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PubMed1999

[Responsibilities of clinical pharmacology in the early phase of drug development].

The path of a new drug from the idea to the product may be divided into 2 phases, namely drug discovery and drug development. Due to the scientific progress new and simple methods could be developed to determine the biological efficacy of a large number of compounds. During the first part of drug development necessary requirements for the first use in man are met by performing preclinical pharmacological, toxicological and pharmacokinetic investigations in the animal and in in-vitro testing. After a first clinical-pharmacological profile of the new substance has been established during phase I on the basis of which a decision for the continuation of the clinical trial is made, the aim of phases II and III is now to answer the important questions of the therapeutic efficacy and tolerability in a large number of patients with the target indication. Due to the continuously increasing time and costs of drug development, drug development should be streamlined combining preclinical and early clinical phases as an exploratory stage and later clinical development as a confirmatory stage. The development and appropriate use of surrogates and models may be helpful to determine drug actions in human and to assist in dose selection as the main requirement for a successful large clinical trial in the confirmatory stage. Identifying the genes responsible for the huge variations in how different patients respond to a drug, in terms of both the product's effectiveness and its side effects, and genotyping patients before including in large clinical trials may prevent selecting the wrong patient population and avoid expensive repetition of these studies. Taking responsibility as the link between research and development gives clinical pharmacology a major opportunity to assume a pivotal role in drug development. To reach this goal, clinical pharmacology must be fully integrated in the whole process of drug development from the candidate selection until the approval.

Animals↗
PubMed2000

[Responsibilities of clinical pharmacology in the early phase of drug development].

The path of a new drug from the idea to the product may be divided into 2 phases, namely drug discovery and drug development. Due to the scientific progress new and simple methods could be developed to determine the biological efficacy of a large number of compounds. During the first part of drug development necessary requirements for the first use in man are met by performing preclinical pharmacological, toxicological and pharmacokinetic investigations in the animal and in in-vitro testing. After a first clinical-pharmacological profile of the new substance has been established during phase I on the basis of which a decision for the continuation of the clinical trial is made, the aim of phases II and III is now to answer the important questions of the therapeutic efficacy and tolerability in a large number of patients with the target indication. Due to the continuously increasing time and costs of drug development, drug development should be streamlined combining preclinical and early clinical phases as an exploratory stage and later clinical development as a confirmatory stage. The development and appropriate use of surrogates and models may be helpful to determine drug actions in human and to assist in dose selection as the main requirement for a successful large clinical trial in the confirmatory stage. Identifying the genes responsible for the huge variations in how different patients respond to a drug, in terms of both the product's effectiveness and its side effects, and genotyping patients before including in large clinical trials may prevent selecting the wrong patient population and avoid expensive repetition of these studies. Taking responsibility as the link between research and development gives clinical pharmacology a major opportunity to assume a pivotal role in drug development. To reach this goal, clinical pharmacology must be fully integrated in the whole process of drug development from the candidate selection until the approval.

Animals↗
PubMedDate not supplied

The prescription Drug User Fee Act of 1992 and the new drug development process.

The Prescription Drug User Fee Act of 1992 (PDUFA) authorizes the US Food and Drug Administration (FDA) to levy user fees on manufacturers who submit applications to the agency. Revenues are dedicated to the achievement of a set of specific performance goals, documented by the FDA Commissioner and referenced in the Act. The FDA currently credits PDUFA with the agency's success in reducing new drug review times and eliminating the formidable new drug application (NDA) backlog. To provide an independent assessment of PDUFA's impact on the new drug development process, the Tufts Center for the Study of Drug Development established an annual user fee survey of over 50 major pharmaceutical and biotechnology firms with operations in the United States. As of December 31, 1996, survey data have been collected for fiscal years 1994, 1995, and 1996. Data from a cohort of user fee drugs approved in 1993-1996 were compared with data from all non-user fee drugs approved in 1990-1992. Whereas the mean approval phase (NDA submission to approval) for the user fee drugs was considerably shorter than that for the non-user fee drugs (14.5 versus 31.0 months, respectively), the mean clinical phase (investigational new drug application filing to NDA submission) was somewhat longer (88.0 versus 81.1 months, respectively). As a result, the total time from the start of clinical testing to drug approval (total phase) was only marginally shorter for the user fee drugs (102.0 versus 112.1 months, respectively). These results highlight the need for efforts to reduce lengthy drug development times.

Biotechnology↗
PubMed2000

Toxicokinetics in drug development: an overview of toxicokinetic application in the development of PNU-101017, an anxiolytic drug candidate.

The importance of toxicokinetics in the drug development has been identified in the last decade. The main objectives of toxicokinetics in general are to define the drug bioavailability, dose proportionality, gender differences, and species differences in pharmacokinetics and metabolism, from which the target organ toxicity can be predicted and the safety doses in the first human clinical trial can be established. Toxicokinetic studies may also serve as a tool for the toxicologic pathologist in understanding models used for predicting and assessing drug-related toxic response. Toxicokinetics/toxicodynamics are critical to investigating the toxicological mechanism and understanding the comparative toxicity between animals and humans. This report presents an overview of the application of toxicokinetics and its impact in the drug development of PNU-101017, a drug candidate for the treatment of anxioety. Serial specifically designed toxicokinetic studies identified a steep dose-response relationship between the clinical signs and PNU-101017 serum or CSF concentrations, characterized the centrally mediated respiratory depression as the toxicity leading to the lethality, and demonstrated marked species differences in the sensitivity to the toxic effects. These findings lead to a termination of PNU-101017 development due to the safety concern in humans.

Animals↗
PubMedDate not supplied

Development and use of biomarkers in oncology drug development.

Successful development and use of biomarkers will improve the productivity of oncology drug development. Recognition of the importance of biomarkers for speeding drug development is reflected in the precise definitions and concepts proposed by an NIH Working Group to standardize terminology and promote a more coherent and systematic approach to the development and use of biomarkers. Potential clinical biomarkers of drug efficacy are often identified through pre-clinical studies or basic research. Identification of potential biomarkers for use in oncology is moving rapidly forward through continuing advances in clinical imaging technologies, especially molecular and functional imaging. Other rapid advances are a product of the growing availability of new scientific reagents for established technologies and of high-throughput genomic and proteomic technologies that can generate hundreds of potential biomarkers for further evaluation. In certain cases, conventional clinical diagnostic techniques or assays can be adapted for use in pre-clinical models to evaluate their ability to serve as biomarkers for predicting clinical responses to new drug candidates. Evaluation (pre-clinical and clinical) of a potential biomarker is often the longest stage of biomarker development, and standards for evaluation or validation depend on the intended use and stage of clinical development. Biomarkers verified for use in preclinical studies can be used to help select appropriate animal models and lead compounds. Biomarkers verified for use in clinical trials can confirm a drug's pharmacological or biological mechanism of action, guide protocol design, aid patient and dose selection, and help to minimize safety risks. Oncology drug development can be optimized by using a tiered set of clinical biomarkers that predict compound efficacy and safety with increasing confidence at each rise in tier thereby aiding corporate decision-making about advancing compounds. In oncology, a special class of extensively evaluated biomarkers of efficacy (surrogate endpoints) that generally correlate with desired clinical outcomes can be used as a basis for corporate decisions as well as for gaining accelerated provisional regulatory approval of a drug.

Animals↗
PubMed2007

Integration of pediatric aspects into the general drug development process.

Drug treatment of children is today less regularly based on formal clinical testing than adults. This has led to concerns regarding the safety and efficacy of pediatric medicines and resulted in public action in the United States and the European Union. The reasons for the increasing awareness include better understanding of child physiology, increased trust in GCP (good clinical practice), improved treatment of several severe childhood diseases, a changed view of the child as a subject in society, and more. The US has successfully introduced pediatric legislation that facilitates participation of children in phar maceutical innovation, and comparable approaches are now being discussed in Europe and Japan. While the outcome of the EU pediatric regulation in the near future is still open, the US pediatric legislation has been highly successful over the past 8 years and will be revised before it expires in September 2007. Innovative drugs are today being developed by global pharmaceutical companies. Adding pediatric aspects to this development process is a complex task where companies need to build up internal competency. Bureaucratic procedures that could be harmful to the companies' economic fundaments need to be avoided, and an appropriate ethical framework is required. This needs to be addressed by all partners in healthcare, including regulatory authorities, the pharmaceutical industry, pediatricians, patients and others in a sense of shared responsibility.

Chemistry, Pharmaceutical↗
PubMed2002

Regulatory and drug development issues related to female sexual dysfunction.

Following the approval of sildenalfil for the treatment of erectile dysfunction, an increased awareness of and interest in female sexual dysfunction developed on the part of the academic and research communities as well as the pharmaceutical industry. This article will focus on regulatory issues related to the development of drug products to treat female sexual dysfunction and will describe a recently published drug development guidance document for this indication.

Clinical Trials as Topic↗
PubMed2005

Non-linear mixed effects modeling - from methodology and software development to driving implementation in drug development science.

Few scientific contributions have made significant impact unless there was a champion who had the vision to see the potential for its use in seemingly disparate areas-and who then drove active implementation. In this paper, we present a historical summary of the development of non-linear mixed effects (NLME) modeling up to the more recent extensions of this statistical methodology. The paper places strong emphasis on the pivotal role played by Lewis B. Sheiner (1940-2004), who used this statistical methodology to elucidate solutions to real problems identified in clinical practice and in medical research and on how he drove implementation of the proposed solutions. A succinct overview of the evolution of the NLME modeling methodology is presented as well as ideas on how its expansion helped to provide guidance for a more scientific view of (model-based) drug development that reduces empiricism in favor of critical quantitative thinking and decision making.

Algorithms↗
PubMed2006

The role of modern biology and medicine in drug development in academia and industry.

This symposium addresses careers in drug development in industry; the performance of translational research by academia, industry, and both; and numerous factors pertinent to alliances essential to drug discovery and development. Drug development is a complex process that regularly involves effective collaborations between academic and physician scientists and industry. There are specific occupational factors affecting recruitment of scientists and physicians in drug development programs in industry; ideal backgrounds for successful applicants for positions in industry in drug development; ethical and regulatory considerations particularly germane to the performance of scientists and physicians in drug development programs in industry and at universities; and particular gratifications available to scientists in industry working on drug development. Both similarities and differences characterize the performance of translational research in industry compared with academia. In industry, logistic, operational, and scientific oversight is complex, especially because it often involves relationships with clinical enterprises outside of the corporation. The process is long and arduous from formulation of a good idea in discovery to acceptance of a novel drug in the marketplace. Collaborations and partnerships by industry often involving academia and confrontation of multiple issues are pivotal.

Academic Medical Centers↗
PubMed2004

Hierarchical models for tumor xenograft experiments in drug development.

In cancer drug development, demonstrated anticancer activity in animal models is an important step to bring a promising compound to clinic. Proper design and analysis of experiments using laboratory animals have received increasing attention recently. These experiments involve informatively censored longitudinal data with small samples. The problem is further complicated because of order constraints due to the intrinsic growth of control tumors without treatment. This article proposes a Bayesian hierarchical model to analyze informatively censored longitudinal data while accounting for the parameter constraints and providing valid small sample inference. We adopt a noniterative sampling approach, the inverse Bayes formulae (IBF) sampler, to generate independent posterior samples, which avoids convergence problems associated with Markov chain Monte-Carlo methods. To effectively deal with the restricted parameter problem, we use a linear transformation to simplify the constraints and exploit the IBF method to generate random samples from truncated multivariate normal distributions. Because diffuse priors are used, the posterior modes approximate the maximum likelihood estimates well, and the hierarchical model can be considered as an extended mixed-effects model. A real xenograft experiment on a new treatment is analyzed by using the proposed method.

Algorithms↗
PubMed2006

Ethical challenges in neonatal research: Summary report of the ethics group of the newborn drug development initiative.

BACKGROUND: The Newborn Drug Development Initiative (NDDI) was established to address the lack of substantive data supporting efficacy and safety of drugs in the neonate. OBJECTIVE: This commentary summarizes some of the ethical issues involved in neonatal drug development. METHODS: At the NDDI workshop held March 29 and 30, 2004, in Baltimore, Maryland, members of the Ethics Group were dispersed among the subspecialty groups before convening to discuss common ethical themes. The Ethics Group then met together to identify and discuss those ethical themes that were both important and shared among the groups. These themes are discussed and illustrated with the other NDDI group reports. This workshop was cosponsored by the National Institute of Child Health and Human Development and the US Food and Drug Administration. RESULTS: Neonatal drug research is scientifically and ethically necessary to establish the efficacy and safety of drugs widely used in newborn medicine. However, research involving neonates must be carefully designed to balance potential risks and benefits, with consideration given to the component analysis of risk. The protocols proposed by the NDDI groups would be considered greater than minimal risk and offering prospect for direct benefit, thus adhering to the Department of Health and Human Services' pediatric research regulations (Subpart D). The NDDI groups all proposed randomized controlled clinical trials, with careful attention to scientifically and ethically appropriate control groups. Multiple regulatory bodies have affirmed that in the absence of proven effective treatment or when a proven treatment offers marginal benefits, study designs with placebo controls are ethical. Obtaining parental permission is a complex issue, with a paucity of evidence describing the feasibility of informed and voluntary consent under conditions of duress and a short therapeutic window. The Subpart D regulations offer sufficient protection to critically ill neonates. The application of the revised Subpart B regulations would restrict the use of a waiver of consent for minimal risk research and for emergency research, and would not allow research that offers no direct benefit and no more than a minor increase over minimal risk. CONCLUSIONS: Multisite collaboration involving standards of care and institutional review board procedures may be important for establishing scientific and ethical consistency. Ongoing dialogue among researchers, clinicians, parents, and other interested parties is essential to promoting ethically and scientifically sound neonatal clinical research.

Biomedical Research↗
PubMed2005

Investigation of toxic metabolites during drug development.

Adverse drug reactions (ADRs) are a significant human health problem. Any organ system can be affected, including the liver, skin and kidney. Drug-induced liver injury is the most frequent reason for the withdrawal of an approved drug from the market, and it also accounts for up to 50% of cases of acute liver failure. The clinical picture is often diverse, even for the same drug. Mild, asymptomatic effects occur at a relatively high frequency with a number of drugs. Idiosyncratic toxicity is rare but potentially life-threatening. Many serious ADRs that occur in man are unpredictable from routine pathology and clinical chemistry in laboratory animals and are therefore poorly understood. The drug metabolist can determine the propensity of a novel chemical entity to either accumulate in the hepatocyte or undergo bioactivation in numerous model systems, from expressed enzymes, genetically engineered cells to whole animals. Bioactivation can be measured using trapping experiments with model nucleophiles or by measurement of non-specific covalent binding. The chemistry of the process is defined and the medicinal chemist can address the issue by seeking a metabolically stable pharmacophore to replace the potential toxicophore. However, we require a more fundamental understanding of the role of drug chemistry and biochemistry in ADRs. This requires knowledge of the ultimate toxin, signalling in cell defense and the sequence of molecular events, which ultimately lead to cell and tissue damage. It is imperative that such studies have a clinical level, but then translated into laboratory-based molecular studies. This will provide a deeper understanding of potential toxicophores for drug design and define candidate genes for pharmacogenomic approaches to individualized medicines.

Animals↗
PubMed2003

An overview of drug development in the United States and current challenges.

Drug development in the United States has undergone many changes in the past 25 years, but relatively few fully realize the complexities involved in developing a new drug. Once a promising compound is identified, it must undergo preclinical testing, have an Investigational New Drug Application filed with the U.S. Food and Drug Administration (FDA), and proceed through clinical testing. When sufficient information is gained, a marketing application is filed with the FDA, who identifies it as a New Drug Application for drugs or a Biologics License Application for biologics. After FDA review and approval, postmarketing studies are frequently performed. The FDA and Congress have undertaken several initiatives to expand access and to accelerate drug development and review of investigational drugs for life-threatening and/or serious illnesses. Although the ultimate goal is to bring safer and more effective medical products to patients in a timely manner, multiple challenges face those who participate in drug development.

Clinical Trials as Topic↗
PubMed2002

The EORTC and drug development. European Organisation for Research and Treatment of Cancer.

Early drug development at EORTC has always been subject to structural changes to adapt to the rapid changes that occur in oncological drug development. The expertise of early drug developers has always been cross-fertilised with disease-/tumour-oriented groups and also backwards to the laboratory research groups. This results in the establishment of a solid and dedicated network of medical oncologists with focused expertise in cancer drug development. The EORTC Data Center is fully equipped with all expertise to support clinical research activities and includes regulatory, safety, and quality assurance desks. The EORTC New Drug development Programme (NDDP) provides methodological expertise to early clinical trials and coordinates phase I and phase II studies addressing various approaches. Through NDDP, the early clinical groups and the disease-/tumour-oriented groups have created specific networks to address early drug development in specific tumour types. This results in very efficient networks which have the resources and the patients to address and conduct challenging clinical trials in a standardised fashion ensuring the highest standards in cancer treatment.

Antineoplastic Agents↗
PubMed1997

Leukemia: A model for drug development.

Early attempts at preclinical model development for cancer drug development relied heavily on mouse leukemias and lymphomas to detect agents with antitumor activity. These models were applied clinically, and the concepts of combination chemotherapy, remission induction, and maintenance treatment all developed in leukemia. Subsequently, the predominant impact of cytogenetics on probability of response to treatment and survival was first illustrated in leukemia. The power of a single drug to change the natural history of a disease was noted in acute myelogenous leukemia, in which a previously incurable disease was rendered potentially curable with 1-beta-D-arabinofuranosylcytosine. Additional studies illustrated the exquisite relationship between karyotype and response to specific agents. The ability to achieve a high proportion of complete remissions and to control the complication of intravascular coagulation, acute promyelocytic was noted with all-trans retinoic acid. The concept that new drug activity would only be demonstrated in patients with minimal prior therapy has been challenged by the curative potential of a number of agents in far-advanced hairy cell leukemia. In addition, fludarabine monophosphate (Fludara) was sufficiently active in advanced refractory patients that approval for this agent in chronic lymphocytic leukemia was granted by the Food and Drug Administration without comparative clinical trials. Fludara was initially a drug with limited therapeutic range, active only in indolent lymphoproliferative disorders. However, understanding of the multiple biochemical actions of this agent has led to its use in combinations with 1-beta-D-arabinofuranosylcytosine in acute myelogenous leukemia and myelodysplastic syndrome and with DNA active agents such as novantrone and cyclophosphamide in other lymphoproliferative disorders. The understanding of the various actions of this drug gives rise to a wide range of possibilities for biochemical modulation with agents active in solid tumors. The evolution of this understanding of the new role of Fludara has occurred over a period of 10 years. A drug with similar potential in the next decade is compound 506U78, an analogue of arabinosyl guanosine. This agent has potent activity in acute T-cell leukemia. Because it shares many of the activities of Fludara in interfering with enzyme systems important in DNA and RNA synthesis and DNA repair, it is likely that this agent will also have a wider scope than is presently obvious. The unique accessibility of leukemia cells for study has allowed hematologists to understand more fully the range of activities of new agents and has led to important new concepts in the area of drug development.

Adult↗
PubMed2004

Pharmacogenetics and drug development: the path to safer and more effective drugs.

Pharmacogenetics provides opportunities for informed decision-making along the pharmaceutical pipeline. There is a growing literature of retrospective studies of marketed medicines that describe efficacy or safety on the basis of patient genotypes. These studies emphasize the potential prospective use of genome information to enhance success in finding new medicines. An example of a prospective efficacy pharmacogenetic Phase-IIA proof-of-concept study is described. Inserting a rapidly performed efficacy pharmacogenetic step after initial clinical data are obtained can provide confidence for a commitment to full drug development. The rapid identification of adverse events during and after drug development using genomic mapping tools is also reviewed.

Animals↗
PubMed2002

Barriers to Alzheimer disease drug discovery and drug development in the pharmaceutical industry.

The drug development process in the pharmaceutical industry has evolved from separate programs, specific for each country, into one coordinated, global development scheme. As a result, such a development program must meet regulatory requirements for all countries in which approval for the new drug will be sought. Barriers to Alzheimer disease (AD) drug discovery and development in the pharmaceutical industry can be categorized as (1) regulatory, (2) logistical, and (3) drug development issues. Some of the regulatory barriers could be overcome by international harmonization of guidelines for the development of antidementia drugs. The logistical issues can be reduced through international collaboration in the conduct of clinical studies, and the developmental issues can be addressed by using an expedited drug development plan that not only can reduce the time but also the resources required to develop the drug.

Alzheimer Disease↗
PubMed2002

Biomedical informatics: the future for drug development.

The problems that exist in drug development are well documented: the limited number of new chemical entities, increased cost of drug development, problems in clinical trials (Phase III), product launches that result in withdrawal, and pressure to reduce the cost of pharmaceuticals from the government. It appears that the promise of genomics has not yet reached its full potential to impact the process. This review identifies the need to develop and implement the area of biomedical informatics for increased success in drug development and healthcare in general.

Aging↗