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PubMed2002

The impact of the National Cholesterol Education Program Adult Treatment Panel III guidelines on drug development.

In the newest guidelines of the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III, more intensive low-density lipoprotein cholesterol-lowering therapy, together with more attention to other lipid and lipoprotein parameters, are recommended for a larger group of dyslipidemic patients than was covered under ATP I and ATP II. A discussion to evaluate how future drug development might be affected by these new guidelines took place at the 14th International Symposium on Drugs Affecting Lipid Metabolism (DALM) conference, held in New York in September 2001. These discussions involved how to develop new lipid-lowering drugs in an era in which so much compelling evidence demonstrates the benefits of statins. Also covered were issues related to the development of drugs with triglyceride indications and whether the proportion of patients achieving NCEP guidelines should be included in the label of lipid-lowering drugs. Additional topics discussed included: (1) the possibility of incorporating a non-high-density lipoprotein cholesterol (HDL-C) indication for lipid-lowering drugs, (2) the possibility of obtaining indications for lipid-lowering drugs specifically in patients with diabetes, (3) the place of combination lipid-lowering drug therapy in drug development, and (4) whether drugs could be approved to increase levels of HDL-C in patients with isolated low HDL-C.

Adult↗

PubMed2003

The price of innovation: new estimates of drug development costs.

The research and development costs of 68 randomly selected new drugs were obtained from a survey of 10 pharmaceutical firms. These data were used to estimate the average pre-tax cost of new drug development. The costs of compounds abandoned during testing were linked to the costs of compounds that obtained marketing approval. The estimated average out-of-pocket cost per new drug is 403 million US dollars (2000 dollars). Capitalizing out-of-pocket costs to the point of marketing approval at a real discount rate of 11% yields a total pre-approval cost estimate of 802 million US dollars (2000 dollars). When compared to the results of an earlier study with a similar methodology, total capitalized costs were shown to have increased at an annual rate of 7.4% above general price inflation.

Capital Expenditures↗

PubMed2003

The importance of pharmacokinetic limited sampling models for childhood cancer drug development.

Since the development of effective chemotherapy for children with cancer, it has been recognized that the response of children to apparently identical therapy, both in terms of efficacy and toxicity, can vary widely. Our understanding of the interindividual differences in drug metabolism and disposition as significant determinants of drug response continues to evolve. An increasing area of clinical investigation is focused on studies to gain a better understanding of the variability in critical drug metabolic and elimination pathways and how this variability translates into varied pharmacological effects. Analyzing how drug metabolism and elimination are affected by patient characteristics such as age, sex, race, organ function, drug interactions, and, perhaps most importantly, genetic polymorphisms, is now a routine component of drug development studies. Recent advances in analytical methodologies, computer hardware, and pharmacokinetic software have improved our ability to conduct studies of the disposition of anticancer drugs in larger, more representative pediatric cancer populations. Along with advances in pharmacogenetics, the advances made in the conduct of pharmacokinetic studies in children with cancer have enabled establishment of sophisticated phenotype-genotype correlations, which may ultimately improve care. However, unique challenges and limitations remain that complicate the performance of pharmacokinetic studies in the child with cancer. This review addresses the need to perform pharmacokinetic studies throughout the drug development process in pediatric oncology patients, methods used to develop and validate limited sampling models, and selected examples of limited sampling models used in pharmacokinetic studies in children with cancer.

Antineoplastic Agents↗

PubMed2002

Maximizing the value of medicines by including pharmacogenetic research in drug development and surveillance.

Genetics provides significant opportunities to maximize the safety and efficacy of medicines. Over the next 3--5 years, it may be possible to develop tools that use selective information from patients' DNA to enable healthcare professionals to predict more accurately those patients at risk of serious adverse events to some medicines currently available. This is likely to be followed, over the next 5--10 years, by the application of the technology to predict more accurately if individual patients will obtain a therapeutic benefit from a particular medicine. The ability to accurately predict patient response will inevitably change the way medicines are developed, evaluated, and prescribed. Advances in single nucleotide polymorphism (SNP) map technology are likely to drive this innovation. Abbreviated SNP profiles will provide the means to define medicine response tests, thereby allowing clinicians to select the medicine to which the patient is likely to gain the greatest benefit and least risk. This will help to maximize efficacy and reduce the incidence of drug-related adverse events. It may be possible to identify SNP profiles during larger Phase II clinical trials which predict efficacy, and use these to form the basis of Phase III entry criteria. As a result, Phase III trials may be streamlined for many medicines making them smaller, more efficient, and more focused. In addition it may be possible to incorporate pharmacogenetics into postmarketing surveillance strategies to provide a means to identify SNPs which predict uncommon serious adverse drug reactions, and so refine the initial medicine response test. The ability to develop drugs with a predictable response will allow clinicians to provide targeted treatment for patients, with greater confidence of safety and efficacy. Patients therefore will receive more efficacious, timely, and well-tolerated medicines. The challenge for those involved in drug development is to model and evaluate the application of pharmacogenetics so that steps can be taken to realize this potential.

Cost-Benefit Analysis↗

PubMedDate not supplied

The management of interim analyses in drug development.

The ethical need for interim analyses in long-term trials of life-threatening conditions is well established, but recently there has been increased enthusiasm for the use of interim analyses in other areas of clinical research. Interim analysis is seen as a powerful tool in drug development to help reduce 'time to market' by allowing key decisions to be made earlier on the basis of one or more ongoing clinical trials. However, this goal can only be achieved without serious penalties if interim analyses are properly designed and executed, so that the integrity of the whole drug development programme is maintained. The purpose of this paper is to define procedures for the design and management of clinical trials which involve interim analyses. These procedures are intended to incorporate good clinical and statistical practice, hence maintaining high scientific standards not only of individual trials but also of the overall development programme. Aspects of design, conduct, analysis and dissemination of results are considered, with particular focus on the effective use of data monitoring committees in confirmatory efficacy trials.

Bias↗

PubMedDate not supplied

Approaches to antiviral drug development.

At present, only a few drugs have been approved by the FDA for therapy of viral infections in humans. There is a great need for antiviral drugs with increased potency and decreased toxicity, as well as drugs to treat viral diseases for which no drug or vaccine is currently available. Two approaches for development of antiviral drugs are described--an empirical strategy and a rational strategy--with several examples of each. Although many compounds have potent antiviral activity in cell culture, only a small fraction of these will go on to become antiviral drugs for use in humans. At this time, only seven synthetic compounds and alpha interferon have been approved by the FDA for therapy of viral infections in humans. None of these approved drugs are without toxicities, however, and hence there is a great need for antiviral drugs with increased potency and decreased toxicity, as well as for drugs to treat viral diseases for which no drug or vaccine is currently available. Two approaches for the development of antiviral drugs--the empirical and the rational strategies--and their applications and future directions are discussed.

Antiviral Agents↗

PubMed2000

Chirality and its implications in transdermal drug development.

Today more than 50% of marketed drugs are chiral. It has been well recognized that the stereochemistry of chiral drugs has a major influence on their pharmacological, pharmacokinetic, and toxicological actions. Studies on enantiomeric differences in the percutaneous permeation of chiral compounds have been actively pursued in recent years. Stratum corneum, the rate-limiting barrier in transdermal permeation, is made up of keratin and ceramide, which could potentially provide chiral environment. Transdermal delivery is often facilitated by the presence of penetration enhancers, which act primarily by altering the diffusion by disrupting the highly ordered membrane structure or by affecting the partitioning behavior of the diffusant molecules. Enantioselective permeation was observed with some chiral excipients including terpene enhancers. While studies on crystalline structures of pure enantiomers and racemates are helpful in understanding the basis for differentiation of physicochemical properties, prediction and control of permeability of enantiomers and racemates based on the physicochemical characteristics would be highly beneficial. The flux characteristics of enantiomers and racemates appear to be dependent upon their thermodynamic properties. Such analyses have a predictive value and are useful in the transdermal drug product development of chiral molecules. While the decision to market either an individual enantiomer or racemate lies strictly under the control of the sponsors, the guidance of the Food and Drug Administration is very helpful. This review presents an overview of the skin structure and transport and a concise review of enantioselective permeation with or without chiral enhancers. Regulatory perspectives on chiral drug product development are also discussed.

Administration, Cutaneous↗

PubMedDate not supplied

Estimating the cost of new drug development: is it really 802 million dollars?

This paper replicates the drug development cost estimates of Joseph DiMasi and colleagues ("The Price of Innovation"), using their published cost estimates along with information on success rates and durations from a publicly available data set. For drugs entering human clinical trials for the first time between 1989 and 2002, the paper estimated the cost per new drug to be 868 million dollars. However, our estimates vary from around 500 million dollars to more than 2,000 million dollars, depending on the therapy or the developing firm.

Clinical Trials as Topic↗

PubMed1997

dUTP pyrophosphatase as a potential target for chemotherapeutic drug development.

Aberrant dUTP metabolism plays a critical role in the molecular mechanism of cell killing induced by inhibitors of dihydrofolate reductase and thymidylate synthase. While considerable effort has been directed towards discovering new, more potent inhibitors of these two enzymes, little attention has been given dUTP pyrophosphatase (dUTPase)--the key modulator of cellular dUTP levels--as a potential target for chemotherapeutic drug development. Recent studies have provided evidence that dUTPase is vital for cellular and, in some cases, viral DNA replication. Furthermore, some retroviruses encode dUTPases--a fact which suggests that cellular dUTP metabolism may be more important than previously realized. Here, we briefly review current knowledge of cellular and viral dUTPases and discuss the potential of these enzymes as targets for cancer chemotherapeutic and anti-viral drug development.

Animals↗

PubMed2002

Nuclear transcription factor-kappaB as a target for cancer drug development.

Nuclear factor kappa B (NF-kappaB) is a family of inducible transcription factors found virtually ubiquitously in all cells. Since its discovery by Sen and Baltimore in 1986, much has been discovered about its mechanisms of activation, its target genes, and its function in a variety of human diseases including those related to inflammation, asthma, atherosclerosis, AIDS, septic shock, arthritis, and cancer. Due to its role in a wide variety of diseases, NF-kappaB has become one of the major targets for drug development. Here, we review our current knowledge of NF-kappaB, the possible mechanisms of its activation, its potential role in cancer, and various strategies being employed to target the NF-kappaB signaling pathway for cancer drug development.

Antineoplastic Agents↗

PubMed1984

The potential use of markers in drug development.

There are at least three recurring questions crucial to the drug and drug formulation development processes that could be addressed by marker methodology: (1) Is the assessment of an effective dose or dose regimen correct? (2) Is an inadequate response or nonresponse secondary to pharmacology or to inadequate compliance? (3) Can various formulations provide significantly better therapy for certain populations? Characteristics of an ideal marker system would include: Simple and reliable to measure. Able to yield reliable evaluation of routine adherence in single or multiple dose situations. Biologically inert. Samples for measurement can be obtained unobtrusively. Samples are painless to obtain (for patient and clinic staff). Absorption and kinetic characteristics approximate those of the therapeutic candidate. Able to be presented in multiple formulations. Current methodology for addressing these questions is far short of ideal. Therefore, if marker methodology that lacks the limitation of present technology could be developed, it potentially would find wide use during the drug development process.

Clinical Trials as Topic↗

PubMed2004

Clinical pharmacology: special safety considerations in drug development and pharmacovigilance.

The dose of a drug is a major determinant of its safety, and establishing a safe dose of a novel drug is a prime objective during clinical development. The design of pre-marketing clinical trials precludes the representation of important subpopulations such as children, the elderly and people with co-morbidities. Therefore, postmarketing surveillance (PMS) activities are required to monitor the safety profile of drugs in real clinical practice. Furthermore, individual variations in pharmacogenetic profiles, the immune system, drug metabolic pathways and drug-drug interactions are also important factors in the occurrence of adverse drug reactions. Thus, the safety of a drug is a major clinical consideration before and after it is marketed. A multidisciplinary approach is required to enhance the safety profile of drugs at all stages of development, including PMS activities. Clinical pharmacology encompasses a range of disciplines and forms the backbone of drug safety consideration during clinical drug development. In this review we give an overview of the clinical drug development process and consider its limitations. We present a discussion of several aspects of clinical pharmacology and their application to enhancing drug safety. Pharmacokinetic-pharmacodynamic modelling provides a method of predicting a clinically safe dose; consideration of drug pharmacokinetics in special populations may enhance safe therapeutics in a wider spectrum of patients, while pharmacogenetics provides the possibility of genotype-specific therapeutics. Pharmacovigilance activities are also discussed. Given the complex nature and unpredictability of type B reactions, PMS activities are crucial in managing the risks drugs pose to the general population. The various aspects of clinical pharmacology discussed make a strong case for this field as the backbone of optimising and promoting safe development and use of drugs.

Adolescent↗

PubMed2002

[The trend of anti-arrhythmic drug development].

New anti-arrhythmic drugs have been developed by the progress of molecular-biological and physiological research on an ion channel and the elucidation of pharmacological effects of traditional anti-arrhythmic drugs. After CAST study, K+ channel blockers instead of Na+ channel blockers were developed and used in anti-arrhythmic treatment. In Sicilian Gambit, it was advocated that the anti-arrhythmic drug selection was based on both pharmacological action of drugs and mechanism of arrhythmias, including electrical remodeling which was mainly studied on atrial fibrillation and structural remodeling such as myocardial fibrosis. Furthermore, the target of anti-arrhythmic treatment will be not only the arrhythmic control with drugs but changing many factors related to the arrhythmic substrates, modulators and triggers of arrhythmias.

Anti-Arrhythmia Agents↗

PubMed2002

HIV-1 regulatory proteins: targets for novel drug development.

Due to the development of HIV-1 resistance to current antiviral drugs and the known toxicity of many of these drugs, there is a clear need to identify and develop novel compounds for use in the treatment of HIV-1 infected patients. The HIV-1 regulatory proteins, Tat and Rev, are required for HIV-1 replication and therefore represent two important viral targets for drug development. Novel drugs that target these proteins would increase the number of available treatment strategies for HIV-1 infection. This could result in better combination therapies in which many different viral targets could be inhibited simultaneously, thereby decreasing the likelihood of selecting for drug-resistant viruses. This review outlines many of the ways that Tat and Rev can be targeted for drug development, describes recently reported lead compounds as inhibitors of these proteins and discusses strategies for implementing drug screens for identifying novel inhibitors.

Antiviral Agents↗

PubMed2005

Issues for clinical drug development in neurodegenerative diseases.

Neurodegenerative diseases pose specific challenges for drug development. These diseases typically have a slow and variable clinical course, an insidious onset, and symptom expression is only observed when a significant proportion of neurons are already lost. It is important to identify vulnerability factors and other determinants of clinical course in order to be able in the future to select patient populations for clinical trials with a predictable prognosis. The neurodegenerative process itself is not amenable to direct observation and, thus, cannot be monitored in clinical trials. For this reason, surrogate biomarkers are required for use as outcome parameters. In this respect, magnetic resonance imaging has proved valuable for assessing disease activity and progression in multiple sclerosis. Rating scales are of use as outcome measures but, as these generally measure symptom severity, they are most appropriate for use in assessing symptomatic treatments. Survival has been used with success as an outcome measure in trials in amyotrophic lateral sclerosis, where disease progression is rapid. The optimal outcome measure, the sample size required and the treatment duration need to be chosen in relation to the phase of the disease. Potential new treatments can be chosen based upon new knowledge of the genetics and physiopathology of neurodegenerative diseases and, in some cases, screened in transgenic mouse models, although it should be recognised that the validity of these models in terms of treatment response has yet to be established empirically.

Animals↗

PubMed2005

Are there lessons to be learned from drug development that will accelerate the use of molecular imaging probes in the clinic?

This special issue of the journal contains contributions from participants of the third La Jolla meeting (The Magic Bullet: A Century Later). The goal of this meeting was twofold: to review approaches to validating molecular imaging agents and to review the progress in advancing the use of molecular imaging from the bench to the bedside, with a special emphasis on how molecular imaging improves patient care and management. Drug development has changed its focus over the years. The original approach depended on direct measurements in patients, whereby, in many cases, the drug was advanced to an NDA based on physiological results (e.g., lowering blood pressure) without identifying a target. Over the past decade, the focus has been on validating a target and choosing the lead compound using combinatorial chemistry and high throughput screening, often at the expense of a focus on the biology of diseases. On the other hand, molecular imaging has been target based since its beginning because of the requirements dictated by external imaging (i.e., a target-to-nontarget ratio). This article explores the possible analogies between current targeted drug development and molecular imaging-targeted probe development with the goal of better defining the path to new molecular imaging probes for the clinic.

Animals↗

PubMed2006

Ethnobotany and ethnopharmacy--their role for anti-cancer drug development.

Local and traditional knowledge has been the starting point for many successful drug development projects over the last decades. Here we discuss some examples of anti-cancer drugs which have had enormous impact as anti-cancer agents (camptothecan, taxol and derivatives) and a few examples of drugs currently under various stages of preclinical development. Ethnobotanists investigate the relationship between humans and plants in all its complexity, and such research is generally based on a detailed observation and study of the use a society makes of plants. The requirements of modern research on natural products as, for example, outlined in the Convention on Biological Diversity (Rio Convention) and the overall approach in ethnobotanical research are also discussed. Selected phytochemical-pharmacological studies based on traditional plant use are used to highlight the potential of ethnobotany driven anti-cancer research. The link between traditionally used plants and targets of the NF-kappaB pathway is discussed using on an EU-funded, multidisciplinary project as an example. Lastly the potential of chemopreventive agents derived from traditional food plants is briefly addressed.

Animals↗

PubMed2005

Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development.

2-[(18)F]Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) assesses a fundamental property of neoplasia, the Warburg effect. This molecular imaging technique offers a complementary approach to anatomic imaging that is more sensitive and specific in certain cancers. FDG-PET has been widely applied in oncology primarily as a staging and restaging tool that can guide patient care. However, because it accurately detects recurrent or residual disease, FDG-PET also has significant potential for assessing therapy response. In this regard, it can improve patient management by identifying responders early, before tumor size is reduced; nonresponders could discontinue futile therapy. Moreover, a reduction in the FDG-PET signal within days or weeks of initiating therapy (e.g., in lymphoma, non-small cell lung, and esophageal cancer) significantly correlates with prolonged survival and other clinical end points now used in drug approvals. These findings suggest that FDG-PET could facilitate drug development as an early surrogate of clinical benefit. This article reviews the scientific basis of FDG-PET and its development and application as a valuable oncology imaging tool. Its potential to facilitate drug development in seven oncologic settings (lung, lymphoma, breast, prostate, sarcoma, colorectal, and ovary) is addressed. Recommendations include initial validation against approved therapies, retrospective analyses to define the magnitude of change indicative of response, further prospective validation as a surrogate of clinical benefit, and application as a phase II/III trial end point to accelerate evaluation and approval of novel regimens and therapies.

Fluorodeoxyglucose F18↗