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PubMed2006

Imaging and oncologic drug development.

For decades anatomic imaging with computed tomography or magnetic resonance imaging has facilitated drug development in medical oncology by providing quantifiable and objective evidence of response to cancer therapy. In recent years metabolic imaging with [18F]fluorodeoxyglucose-positron emission tomography has added an important component to the oncologist's armamentarium for earlier detection of response that is now widely used and appreciated. These modalities along with ultrasound and optical imaging (bioluminescence, fluorescence, near-infrared imaging, multispectral imaging) have become used increasingly in preclinical studies in animal models to document the effects of genetic alterations on cancer progression or metastases, the detection of minimal residual disease, and response to various therapeutics including radiation, chemotherapy, or biologic agents. The field of molecular imaging offers potential to deliver a variety of probes that can image noninvasively drug targets, drug distribution, cancer gene expression, cell surface receptor or oncoprotein levels, and biomarker predictors of prognosis, therapeutic response, or failure. Some applications are best suited to accelerate preclinical anticancer drug development, whereas other technologies may be directly transferable to the clinic. Efforts are underway to apply noninvasive in vivo imaging to specific preclinical or clinical problems to accelerate progress in the field. Because resources are limited, and patient suffering from failed or ineffective therapy continues, a concerted effort is being made to address these issues. Many simultaneous activities involving academia; the pharmaceutical, device, and biotechnology industries; US Food and Drug Administration; National Cancer Institute; Centers for Medicare and Medicaid Services; and specialized networks sponsored by the National Institutes of Health are beginning to address these issues to develop consensus recommendations and progress in this important area.

Drug Approval↗

PubMedDate not supplied

Implications and consequences of enzyme induction on preclinical and clinical drug development.

1. Enzyme induction has traditionally been studied during drug development to assess the potential of drug entities to interact with concomitant medications and alter their pharmacological effects, and clearly it is an unwanted phenomenon. However, another hurdle caused by induction occurs during preclinical development via the attainment of safety data, obtained by dosing high quantities of compound to species used in toxicology assessment. This review considers the techniques that can now be utilized in drug discovery, their relevance, the pharmacokinetic aspects of this phenomenon, and it discusses the consequences and implications of induction during preclinical and clinical development. 2. It is becoming increasingly routine to employ hepatocyte cultures and novel techniques such as quantitative real-time reverse transcriptase PCR to identify enzyme inducers in vitro. The major challenge is to utilize these in vitro data to predict the consequences of induction in vivo. From an understanding of pharmacokinetic principles and low clinical doses relative to preclinical studies, there is limited potential for induction by a development candidate to significantly alter the pharmacological efficacy of a co-administered drug. 3. The most comprehensive approach when considering induction involves integrating quantitative in vitro data, information on the pharmacokinetic behaviour of the compound and the PK/PD) relationship in order to predict its consequences. The generation of this holistic strategy would enable more detailed and informed decision-making about both the suitability of molecules for development and the development strategy itself.

Animals↗

PubMed1999

Alternative strategies in drug development: clinical pharmacological aspects.

Due to the continuous increase in time and cost of drug development and the considerable amount of resources required by the traditional approach, companies can no longer afford to continue to late phase 3 with drugs which are unlikely to be therapeutically effective. The future challenge must be for the pharmaceutical industry to slash its research and development costs by achieving a significant cut in the attrition rate for drugs entering preclinical and clinical development, and to reduce the development time and to increase the probability of success in later clinical trials by streamlining the development processes. In the 100 years to 1995, the pharmaceutical industry worked on about 500 targets with a limited number of compounds, whereas now, using new technologies like genomics, high throughput screening and combinatorial chemistry, drug companies will see an explosion in the number of targets and leads it can explore. Therefore, a tough selection process for picking candidate compounds out of research and a quick kill process for the candidate, which does not measure up in advanced trials, is mandatory to avoid wasting time, energy and money. To improve the transition from research to development it is necessary to validate new targets, define success criteria for research, integrate bioinformation at every stage in drug discovery, define prerequisites for development, identify the "losers" and select the "winners" early and concentrate efforts on them, and to automate the research and development (R&D) process to optimize resource requirements versus time lines and to ensure effective flow of information from drug discovery to late phase of development. In drug development a deeper understanding of a drugs' action is necessary from animal models and phase I, IIa studies prior to taking the drug further in development. Instead of moving from discovery thorough development phases in sequential steps, drug development should be streamlined combining preclinical and early clinical development as an exploratory stage and phases IIb, III as a confirmatory stage. Preclinical and clinical-pharmacological studies in the exploratory stage of drug development should be designed for decision making in contrast to later clinical trials that require power for proof-of-safety and efficacy. Strategies to improve the quality of decisions in drug development are: the use and integration of new tools and technologies such as pharmacogenomics to improve our knowledge about the origin of the disease and to identify new therapeutic strategies; modelling and simulation of preclinical and clinical trials to bridge the gap between the early stages of the development of a new drug and its potential effects in humans; more sophisticated clinical pharmacokinetics to answer the question if the drug is present at the disease site for a sufficient time and to provide information on concentration-effect-relationships; selecting and evaluating surrogates/biomarkers for safety and efficacy; involvement of the target population as soon as possible; using information technologies to make better use of existing data. The more thorough and profound studies have been carried out during this exploratory stage of development, the earlier a decision can be made on the continuation or discontinuation of further development, thus saving development time and money and assessing and considerably reducing the risk for the patients and increasing the success-rate of the project in the later confirmatory effectiveness trial. Taking responsibility as the link between research and development gives clinical pharmacology a major opportunity to assume a pivotal role in research and development of new drugs. To reach this goal, clinical pharmacology must be fully integrated in the whole process from the candidate selection to its approval.

Chemistry, Pharmaceutical↗

PubMed2004

Spontaneous and genetically engineered animal models; use in preclinical cancer drug development.

The preclinical development of anticancer drugs has been based primarily on the transplantation of murine or human cancers into mice. Alternatives to these transplantation models are animals that naturally develop cancers with features relevant to the human disease. The first group of these models arises in mice that are genetically engineered to develop cancer. The second group includes pet dogs and cats that naturally develop cancer. This review will discuss the use and integration of these spontaneous cancer models into a comprehensive and comparative approach to preclinical drug development. Examples of their successful use and an outline of their relative strengths and weaknesses will be provided.

Animals↗

PubMed2000

Drug discovery, drug development and the emerging world of pharmacogenomics: prospecting for information in a data-rich landscape.

Drug development is a very expensive and inefficient process. Currently, it takes on average 15 years and costs approximately US $500 million to bring a new drug to market, with the pharmaceutical industry spending more than US $20 billion in identifying and developing drugs in 1998. Twenty-two percent of this total was spent on screening assays and toxicity testing. Yet the rapidly accelerating advances in high-throughput technologies, including screening and robotics, combinatorial chemistry, and genomics makes this an extremely data-rich environment. Add to that the new paradigms of pharmacogenomics and 'customized medicine', and the question is, are we helping or hurting our cause? Clearly, interpreting this flood of data and turning it into useful information is our next great hurdle. By extending the pharmacogenomic paradigm to the drug discovery process, this paper intends to put the scope of the problem into context.

Animals↗

PubMed2004

The application of the principles of clinical drug development to pharmacological challenge tests of the serotonergic system.

Pharmacological challenge tests of the serotonergic system have extensively been used during the past 20 years and new tests are in development. It is of crucial importance to standardize challenge tests to ascertain that observed variability is due to the state of the challenged system and not caused by variability of the test itself. This is even more important now that challenge tests increasingly are used in complex studies (e.g. in combination with neuroimaging and in large population studies with repeated tests over time). The Guideline for Good Clinical Practice may be of great help in the standardization of these tests. This is a recently developed guideline for pharmaceutical drug-development, which increasingly is used as a reference for all research in humans. To exemplify the possible usefulness of this approach, we apply it to meta-chlorophenylpiperazine, one of the most commonly used drugs in serotonergic challenge tests. We conclude that much can be learned from the development of this particular challenge. In the discussion, we address general issues that emerged from this review and their relevance to the development of future challenge tests.

Animals↗

PubMed2002

Conflicts of interest in drug development: the practices of Merck & Co., Inc.

Conflicts of interest are common and exist in academia, government, and many industries, including pharmaceutical development. Medical journal editors and others have recently criticized "the pharmaceutical industry," citing concerns over investigator access to data, approaches to analysis of clinical trial data, and publication practices. Merck & Co., Inc. is a global, research-driven pharmaceutical company that discovers, develops, manufactures, and markets a broad range of human and animal health products, directly and through its joint ventures. Although part of its mission is to provide a superior rate of return to its investors, Merck does not believe this creates an irreconcilable conflict of interest, particularly in activities concerning clinical drug development. We employ rigorous scientific methods to design, conduct, analyze, and report results of clinical trials in the development of innovative drugs and vaccines, with a focus on meeting unmet medical needs and with an ethic that puts the interests of the patient first. This article describes Merck's approaches to potential conflicts of interest in drug development, particularly with regard to clinical trials. We believe that proprietary interests of the Company can be respected while observing objectivity and transparency in communicating clinical research results. The standards for the review of manuscripts reporting such trials for peer-reviewed publication should be the same, whether they are from Merck or elsewhere.

Chemistry, Pharmaceutical↗

PubMed1991

Growth factor and oncogene signalling pathways as targets for rational anticancer drug development.

There is a critical need for new targets, in addition to DNA, for anticancer drug development. A recently discovered target is the intracellular signalling pathways that mediate the actions of growth factors and oncogenes on cell proliferation. Two important pathways, the myo-inositol and protein tyrosine kinase signalling pathways are reviewed. Three classes of compounds that modulate myo-inositol signalling are discussed. These are: 1) the D-3-substituted-3-deoxy-myo-inositol analogues that act as antimetabolites of myo-inositol and show selective growth inhibition of some transformed cells; 2) the alkaloid staurosporine that acts as a potent inhibitor of protein kinase C and of platelet-derived growth factor (PDGF) receptor protein tyrosine kinase activity; 3) the ether lipid analogues that block growth factor signalling at several points by acting as inhibitors of protein kinase C, phosphoinositide specific phospholipase C and inositol(1,4,5)trisphosphate-induced Ca2+ release. It is suggested that inhibition of signalling pathways may explain the growth inhibitory effects of these compounds. Other potential signalling target sites for anticancer drug development are discussed.

Alkaloids↗

PubMed1997

The new drug approvals of 1993, 1994, and 1995: trends in drug development.

Growing concern within Congress, the pharmaceutical industry, and the Food and Drug Administration (FDA) over the excessive time and cost required to develop new drugs and bring them to market has led to several initiatives designed to speed the drug development process, e.g., the Prescription Drug User Fee Act of 1992 and recent efforts at legislative reform of the agency. To assess the impact of these initiatives, it is useful to examine recent trends in new drug development and review. This report is the fourth in a series in which we analyze new chemical entities (NCEs) recently approved by the FDA. In 1993, 1994, and 1995, the FDA approved 75 new drugs, 67 of which met the Tufts Center's definition of an NCE. Of the 67, 31 (46%) received priority review, 13 (19%) had orphan drug status, and 5 (7%) were approved under the accelerated approval regulations. For the 67 NCEs, the mean length of the clinical phase (investigational new drug filing to new drug application submission) was 7.1 years, and the approval phase (new drug application submission to approval) was 2.0 years. The mean approval phase for the 31 priority NCEs (1.5 years) was 38% shorter than that for the 36 standard NCEs (2.5 years). Compared with similar values for the previous 3-year period, the mean clinical phase for all NCEs increased by 16%, whereas the mean approval phase decreased by 23%. Of the 66 NCEs for which foreign marketing data were available, 34 (52%) were available in foreign markets one or more years prior to U.S. approval, with a mean of 7.7 years of earlier foreign marketing.

Drug Approval↗

PubMed2003

Ligand structure-function relationships in the vitamin D endocrine system from the perspective of drug development (including cancer treatment).

It has become readily apparent to many scientists and pharmaceutical companies that the vitamin D endocrine system offers a wide array of drug development opportunities. There are already successes, as noted by 1alpha,25(OH)2D3 (Roche, and Abbott) for renal osteodystrophy and osteoporosis and 1alpha(OH)D3 (Leo, Chugai, Teijin) for renal osteodystrophy and (in Japan) osteoporosis, 1alpha,24(OH)2-24-cyclopropyl-D3 (Dovonex) and 1alpha,24(OH)2D3 (Teijin) for psoriasis, and 19-nor-1alpha,25(OH)2D2 (Abbott) for renal osteodystrophy, as well as drugs under active development. Yet there are still many important and challenging drug development frontiers, particularly in the area of cancer treatment and immune system disorders where exploration is only in the initial early stages. In addition, the application of vitamin D-related drugs in neurology and brain pathology should not be overlooked. It is to be hoped that the cellular and molecular basis for the vexing problem of analog-induced hypercalcemia will be elucidated. Given that there are believed to be over 2000 analogs of 1alpha,25(OH)2D3 already available for consideration, it is to be expected that over the next decade a significant number of new vitamin D structure-function drug development projects will be brought to conclusion.

Animals↗

PubMed1997

The choice of pharmacoeconomic study design during drug development--part 1.

Given the rising cost of health care, it is no longer sufficient to demonstrate the safety and efficacy of a medical intervention. A medication must have exhibited economic benefit as well. Pharmaceutical manufacturers are faced with the challenge of when and how to conduct pharmacoeconomic (PE) evaluations to satisfy third-party drug formulary decision-makers. A wide variety of study designs and methodologies are available to assess economic benefit during drug development. Choosing the best strategy is a complex process. To illustrate the usefulness of decision analysis for strategic planning in drug development, a model was created to compare the cost-benefit of three PE design options: (1) add-on to a phase III safety and efficacy randomized controlled clinical trial (RCT), (2) stand-alone phase IIIb trial and (3) a post-marketing phase IV observational study. Although this model does not represent all the factors involved in a complicated drug development decision, the exercise may facilitate the decision process by rendering the inputs and probable consequences of various options more transparent to the decision-maker. Thus decision analysis can be a useful tool for preparing a sensible development strategy or uncovering deficiencies in an existing plan.

Journal Article↗

PubMed2001

Computer-assisted drug development (CADD): an emerging technology for designing first-time-in-man and proof-of-concept studies from preclinical experiments.

Computer-assisted drug development (CADD) is an emerging technology for accelerating drug development based on the integration of mathematical modelling and simulation. This methodology provides a knowledge-based decisional tool on alternative development strategies based on the evaluation of potential risks on drug safety, and the definition of experimental design of new trials with expected power and probability of success. An example of CADD implementation is presented to design the first-time-in-man (FTIM) and the proof-of-concept (PoC) study of a new CNS compound. The final objective of the example presented is not necessarily to supply a success story of a correct prediction of human data from animal studies but to define a credible strategy suitable to design FTIM and PoC studies using preclinical data without the support of any human in vivo information. Rhesus monkey and human PK were initially estimated using allometric scaling on data collected in dogs, cynomolgus monkeys and rats. A PK/PD model was derived from a study conducted in rodent and validated by comparing the model predicted response to the one observed in a PET experiment conducted in rhesus monkey. The final PK/PD model, incorporating potential variability and uncertainty on scaled human prediction together with a receptor affinity adjustment derived from in vitro binding studies, was used to design the first-time-in-man and the proof-of-concept study.

Animals↗

PubMed2006

Impact of genetic diagnostics on drug development strategy.

Innovation in diagnostics will be essential for the successful adoption of personalized medicine and will also have a major impact on the success of drug development strategies. To remain competitive, companies will need to embrace the rapid innovation in the diagnostic market, utilize diagnostic tools concurrently with research and development, and re-invent how new drugs are brought to market. In this article, specific examples of targeted oncology drugs are used to illustrate the general impact of genetic diagnostics on drug development.

Antineoplastic Agents↗

PubMed1985

Orphan drug development in the United States.

Drug research and development in the U.S. tends to focus on drugs to treat common diseases because of the anticipated return on investment. To stimulate pharmaceutical manufacturers to pursue the development of drugs for rare conditions, the Orphan Drug Act was enacted by Congress on January 4, 1983. Under the provisions of this Act, the FDA can make recommendations on the investigations necessary for marketing approval; exclusive marketing privileges can be obtained; tax credits for expenses incurred are allowed; availability of orphan drugs on an investigational basis is encouraged; and the Orphan Product Board is established for the coordination of research efforts and their reimbursement. The effects of this legislation are evident in the continuing increase in orphan drug designations.

Drug Evaluation↗

PubMed1996

Pharmacologic considerations for antiviral drug development.

OBJECTIVE: To discuss pharmacologic considerations for the development of antiviral agents. DATA SOURCES: English-language literature pertaining to the development and clinical evaluation of antiviral compounds, primarily agents targeted against herpes group viruses and HIV. STUDY SELECTION AND DATA EXTRACTION: Pertinent information, as judged by the author, was selected for discussion. DATA SYNTHESIS: Drug development of antiviral agents presents unique problems compared with that of antimicrobial and other agents. Understanding the mechanism of action and both pharmacokinetic and pharmacodynamic considerations is critical to developing a rational dosing strategy and safe, effective use. The lack of standardized methods for antiviral susceptibility testing and the influence of factors such as strain of virus, host cell type, culture medium, inoculum size, end point, and method of measurement on the results obtained illustrate factors that complicate preclinical pharmacologic analysis of antiviral agents. Acyclovir offers a model for clinical drug development. Its mechanism of action, pharmacokinetics, and pharmacodynamics have been studied extensively. Rational guidelines for usage are available, including guidelines in special patient populations such as kidney transplant recipients and neonates. A pregnancy registry has allowed evaluation of the incidence of birth defects in fetuses exposed to systemic acyclovir. Several pitfalls in antiviral drug development are associated with inadequate pharmacologic information. The development of dextran sulfate and fialuridine provides two examples. Integration of pharmacokinetic and pharmacodynamic analyses using modern sampling and analysis techniques may facilitate more rapid development of antiviral agents and more informed dosage regimens to achieve the highest probability of therapeutic success.

Antiviral Agents↗

PubMed2000

Financing new drug development in ophthalmology.

Previously, the author presented an overview of the procedural aspects of ophthalmic drug development. In that article, aspects of drug discovery and development were discussed, including application of the scientific method, compound selection, biological evaluation, pharmaceutical formulation, clinical development, and regulatory approval. An important part of drug discovery and development is funding the work. In this article, the author presents key issues involved in this funding process.

Antihypertensive Agents↗

PubMedDate not supplied

Signalling pathways as targets for anticancer drug development.

Intracellular signalling pathways mediating the effects of oncogenes on cell growth and transformation offer novel targets for the development of anticancer drugs. With this approach, it may be sufficient to target a component of the signalling pathway activated by the oncogene rather than the oncogene product itself. In this review, the abilities of some antiproliferative drugs to inhibit signalling targets are considered. There are some anticancer drugs already in clinical trial that may act by inhibiting signalling targets, as well as drugs in preclinical development. Some problems that may be encountered in developing this new class of anticancer drugs are discussed.

Antineoplastic Agents↗

PubMed1985

The Antiepileptic Drug Development Program: an example of government-industry collaboration.

By collaborating with the pharmaceutical industry in key areas of drug development, the ADD Program of the Epilepsy Branch, National Institute of Neurological and Communicative Disorders and Stroke, has responded to the need for more effective and less toxic antiepileptic drugs than those currently available. The program screens large numbers of compounds for anticonvulsant activity, conducts toxicology studies, and sponsors clinical trials of promising new drugs for the treatment of epilepsy. This collaboration with the pharmaceutical industry is providing a valuable model for a shared drug development program.

Anticonvulsants↗