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PubMed2006

Selected Proceedings of the NICHD/FDA newborn drug development initiative: Part II.

BACKGROUND: In February 2003, the National Institute of Child Health and Human Development (NICHD) and the US Food and Drug Administration (FDA) created the Newborn Drug Development Initiative (NDDI), an ongoing program to determine gaps in knowledge in neonatal therapeutics and to explore clinical study designs for use in the newborn population. Working groups were established in 3 therapeutic areas: the central nervous, pulmonary, and cardiovascular systems. Three additional groups discussed pain control, drug prioritization, and ethics in neonatal clinical trials. OBJECTIVE: The purpose of this article was to provide an overview of the 5 articles written by members of the Neurology, Cardiology, Drug Prioritization, and Ethics Groups. METHODS: Information for the current article, as well as the 5 articles presented in this supplemental section, was gathered from the proceedings of a workshop cosponsored by the NICHD and the FDA. This workshop took place March 29 and 30, 2004, in Baltimore, Maryland. RESULTS: The Neurology Group addressed the treatment of 2 common and interrelated conditions in the newborn population: neonatal seizures and hypoxic-ischemic encephalopathy. The unsubstantiated clinical preference for using phenobarbital to treat neonatal seizures, coupled with the development of several newer antiepileptic drugs with application in children, dictates the need for rigorous clinical trials of these drugs in the neonatal population. A number of pharmacologic agents currently undergoing extensive investigations in experimental animals and adult humans may have application in the newborn population. The Cardiology Group reviewed controversial approaches to the diagnosis and treatment of cardiovascular instability of preterm infants and identified gaps in knowledge. The group discussed issues of study design and developed 2 study proposals: (1) a placebo-controlled trial with a rescue arm for symptomatic infants; and (2) a targeted blood pressure (BP) trial. The Drug Prioritization Group focused on the fact that the uniqueness of the newborn population is due to distinctive and changing physiologic characteristics, conditions, and diseases that are different from those affecting older children, as well as the large differences in developmental patterns between 23 weeks of gestation and term. All of these factors help explain the lack of adequate trials and the sparseness of evidence regarding efficacy and toxicity risks of most drugs used in the newborn population. Unfortunately, the frequency of drug use and polypharmacy is highest in very-low-birth-weight infants. The large number of drugs requiring study and the uniqueness of the indications for those drugs preclude the use of the prioritization process used in older children. The focus of the Drug Prioritization Group was the determination of factors that identify which drugs are most important for study. The Ethics Group was unique in that its members were integrated into the therapeutic groups. This approach allowed for the identification of similarities and dissimilarities in the proposed clinical trial design framework. The summary report included here identifies common themes voiced in the various NDDI reports and deliberations. CONCLUSIONS: The 5 articles included in this issue address different issues but share common themes: the need to develop innovative trial designs and biomarkers of efficacy, consideration of ethical concerns, and selection of appropriate drugs for study.

Drug Approval↗
PubMed1991

Signalling targets for anticancer drug development.

Intracellular signalling pathways mediating the effects of growth factors and oncogenes on cell growth and transformation present a challenging new class of target sites for anticancer drug development. Several drugs are already available that may act in this way, including drugs that act on protein serine/threonine kinases, protein tyrosine kinases and phospholipase C, as well as inhibitors of myo-inositol signalling. As our understanding of the signalling pathways involved in growth control increases, new sites for pharmacological intervention will become apparent. Garth Powis reviews the evidence that this approach may eventually lead to new, more selective drugs for treating cancer.

Animals↗
PubMed1992

Opioid peptide drug development: transport of opioid chimeric peptides through the blood-brain barrier.

The use of chimeric peptides and physiologic-based strategies for drug delivery through the BBB may be applied to opioid peptides (dynorphins, endorphin analogs, and enkephalin analogs), and these agents have considerable advantages in drug development with respect to drug addiction. Recent research has allowed for the development of efficacious BBB drug transport vectors, as well as the demonstration that these vectors allow for shuttling of opioid peptides through the BBB in vivo. The major challenge to future research is the development of coupling strategies that allow for the release of biologically active opioid peptide from the drug transport vector following its cleavage by disulfide reductase enzymes, which are abundant in brain. These coupling strategies must be developed in advance since the amino groups necessary for coupling are incorporated into the opioid peptide at the level of solid-state synthesis.

Animals↗
PubMed2001

Economic evaluations during early (phase II) drug development: a role for clinical trial simulations?

Faced with increasing demands on demonstrating cost effectiveness, pharmaceutical companies are required to conduct pharmacoeconomic evaluations throughout the drug development programme. At present, there is particular emphasis in the literature on burden-of-illness studies and on economic evaluations conducted alongside phase III clinical trials but not on those conducted during phase II clinical trials. This article describes modelling techniques, namely clinical trial simulations (CTS), which are gaining popularity in the clinical research community, but which might also prove to be beneficial during the conduct of these early pharmacoeconomic evaluations. The basic concepts and structure of CTS are described by using published examples of simulations of antipsychotic and anticancer drugs. With the use of an illustrative example of a hypothetical cholinesterase inhibitor for Alzheimer's disease, an integrated CTS-based pharmacoeconomic evaluation is presented. The results demonstrate how the modelling may be of value in 'go/no-go' decisions during the drug development programme.

Antipsychotic Agents↗
PubMed2003

Use of positron emission tomography in anticancer drug development.

Positron emission tomography (PET) is increasingly being used in anticancer drug development. The technique is applicable to studies of drug delivery, and where specific probes are available, to provide pharmacodynamic readouts noninvasively in patients. Mathematical modeling of the imaging data enhances the quality of information that is obtained from such studies. This section provides a review of the PET methodologies that have been used for the development of new cancer therapies. Other than imaging of radiolabeled drugs, PET modeling has found extensive application in studies with 2-[11C]thymidine, [18F]fluorodeoxyglucose, H2(15)O, C15O, and receptor ligands.

Animals↗
PubMed2005

The global alliance for tuberculosis drug development--accomplishments and future directions.

The Global Alliance for Tuberculosis Drug Development (TB Alliance) aims to stop the spread of tuberculosis by developing new, faster-acting, and affordable tuberculosis drugs. The TB Alliance is a public-private partnership, a not-for-profit enterprise, that draws upon the resources of both private and public institutions to help address this urgent health need. This article summarizes some of the achievements of the TB Alliance to date and outlines potential future directions.

Antitubercular Agents↗
PubMed2003

Integration of genomic technologies for accelerated cancer drug development.

New technologies have greatly increased the scientist's ability to investigate complex molecular interactions that occur in cancer development and to identify genetic alterations and drug targets. However, these new capabilities have not accelerated drug development efforts; rather, they may be contributing to increased research and development costs because the large number of new drug targets discovered through genomics need to be investigated in great detail to characterize their putative functional involvement in the disease process. One solution to this bottleneck in functional analysis is the use of high-throughput technologies to produce efficient processes that can rapidly handle the large flood of information at every stage of disease. This review examines the use of new and emerging DNA, tissue, and live-cell transfection microarray technologies that can be used to discover, validate, and translate information resulting from the completion of the Human Genome Project.

Biotechnology↗
PubMed2001

Gene expression microarray analysis in cancer biology, pharmacology, and drug development: progress and potential.

With the imminent completion of the Human Genome Project, biomedical research is being revolutionised by the ability to carry out investigations on a genome wide scale. This is particularly important in cancer, a disease that is caused by accumulating abnormalities in the sequence and expression of a number of critical genes. Gene expression microarray technology is gaining increasingly widespread use as a means to determine the expression of potentially all human genes at the level of messenger RNA. In this commentary, we review developments in gene expression microarray technology and illustrate the progress and potential of the methodology in cancer biology, pharmacology, and drug development. Important applications include: (a) development of a more global understanding of the gene expression abnormalities that contribute to malignant progression; (b) discovery of new diagnostic and prognostic indicators and biomarkers of therapeutic response; (c) identification and validation of new molecular targets for drug development; (d) provision of an improved understanding of the molecular mode of action during lead identification and optimisation, including structure-activity relationships for on-target versus off-target effects; (e) prediction of potential side-effects during preclinical development and toxicology studies; (f) confirmation of a molecular mode of action during hypothesis-testing clinical trials; (g) identification of genes involved in conferring drug sensitivity and resistance; and (h) prediction of patients most likely to benefit from the drug and use in general pharmacogenomic studies. As a result of further technological improvements and decreasing costs, the use of microarrays will become an essential and potentially routine tool for cancer and biomedical research.

Animals↗
PubMedDate not supplied

Drug development in spinal cord injury: what is the FDA looking for?

It has long been recognized that much of the post-traumatic degeneration of the spinal cord following injury is caused by a secondary injury process that occurs during the first minutes, hours, and days after spinal cord injury (SCI). A key biochemical event in that process is reactive oxygen-induced lipid peroxidation (LP). Indeed, the administration of a high-dose regimen of the glucocorticoid steroid methylprednisolone (MP) has been shown to inhibit post-traumatic LP in animal models of SCI, and to improve neurological recovery in spinal cord-injured humans. This resulted in the registration of high-dose MP for acute SCI in several countries, although not in the U.S. Nevertheless, this treatment quickly became the standard of care for acute SCI, since it was already on the U.S. market for many other indications. Subsequently, it was demonstrated that the nonglucocorticoid 21-aminosteroid tirilazad could duplicate the antioxidant neuroprotective efficacy of MP in SCI models, and evidence of human efficacy has been obtained. This article explains the process of the discovery, development, and Food and Drug Administration regulation of new drugs for SCI; reviews the past development of MP and tirilazad for acute SCI; identifies the regulatory complications involved in future SCI drug development; and suggests some promising therapeutic approaches that could either replace or be added to high-dose MP.

Animals↗
PubMed2006

Effective partnering of academic and physician scientists with the pharmaceutical drug development industry.

This manuscript briefly addresses the drug discovery and development process. It is a long road from the formulation of a good discovery idea to the acceptance of a new drug in the marketplace, and there are many challenges faced along the way to the patient. Collaborations and partnerships are an important part of this process. There are a variety of partnering opportunities, ranging from the discovery of novel technologies and drug targets to lead discovery, compound gifts, and external sourcing. These partnerships help increase confidence and improve decision making on issues of safety and efficacy preclinically, which can reduce attrition and expedite the provision of new quality drugs to patients more quickly and at lower costs. Collaborations involve addressing multiple issues that include infrastructure, safety, regulatory matters, intellectual property, technical and personnel considerations, source document capture and data analysis issues, and legal and strategic alliances. A number of success factors are identified as important for quality collaborations in the drug development process.

Drug Industry↗
PubMed1978

Selected animal models for systematic antiatherosclerotic drug development.

We have developed an integrated system for antiatherosclerosis drug development utilizing rats, SEA quail, and cynomolgus monkeys as animal models. In general, the way the system is presently functioning is that thousands of compounds per year are randomly screened for hypobeta- or hyperalphalipoproteinemic activity in rats, and hundreds of compounds per year are screened in SEA quail for antiatherosclerotic and hypocholesterolaric activity. A few selected compounds that have activity in both rats and quail are then tested for lipoprotein modifying activity in cynomolgus monkeys. Nontoxic compounds having very good lipoprotein modifying activity in the monkey will then be recommended for clinical trials in man. We do not anticipate that this battery of testing will guarantee activity in man, but are hoping that it will at least increase the probability for finding a truly effective antiatherosclerotic drug to control the human disease.

Animals↗
PubMed2006

The cell cycle hypothesis of Alzheimer's disease: suggestions for drug development.

The cell cycle of hypothesis of neural dysfunction in chronic neurodegenerative conditions such as Alzheimer's disease (AD) offers a unified approach to understanding both existing and novel strategies for drug development. At the present time, a ligand based approach is a pragmatic solution for identifying new chemical leads on which to base future discovery and optimisation. We have pursued a ligand based approach on the basis of public domain data to identify existing compounds capable of abrogating the cell cycle at the G0-G1 interface. Selected on this basis, irrespective of the tissue under study, we identified several classes of compounds as potential chemical leads. Of these compounds, at least ten have already been shown to be neuroprotective in animal models of acute neurodegeneration. Such compounds could form the basis of a screening exercise after development of suitable screening tools. Progressing of chemical leads through such an approach will be more efficient if future leads display relevant "drug-like" properties. Further, drug development in this arena should take account of the special concerns raised by targeting an elderly population. This will involve accounting for frequent polypharmacy in the aging population, and age-related alterations in physiology.

Aged↗
PubMed2004

Drug development strategies for asthma: in search of a new paradigm.

The spiraling costs of asthma treatment seem set to continue rising, given the equivocal performance of the latest generation of specific anti-inflammatory drugs in trials in adult asthmatics. We argue that the continuation of this trend is inevitable unless there is a substantial realignment of entrenched drug development policy in the pharmaceutical industry and a parallel shift in licensing policy by regulatory authorities to encourage the development of drugs capable of halting the progression from acute to chronic asthma when the disease first manifests in childhood. The theoretical framework for such an approach, including proof-of-principle data from studies in children with early-stage disease and a range of candidate drugs, already exists. What is needed is informed debate on the risks versus potential benefits of this approach.

Animals↗
PubMedDate not supplied

A primer of drug safety surveillance: an industry perspective. Part I: Information flow, new drug development, and federal regulations.

OBJECTIVE: To place the fundamentals of clinical drug safety surveillance in a conceptual framework that will facilitate understanding and application of adverse drug event data to protect the health of the public and support a market for pharmaceutical manufacturers' products. Part I of this series provides a background for the discussion of drug safety by defining the basic terms and showing the flow of safety information through a pharmaceutical company. The customers for adverse drug event data are identified to provide a basis for providing quality service. The development of a drug product is briefly reviewed to show the evolution of safety data. Drug development and safety are defined by federal regulations. These regulations are developed by the FDA with information from pharmaceutical manufacturers. The intent of the regulations and the accompanying guidelines is described. An illustration from the news media is cited to show an alternative, positive approach to handling an adverse event report. DATA SOURCES: This review uses primary sources from the federal laws (regulations), commentaries, and summaries. Very complex topics are briefly summarized in the text and additional readings are presented in an appendix. Secondary sources, ranging from newspaper articles to judicial summaries, illustrate the interpretation of adverse drug events and opportunities for drug safety surveillance intervention. STUDY SELECTION: The reference materials used were articles theoretically or practically applicable in the day-to-day practice of drug safety surveillance. DATA SYNTHESIS: The role of clinical drug safety surveillance in product monitoring and drug development is described. The process of drug safety surveillance is defined by the Food and Drug Administration regulations, product labeling, product knowledge, and database management. Database management is subdivided into the functions of receipt, retention, retrieval, and review of adverse event reports. Emphasis is placed on the dynamic interaction ;of the components of the process. Suggestions are offered to facilitate communication of a review of adverse event data for various audiences. CONCLUSIONS: Careful drug safety surveillance is beneficial to the health of the public and the commercial well-being of the manufacturer. Attention to basic principles is essential and, as illustrated, may be sufficient to resolve some problems.

Adverse Drug Reaction Reporting Systems↗
PubMed2005

A new paradigm for developing drugs in children: atomoxetine as a model.

When prescribing drugs for children, it is fundamental to acknowledge that they are distinct from adults with a different physiology and metabolism. They are also still maturing. The development of drugs with a primarily paediatric indication thus requires the trialling of these drugs in a paediatric population to assess safety, tolerability, and efficacy as appropriately as possible. When designing and running a paediatric clinical trial, a number of complexities must be addressed to ensure a successful study, including practical considerations, ethical issues, and tailoring communication appropriately to study participants and parents. The drug development process for atomoxetine, a novel, non-stimulant treatment for attention deficit/hyperactivity disorder (ADHD), encompassed a preclinical programme, initial trials in healthy adults, and a proof of concept trial in adults with ADHD. Open label and placebo controlled studies in paediatric patients followed, thus establishing the drug's safety and efficacy in children with ADHD. Further trials have addressed, and continue to address, wider aspects of the atomoxetine response in a paediatric setting.

Age Factors↗
PubMed2005

[Network for the collection and distribution of Japanese liver tissues resected surgically for drug development and research use].

We focused on the establishment of a trial procedure for the collection and distribution of Japanese liver tissues obtained from waste surgical resections for drug development and research use. The following procedures were prepared for this project: the pretreatment of liver tissues before storage, their storage at 4 degrees C, the transport of liver samples, the setting up of a communication network among the participating hospitals and laboratories and the approval of each ethics committee. Thirteen liver samples (1.6-7.6 g) obtained from patients whose livers were excised due to cirrhosis, hepatocellular carcinoma, cholangiocarcinoma, or metastasis from colorectal carcinoma and were donated for research. Informed consent was obtained from every patient. Freshly isolated human hepatocytes were prepared from nine liver samples (viability 34.3-86.1%). Four samples were unsuitable to prepare hepatocytes. The profile of testosterone metabolism as 6beta-, 2beta-, 16beta-, 16alpha- and 2alpha-hydroxytestosterone and androstenedione in freshly isolated hepatocytes was shown to be specific for human liver. The 6beta-hydroxylation activity catalyzed by CYP3A4/5 indicated a high level of metabolism (139-996 pmol/min/million cells). Levels of 7-ethoxycoumarin O-deethylation and glucronidation activities were sufficient for analysis in freshly isolated human hepatocytes. We conclude that liver tissues from waste surgical resections supplied from a participating hospital can constitute a valuable source of freshly isolated human hepatocytes for drug development and safety evaluation.

Aged↗