its value.

Acute Disease↗

PubMed2002

Oncology drug development: United States Food and Drug Administration perspective.

The Food and Drug Administration (FDA) in the United States has multiple roles. The primary responsibilities for oncology drug products are the supervision of clinical research, the evaluation of marketing claims for new and previously approved drugs, the granting of exclusive marketing licenses for approved claims, and the monitoring of post-marketing activity for safety. Additional roles include providing incentives for developing products for rare diseases and children. The principles used for monitoring clinical studies are based on science, law and ethical guidelines. The principles used for evaluation of evidence to support marketing claims are based in science, law, regulation, and frequently the advice of a panel of external experts. Approved products should demonstrate patient benefit that is commensurate with the probable risks. The types of endpoints and their advantages and disadvantages for regulatory review are discussed. There are regulatory options available for conditional approval based on surrogate endpoints that are likely to predict patient benefit, a mechanism for reducing the time to review an application for indications with no known effective therapy, and procedures for providing access to patients for unapproved drugs.

Antineoplastic Agents↗

PubMed1997

Positron emission tomography in drug development.

There are four kinds of measurements that can be carried out with positron emission tomography (PET) that can contribute significantly to the process of drug development: pharmacodynamic measurements of tissue metabolism influenced by a given drug; precise measurements of tissue blood flow; tissue pharmacokinetics of a given drug following administration of a particular dose; and the temporal course of ligand-receptor interaction. One or more of these measurements can greatly improve the decision making involved in determining the appropriate dose of a drug, the clinical situations in which a drug might be useful, and the linkage of pharmacokinetics with pharmacodynamics, which is at the heart of effective drug development. The greater the potential of a particular compound as a therapeutic agent, the greater the potential for PET to contribute to the drug development process.

Animals↗

PubMed2005

If 'atypical' neuroleptics did not exist, it wouldn't be necessary to invent them: perverse incentives in drug development, research, marketing and clinical practice.

Perverse incentives in drug development, research, marketing and clinical usage can be illustrated by considering the example of the so-called 'atypical' neuroleptics which have grown to become a standard - indeed expanding - part of psychiatric practice despite their probable inferiority to older sedative agents. There is now ample evidence to suggest that neuroleptics (aka. anti-psychotics and major tranquillizers) are dangerous drugs, and patients' exposure to them should be minimized wherever possible. This clinical imperative applies whether neuroleptics are of the traditional type or atypical variety, albeit for different reasons since the traditional agents are neurotoxic, while atypicals are mainly metabolic poisons. Usage of traditional neuroleptics seems indeed to be declining progressively, but the opposite seems to be happening for 'atypicals', and new indications for these drugs are being promoted. Yet the atypical neuroleptics are a category of pharmaceuticals which are close to being un-necessary since there are safer, cheaper and pleasanter substitutes, such as benzodiazepines and the sedative antihistamines (e.g. promethazine). If 'atypical' neuroleptics did not exist, it would not be necessary to invent them. Analysis of how such expensive, dangerous and inferior drugs as the 'atypicals' have nevertheless come to dominate clinical practice casts light on the perverse incentives which now motivate the pharmaceutical industry in an era of massive state regulation. The lack of positive incentives to deploy off-patent drugs is longstanding, but there is a new disincentive in the widespread but erroneous belief that only randomized controlled trials (RCTs) can provide valid 'evidence' of effectiveness. Consequently, those who control RCTs now control clinical practice. It sometimes makes commercial sense to develop and market new drugs that are inferior to existing agents, since new drugs are patent-protected and can be promoted on the back of a mass of new RCTs funded and 'owned' by the pharmaceutical corporations. The current regulatory and patenting situation, therefore, requires major reform if drug efficacy and patient safety are to become higher priorities. Given that psychiatric practice is apparently 'locked-in' to prescribing atypicals, and if (as seems likely) most informed individuals would wish to avoid neuroleptics for themselves and their loved-ones except as a last resort; then in the short-term it may be wise for patients and their families to explore the possibilities of increased self-management of psychiatric problems using over-the-counter drugs, such as the sedative antihistamines. In the long-term, there need to be legal reforms to change the regulatory and commercial framework of incentives relating to drug development. These might include new forms of short-term re-patenting of old drugs.

Antipsychotic Agents↗

PubMed2004

How to improve drug development for functional disorders.

Although several studies and publications have been devoted to the evaluation of novel pharmacotherapeutic approaches in functional bowel disorders, the number of successful drug development programs has been disappointingly small. The difficulties of adequate drug development are related to the heterogeneity of the functional disorders, the lack of understanding of the underlying pathophysiology, and the lack of short-term mechanistic studies that predict clinical outcome. When drugs address a single pathophysiological mechanism, the heterogeneity has a negative impact on the possible margin when patients are not selected on the basis of the specific pathophysiological disorder. Although mechanistic studies may provide a rationale for drug development, they do not predict symptomatic success and do not identify the most appropriate dose for clinical trials. Further mechanistic studies are badly needed to improve our understanding of the pathophysiological basis of functional disorders. Future studies might aim at the development of non-invasive test that identify relevant pathophysiological mechanisms, at refining assessment of symptom pattern and at the development of short-term therapeutic trials.

Drug Design↗

PubMed1998

The use of hyphenated LC-MS technique for characterisation of impurity profiles during drug development.

As part of an integrated quality concept for impurities during drug development, the multidimensional evaluation of impurity profiles by LC MS coupling is presented using peptide drugs as an example. This quality concept can be regarded as an adaptation of the ICH-requirements to the special situation during the drug development process. The primary goal is to obtain qualitative molecular weight information for impurity peaks detected at the same UV wavelength as for the impurity test procedure. The approach is focused on the investigation, if the impurities in a clinical batch were also present in the toxicologically qualified batch(es). Depending on the relevance of individual impurities in further batches or as degradation products, the molecular weight can be used as a starting point for further characterization and identification. Often, eluents with volatile buffers required for MS result in different selectivities and/or inferior chromatographic separation and sensitivity compared with nonvolatile buffers (e.g. phosphates). In these cases, peak 'tracking' especially for small peaks can become critical. A procedure is presented for on-line coupling of LC methods with non-volatile eluents to mass spectrometry.

Antineoplastic Agents↗

PubMed2000

Modelling during drug development.

With the advancement of both biological and computer sciences, new drug development faces the challenge to integrate a huge amount of knowledge accumulated from the very early quantitative structure-activity relationship investigations of the candidate molecule to the large scale clinical trials in patients. Whereas pharmacokinetics and pharmacodynamics are fields in which modelling has long demonstrated its value, its potential in many other areas of drug development has recently been the object of intensive scientific activity. The present review places emphasis on these newer applications; it includes the opinion of many experts in often highly specialised areas such as in vitro to in vivo extrapolation, toxicokinetics, non-continuous response models, population approaches and computer assisted simulation of clinical trials. It is most probable that in the near future many of these areas of research will be the objects of intensive and interesting developments. This will undoubtedly lead to improve developmental strategies for new drugs as well as more individualised pharmacological strategies for patients.

Animals↗