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PubMed2006

Imaging biomarkers as surrogate endpoints for drug development.

The employment of biomarkers (including imaging biomarkers, especially PET) in drug development has gained increasing attention during recent years. This has been partly stimulated by the hope that the integration of biomarkers into drug development programmes may be a means to increase the efficiency and effectiveness of the drug development process by early identification of promising drug candidates--thereby counteracting the rising costs of drug development. More importantly, however, the interest in biomarkers for drug development is the logical consequence of recent advances in biosciences and medicine which are leading to target-specific treatments in the framework of "personalized medicine". A considerable proportion of target-specific drugs will show effects in subgroups of patients only. Biomarkers are a means to identify potential responders, or patient subgroups at risk for specific side-effects. Biomarkers are used in early drug development in the context of translational medicine to gain information about the drug's potential in different patient groups and disease states. The information obtained at this stage is mainly important for designing subsequent clinical trials and to identify promising drug candidates. Biomarkers in later phases of clinical development may--if properly validated--serve as surrogate endpoints for clinical outcomes. Regulatory agencies in the EU and the USA have facilitated the use of biomarkers early in the development process. The validation of biomarkers as surrogate endpoints is part of FDA's "critical path initiative".

Biomarkers↗

PubMed2000

[Understanding of molecular pathogenesis of Alzheimer's disease: implications for drug development].

Recent advances in the knowledge about Alzheimer pathogenesis indicate several tactics for the development of drugs to treat Alzheimer's disease. Firstly, the function of presenilin, the causative gene for most familial Alzheimer's disease, has been demonstrated to be the protease in the Notch signaling system. Presenilin cleaves the transmembrane domain of the C-terminal fragment of the Notch-1 molecule, which is generated by proteolysis by furin-like proteases. APP is also cleaved by presenilin at the gamma cut site, implying that presenilin is gamma-secretase itself or at least closely functioning with gamma-secretase. A recent paper has demonstrated that immunization of APP transgenic mouse with amyloid beta 42 may decrease and prevent amyloid deposition in brain tissue. This unique and novel approach may open the new tactics for developing anti-dementia drugs. Another important finding comes from the identification of the function of prolyl isomerase. It is demonstrated that pin 1, intra-nuclear prolyl isomerase, can restore the microtubule binding capacity of phosphorylated tau, which clearly shows a solid strategy for developing drugs for preventing neuronal degeneration.

Alzheimer Disease↗

PubMed2006

Successful gastrointestinal cancer drug development.

A large number of new drugs have been approved over the past 10 years for the treatment of both common and rare gastrointestinal malignancies. Many other agents, however, have failed at a great cost of financial and patient resources. Drug development must identify potentially active compounds and reveal the most effective and least toxic manner and population in which to administer compounds. Pharmaceutical companies must show therapeutic efficacy and achieve regulatory approval as well as success in the marketplace to recoup their investment. It is worth examining successful examples of drug development such as imatinib, delayed but eventually successful agents such as oxaliplatin, as well as failures such as SU-5416, and applying those lessons to current and future drug development.

Antineoplastic Agents↗

PubMed2003

Predictive toxicology in drug development.

A critical issue in drug development remains the failure to identify toxicological problems in new chemical entities sufficiently early in development to avoid the expense of terminating drugs in late-stage clinical development. The Society of Chemical Industry's BioActive Sciences Group arranged a one-day meeting in London, United Kingdom, on February 27, 2003, devoted to progress in the development of in silico modeling and expert systems. The meeting provided an assessment of the progress that has been made in the development of models that can be used to evaluate chemical libraries at the design stage, or to predict potential toxic effects while chemical projects are still in the lead optimization stage. Although success in developing such models might reduce the number of new chemical entities progressing to clinical development, its potential for reducing the high attrition rate (approximately 50%) in late-stage (phase II and later) clinical development could produce a substantial cost saving and might also shorten the time frame of drug development.

Drug Design↗

PubMed1996

Role of pharmacokinetic-pharmacodynamic principles in rational and cost-effective drug development.

An important goal of drug development is to define dose and concentration-response relationships for new drugs and biologics. Such critical information from controlled clinical trials can provide primary evidence of efficacy and safety and an informative database for devising dosing instructions for clinical use. This article describes applications of pharmacologic principles [pharmacokinetic-pharmacodynamic (PK-PD)] and modeling methods for drugs in which the evaluation process is guided by and/or identifies significant PK and/or PD variability in drug response. In the case of the recently registered immunosuppressive agent, tacrolimus, preclinical PK-PD in model systems can be used to rationally design safe and effective immunomodulatory dosing regimens for phase 1 clinical studies. Furthermore, a study design based on concentration control guided by a novel artificial intelligence modeling system (AIMS) can be efficiently applied to conduct randomized clinical trials in auto-immunity and to implement cost-effective therapeutic drug monitoring of tacrolimus and cyclosporine in clinical transplantation. In the case of a cardioselective beta-adrenergic blocking agent, betaxolol, marketed for essential hypertension, population PD modeling can be shown to be a more efficient method for estimating dose response compared with standard statistical tests. Using a sigmoid Emax PD model, only a fraction (40 of 300) of the randomized patients was needed to demonstrate dose response. Therefore, two methods, i.e., PD modeling of dose response and AIMS-guided dosing, can achieve significant cost benefits for drug developers, patient care, and the health care system.

Artificial Intelligence↗

PubMedDate not supplied

Drug development in India.

The drug development process is complex. It takes about 5--7 years before a compound synthesised in the laboratory can be made available the general practitioner for therapeutic usage. Furthermore, only a few of the compounds developed and synthesised in the laboratory with possible hope of therapeutic application, satisfactorily pass through all the stages of development process. Complete development of a new drug may cost 10--15 million rupees and needs the technical expertise of the highest order. Obviously this calls for tremendous financial and human resources. It is, therefore, imperative that research investments are properly planned and wisely made. It should be a well coordinated team effort with deep considerations of economic management. Clinical pharmacology plays an essential and a meaningful role in this process and its interactions with the pharmaceutical industry should be such as to ensure therapeutic efficacy and safety of new drugs.

Animals↗

PubMed1997

An evaluation of the integration of pharmacokinetic and pharmacodynamic principles in clinical drug development. Experience within Hoffmann La Roche.

The integration of pharmacokinetic and pharmacodynamic principles into drug development has been proposed as a way of making it more rational and efficient. The use of these principles in drug development to make scientific and strategic decisions is defined as the 'pharmacokinetic-pharmacodynamic guided approach to drug development'. The objectives of this survey were: (i) to assess the extent the pharmacokinetic-pharmacodynamic guided approach to drug development has been used in a large multinational pharmaceutical company: (ii) to evaluate the impact of pharmacokinetic and/or pharmacodynamic results on clinical drug development; and (iii) to identify factors which prevented the full application of the pharmacokinetic-pharmacodynamic guided approach. This was done by looking at 18 projects in the current development portfolio at Hoffman La Roche and evaluating the use of this approach by interviewing the responsible clinical pharmacologist using a standardised questionnaire. (i) Benefits from using the pharmacokinetic-pharmacodynamic guided approach were reported in every project, independent of development phase and therapeutic area. This approach was more extensively used in the recent projects. The selection of dosages in clinical studies was found to be the most important application of pharmacokinetic-pharmacodynamic results in terms of an impact on drug development. (ii) Time savings, up to several months, could be quantified in 8 projects during the entry-into-man studies and in 6 projects during the phase II or III studies. In 4 projects, 1 clinical study was avoided. (iii) The most important scientific factor preventing the full application of the approach was the lack of knowledge on the predictive value of the pharmacodynamic or surrogate marker for effect (6 projects). The results of the survey have shown that the use of the pharmacokinetic-pharmacodynamic guided approach has contributed to making clinical drug development more rational and more efficient. Opportunities to apply the pharmacokinetic-pharmacodynamic approach should be identified in each project and a project specific strategy for the pharmacokinetic-pharmacodynamic guided approach should be defined during phase 0 of drug development.

Cost-Benefit Analysis↗

PubMed2005

Emerging applications of kinetic biomarkers in preclinical and clinical drug development.

The cost of drug discovery and development is increasing, while the rate of new drug approvals is declining. In contrast to major technological advances with in silico and in vitro screening tools, there have been almost no advances in the tools available for establishing the actions of agents in the complex biochemical networks characteristic of fully assembled living systems. The resulting poor capacity to predict clinical response underlies the high attrition rate of leads at every step of drug development. A potential solution would be provided by kinetic biomarkers (in vivo measurement of fluxes though the key pathways that drive disease processes and therapeutic response). Novel approaches using stable isotope labeling with mass spectrometric analysis have recently emerged for measuring molecular kinetics relevant to drug targets with some applications to drug development. This review discusses the general principles of kinetic biomarkers, providing examples where kinetics have generated meaningful insights into drug activity and highlighting areas where the application of kinetic biomarkers may be particularly useful for future drug discovery and development. Stable isotope mass spectrometric technologies may provide a parallel efficiency for converting molecules into approved drugs with sufficient throughput and reproducibility to maintain pace with the modern engine for generating leads.

Animals↗

PubMed2007

2nd Ophthalmic Drug Development and Delivery Summit.

The Second Annual Ophthalmic Drug Development and Delivery Summit was held on 19 - 20 September 2006 in San Diego, CA, US. The 2-day symposium, having a highly focused theme, was packed with cutting-edge science, insightful overviews and networking opportunities. With a total of 11 recognized specialists presenting reviews and recent results in the advancement of ocular drug development and delivery, the invited expert speaking faculty presented the latest preclinical and clinical developments in novel ophthalmic therapies and drug delivery technology. The talks included various case studies from primary investigators and pharmaceutical companies touching upon key topics: updates on current clinical trials, study design issues, sustained delivery to the eye, views of the vitreous space as a drug reservoir, new developments in dry and wet age-related macular degeneration and diabetic retinopathy, formulation for optimal drug delivery, differences and similarities in developing drugs for the eye compared with other targets, pharmacokinetics, novel ocular delivery methods and devices, delivery of proteins and peptides, focal drug delivery, non-invasive drug delivery to the eye, neuroprotection challenges, in vitro and in vivo models for glaucoma and angiogenesis for early efficacy estimation, and toxicology. Overall, the 2-day annual symposium continues to grow as an efficient platform for fostering discussion on a range of scientific topics and challenges and avenues for building collaborative partnerships in ophthalmic drug development.

Animals↗

PubMed2007

Using exposure-response and biomarkers to streamline early drug development.

Biomarkers (BMs) are biological measures of PD drug effects or disease markers that may represent clinically significant patient outcomes, either efficacy or toxicity. Their use in drug development, especially as an integral part of PK/PD modeling, has become a popular strategy for optimizing development time and resources. This approach supports quantitative integration of information across different species and throughout the clinical phases I-III. If the BM is based on the mechanism of action (MOA) of the drug, it is expected to follow an exposure-response relationship (E-R). If it is also involved in causal pathways in the pathophysiology of the disease (POD), it may become a surrogate marker (SM). SMs allow prediction of clinical outcomes for different dosing regimens of drug candidates and patient individualization of treatment in clinical practice. Appropriate evaluation of BMs by mechanistic, epidemiological, and clinical pharmacology studies as part of the drug development process allow scientists to establish clinically relevant ER. In early drug development, known ERs for BMs facilitate translation of in vitro findings to in vivo consequences, interspecies PK/PD comparisons, and streamlining of dose-finding phase I and II studies, as well as assessment of new dosing regimen candidates for their likely clinical efficacy and safety, extrapolation of clinical study results to special populations (e.g., pediatrics), and interpretation of exposure differences found in food, drug interaction and special populations studies. Recently, two novel BMs, namely, P50, a measure of ex vivo/in vitro whole blood oxygen affinity and S(pO2), i.e., in vivo pulse oximetry, were used in the development of an allosteric synthetic hemoglobin modifier (SAM), efaproxiral, as PD endpoints; these BMs are based on the MOA of SAMs. Early use of these BMs established excellent in vitro/in vivo PK/PD correlations, appropriate interspecies PK and PD scaling as well as PD-guided phase I and II dose-finding studies. This approach allowed appropriate translation of in vitro and preclinical information along with early identification of sources of PK/PD variability. Frontloading drug development with the identification and use of mechanism-based (MOA/POD) BMs constitutes a rational strategy to quantitatively integrate PK/PD information and optimize dose finding.

Allosteric Site↗

PubMedDate not supplied

A forecasting approach to accelerate drug development.

The clinical phase of drug development should be concluded sooner and at a lower cost if primarily only the pivotal and supportive studies were to be conducted. Such improved efficiency requires development of a decision support system that delivers five new capabilities: (i) it enables one to predict a result of a clinical study and to identify those studies that are expected to have an acceptable probability of success; (ii) it will allow one to optimally utilize available pharmacokinetic and pharmacodynamic (PK/PD) data and improve its predictive capability as more data become available; (iii) it will enable one to project useful population results, not just mean results; (iv) predictions will be accompanied by a measure of reliability; and (v) expected initial clinical results will be predictable from animal and related drug class data. With such a tool population targets could be specified very early in the drug development programme, challenged, and then rationally revised at each step during the development process. This report describes progress in developing and testing a clinical trials Forecaster, a prototype for such a system. The Forecaster generates estimates of the joint density for a population of combined PK/PD parameters. That population then serves as a surrogate for the population of individuals. When the resulting joint density is sampled, the obtained sets of parameters may be used to generate data that is statistically indistinguishable from the original experimental data. Such simulated data can be used to validate assumptions, and make inferences on specified population targets that are accompanied by a measure of prediction reliability. We demonstrate use of the forecaster by employing N = 22 PK/PD parameter sets for an orally administered analgesic.

Bias↗

PubMed2003

Positron emission tomography microdosing: a new concept with application in tracer and early clinical drug development.

The realisation that new chemical entities under development as drug candidates fail in three of four cases in clinical trials, together with increased costs and increased demands of reducing preclinical animal experiments, have promoted concepts for improvement of early screening procedures in humans. Positron emission tomography (PET) is a non-invasive imaging technology, which makes it possible to determine drug distribution and concentration in vivo in man with the drug labelled with a positron-emitting radionuclide that does not change the biochemical properties. Recently, developments in the field of rapid synthesis of organic compounds labelled with positron-emitting radionuclides have allowed a substantial number of new drug candidates to be labelled and potentially used as probes in PET studies. Together, these factors led to the logical conclusion that early PET studies, performed with very low drug doses-PET-microdosing-could be included in the drug development process as one means for selection or rejection of compounds based on performance in vivo in man. Another important option of PET, to evaluate drug interaction with a target, utilising a PET tracer specific for this target, necessitates a more rapid development of such PET methodology and validations in humans. Since only very low amounts of drugs are used in PET-microdosing studies, the safety requirements should be reduced relative to the safety requirements needed for therapeutic doses. In the following, a methodological scrutinising of the concept is presented. A complete pre-clinical package including limited toxicity assessment is proposed as a base for the regulatory framework of the PET-microdosing concept.

Animals↗

PubMed2000

The roles of the pharmaceutical industry and drug development in dermatology and dermatologic health care.

Drug development is becoming shorter, more high-tech and strategic, more costly, and more complicated. The pharmaceutical, biotech, and cosmetic companies, along with regulatory agencies such as the FDA, are struggling to cope with and master the scientific, medical, and economic implications of this new environment. There are rapidly growing new classes of drugs, including biologicals, genomics, antibodies, and novel receptor-ligand antagonists. Dermatologic drug development has several idiosyncrasies, including the vehicle in topical drugs. Development for dermatology is much cheaper than for other therapeutic areas but also generates much less sales. The pharmaceutical industry's search for blockbusters threatens to leave dermatology without access to these new technologies, therapeutic modalities, and drug classes. The pharmaceutical industry is interested, invested, and intertwined, at many different levels, in the efforts and practices of academic dermatology, dermatology specialty organizations, and clinical dermatologists.

Cosmetics↗

PubMed2005

The impact of FDA guidance on pharmacogenomic data submissions on drug development.

After a long wait, the US Food and Drug Administration (FDA) finally released the much anticipated 'Guidance on Pharmacogenomic Data Submissions on Drug Development' in March 2005, but what impact will this have on the drug industry as a whole? It is becoming increasingly apparent that the field of pharmacogenomics can add value to both clinical trial design and the drug development process, but uptake by the pharmaceutical industry has so far been variable between companies. The opinion of the FDA is that the use of pharmacogenomics in drug development is a 'good thing' and one that it wishes to promote, hence, this new guidance is designed to assist drug companies to adopt pharmacogenomic technology in clinical development, and covers both targeted and exploratory aspects. While targeted pharmacogenomics must be included as part of any regulatory submission, exploratory approaches may be submitted voluntarily with assurances from the FDA that any such submissions will not be used to make regulatory decisions. With this regulatory framework now in place it is only a matter of time before it is known how the industry reacts and the impact it will have on drug development.

Databases, Genetic↗

PubMed2000

Pharmacokinetic/pharmacodynamic modeling in drug development.

We propose a framework for considering the role of pharmacokinetic/pharmacodynamic modeling in drug development and an appraisal of its current and potential impact on that activity. After some introduction, definitions, and background information on drug development, we discuss subject-matter models that underlie pharmacokinetic/pharmacodynamic modeling and show how they determine appropriate statistical models. We discuss the broad role modeling can play in drug development, enhancing primarily the "learning" steps, i.e. acquiring the information needed for the label and for planning efficient confirmatory clinical trials. Examples of past applications of modeling to drug development are presented in tabular form, followed by a discussion of some practical issues in application. Modeling will not reach its potential utility until it is manifest as a visible and separate work unit within a drug development program. We suggest that that work unit is the "in numero" study: a protocol-driven exercise designed to extract additional information, and/or answer a specific drug-development question, through an integrated model-based (meta-) analysis of existent raw data, often pooled across separate (clinical) studies.

Animals↗

PubMed2002

Biomarkers and surrogate endpoints: how and when might they impact drug development?

As the pharmaceutical industry starts developing novel molecules developed based on molecular biology principles and a better understanding of the human genome, it becomes increasingly important to develop early indicators of activity and/or toxicity. Biomarkers are measurements based on molecular pharmacology and/or pathophysiology of the disease being evaluated that may assist with decision-making in various phases of drug development. The utility of biomarkers in the development of drugs is described in this review. Additionally, the utility of pharmacokinetic data in drug development is described. Development of biomarkers may help reduce the cost of drug development by allowing key decisions earlier in the drug development process. Additionally, biomarkers may be used to select patients who have a high likelihood of benefit or they could be used by clinicians to evaluate the potential for efficacy after start of treatment.

Biomarkers↗

PubMed2002

Pharmacogenomics in anticoagulant drug development.

The emergence of pharmacogenomic-guided anticoagulant drug development has unraveled novel approaches in the management of patients and ensured individualized therapy to one and all. Gene expression profiling will be useful in the diagnoses of various diseases, in preclinical phases of drug development and in developing markers for adverse drug reactions and desired pharmacological effects. Hence, the adverse drug reactions can be avoided by withdrawing a particular drug. Through cheminformatics, decisions could be made in anticoagulant drug discovery, tailored to the individual needs of the patient at the right dosage and right time. As the human genome is now completely mapped, gene-based single nucleotide polymorphism will be valuable in the diagnosis of diseases. In this review, various polymorphism of coagulation factors will be discussed. Newer anticoagulant drugs could be withdrawn from drug discovery and development pipelines should they exhibit hepatic metabolism requiring CYP450 enzymes known to manifest single nucleotide polymorphism resulting in adverse drug reactions. Pharmacogenomics and cheminformatics should be incorporated in the current study designs of prospective clinical trials. Pharmacogenomic and pharmacogenetic data should be included in the Investigational New Drug (IND) applications, which would enable the FDA to better understand its true impact on pharmacoeconomics. Pharmacogenomics will eventually revolutionize anticoagulant drug development and future practice of medicine.

Animals↗

PubMedDate not supplied

Pharmacometrics: modelling and simulation tools to improve decision making in clinical drug development.

There is broad recognition within the pharmaceutical industry that the drug development process, especially the clinical part of it, needs considerable improvement to cope with rapid changes in research and health care environments. Modelling and simulation are mathematically founded techniques that have been used extensively and for a long time in other areas than the pharmaceutical industry (e.g. automobile, aerospace) to design and develop products more efficiently. Both modelling and simulation rely on the use of (mathematical and statistical) models which are essentially simplified descriptions of complex systems under investigation. It has been proposed to integrate pharmacokinetic (PK) and pharmacodynamic (PD) principles into drug development to make it more rational and efficient. There is evidence from a survey on 18 development projects that a PK/PD guided approach can contribute to streamline the drug development process. This approach extensively relies on PK/PD models describing the relationships among dose, concentration (and more generally exposure), and responses such as surrogate markers, efficacy measures, adverse events. Well documented empirical and physiologically based PK/PD models are becoming available more and more, and there are ongoing efforts to integrate models for disease progression and patient behavior (e.g. compliance) as well. Other types of models which are becoming increasingly important are population PK/PD models which, in addition to the characterization of PK and PD, involve relationships between covariates (i.e. patient characteristics such as age, body weight) and PK/PD parameters. Population models allow to assess and to quantify potential sources of variability in exposure and response in the target population, even under sparse sampling conditions. As will be shown for an anticancer agent, implications of significant covariate effects can be evaluated by computer simulations using the population PK/PD model. Stochastic simulation is widely used as a tool for evaluation of statistical methodology including for example the evaluation of performance of measures for bioequivalence assessment. Recently, it was suggested to expand the use of simulations in support of clinical drug development for predicting outcomes of planned trials. The methodological basis for this approach is provided by (population) PK/PD models together with random sampling techniques. Models for disease progression and behavioral features like compliance, drop-out rates, adverse event dependent dose reductions, etc. have to be added to population PK/PD models in order to mimic the real situation. It will be shown that computer simulation helps to evaluate consequences of design features on safety and efficacy assessment of the drug, enabling identification of statistically valid and practically realisable study designs. For both modelling and simulation a guidance on 'best practices' is currently worked out by a panel of experts comprising representatives from academia, regulatory bodies and industry, thereby providing a necessary condition that model-based analysis and simulation will further contribute to streamlining pharmaceutical drug development processes.

Clinical Trials as Topic↗