Landscape Of Drug Development Research Articles

GBOIN: A Unified Model-Assisted Phase I Trial Design Accounting for Toxicity Grades, and Binary or Continuous End Points

SummaryThe landscape of oncology drug development has recently changed with the emergence of molecularly targeted agents and immunotherapies. These new therapeutic agents appear more likely to induce multiple low or moderate grade toxicities rather than dose limiting toxicities. Various model-based dose finding designs and toxicity severity scoring systems have been proposed to account for toxicity grades, but they are difficult to implement because of the use of complicated dose–toxicity models and the requirement to refit the model at each decision of dose escalation and de-escalation. We propose a generalized Bayesian optimal interval design, gBOIN, that accommodates various existing toxicity grade scoring systems under a unified framework. As a model-assisted design, gBOIN derives its optimal decision rule on the basis of the exponential family of distributions but is carried out in a simple way as the algorithm-based design: its decision of dose escalation and de-escalation involves only a simple comparison of the sample mean of the end point with two prespecified dose escalation and de-escalation boundaries. No model fitting is needed. We show that gBOIN has the desirable finite property of coherence and a large sample property of consistency. Numerical studies show that gBOIN yields good performance that is comparable with or superior to that of some existing, more complicated model-based designs. A Web application for implementing gBOIN is freely available from http://www.trialdesign.org.

Systematic Review of Epigenetic Effects of Pharmacological Agents for Bipolar Disorders.

Epigenetic effects of medications are an evolving field of medicine, and can change the landscape of drug development. The aim of this paper is to systematically review the literature of the relationship between common medications used for treatment of bipolar disorders and epigenetic modifications. MedLine/PubMed searches were performed based on pre-specified inclusion criteria from inception to November 2017. Six animal and human studies met the inclusion criteria. These studies examined the epigenetic changes in the main classes of medications that are used in bipolar disorders, namely mood stabilizers and antipsychotics. Although these initial studies have small to moderate sample size, they generally suggest an evolving and accumulating evidence of epigenetic changes that are associated with several of the medications that are used in bipolar I and II disorders. In this manuscript, we describe the specific epigenetic changes that are associated with the medications studied. Of the studies reviewed, five of the six studies revealed epigenetic changes associated with the use of mood stabilizers or antipsychotic medications. This review contributes to future research directions. Further understanding of the complexities of the epigenome and the untangling of the effects and contributions of disease states versus medications is crucial for the future of drug design and the development of new therapeutics. Epigenetic therapeutics hold great promise for complex disease treatment and personalized interventions, including psychiatric diseases.

Public drug policy for children in Canada.

KEY POINTS Recent efforts have helped reform the global landscape of drug development to incorporate the unique needs of children into research and regulation.[1][1] However, an area of persistent inadequacy is public policy on funding for pediatric drugs, which varies widely by jurisdiction. Health

Navigating the Future of Cardiovascular Drug Development-Leveraging Novel Approaches to Drive Innovation and Drug Discovery: Summary of Findings from the Novel Cardiovascular Therapeutics Conference.

The need for novel approaches to cardiovascular drug development served as the impetus to convene an open meeting of experts from the pharmaceutical industry and academia to assess the challenges and develop solutions for drug discovery in cardiovascular disease. The Novel Cardiovascular Therapeutics Summit first reviewed recent examples of ongoing or recently completed programs translating basic science observations to targeted drug development, highlighting successes (protein convertase sutilisin/kexin type 9 [PCSK9] and neprilysin inhibition) and targets still under evaluation (cholesteryl ester transfer protein [CETP] inhibition), with the hope of gleaning key lessons to successful drug development in the current era. Participants then reviewed the use of innovative approaches being explored to facilitate rapid and more cost-efficient evaluations of drug candidates in a short timeframe. We summarize observations gleaned from this summit and offer insight into future cardiovascular drug development. The rapid development in genetic and high-throughput drug evaluation technologies, coupled with new approaches to rapidly evaluate potential cardiovascular therapies with in vitro techniques, offer opportunities to identify new drug targets for cardiovascular disease, study new therapies with better efficiency and higher throughput in the preclinical setting, and more rapidly bring the most promising therapies to human testing. However, there must be a critical interface between industry and academia to guide the future of cardiovascular drug development. The shared interest among academic institutions and pharmaceutical companies in developing promising therapies to address unmet clinical needs for patients with cardiovascular disease underlies and guides innovation and discovery platforms that are significantly altering the landscape of cardiovascular drug development.

Early phase clinical trials of anticancer agents in children and adolescents - an ITCC perspective.

In the past decade, the landscape of drug development in oncology has evolved dramatically; however, this paradigm shift remains to be adopted in early phase clinical trial designs for studies of molecularly targeted agents and immunotherapeutic agents in paediatric malignancies. In drug development, prioritization of drugs on the basis of knowledge of tumour biology, molecular 'drivers' of disease and a drug's mechanism of action, and therapeutic unmet needs are key elements; these aspects are relevant to early phase paediatric trials, in which molecular profiling is strongly encouraged. Herein, we describe the strategy of the Innovative Therapies for Children with Cancer (ITCC) Consortium, which advocates for the adoption of trial designs that enable uninterrupted patient recruitment, the extrapolation from studies in adults when possible, and the inclusion of expansion cohorts. If a drug has neither serious dose-related toxicities nor a narrow therapeutic index, then studies should generally be started at the adult recommended phase II dose corrected for body surface area, and act as dose-confirmation studies. The use of adaptive trial designs will enable drugs with promising activity to progress rapidly to randomized studies and, therefore, will substantially accelerate drug development for children and adolescents with cancer.

The Current Landscape of Early Drug Development for Patients With Sarcoma.

Until recently, advancements in the treatment of patients with adult soft tissue sarcomas have been relatively slow. This is, in part, due to their heterogeneity and rarity. A better understanding of the biology and differences among the various histologies has led to substantial growth in novel strategies. In addition to novel cytotoxic chemotherapies, agents targeting platelet-derived growth factor receptor-α (PDGFRα), mTOR, and angiogenesis are areas of active investigation. Additionally, with the success of checkpoint inhibitors in other malignancies and early encouraging results of checkpoint inhibitors in some sarcoma subtypes, this approach is being widely investigated in various sarcomas. As we increasingly recognize and treat each sarcoma histology as a separate disease, it is important to spread awareness of the exciting clinical trials available to our patients with these rare malignancies.

The Current Landscape of Early Drug Development for Patients With Sarcoma

Until recently, advancements in the treatment of patients with adult soft tissue sarcomas have been relatively slow. This is, in part, due to their heterogeneity and rarity. A better understanding of the biology and differences among the various histologies has led to substantial growth in novel strategies. In addition to novel cytotoxic chemotherapies, agents targeting platelet-derived growth factor receptor-α (PDGFRα), mTOR, and angiogenesis are areas of active investigation. Additionally, with the success of checkpoint inhibitors in other malignancies and early encouraging results of checkpoint inhibitors in some sarcoma subtypes, this approach is being widely investigated in various sarcomas. As we increasingly recognize and treat each sarcoma histology as a separate disease, it is important to spread awareness of the exciting clinical trials available to our patients with these rare malignancies.

Drug Development Pipeline for Myeloproliferative Neoplasms: Potential Future Impact on Guidelines and Management

The unprecedented success of ruxolitinib in myelofibrosis (MF) has paved the way for the development of other Janus kinase (JAK) inhibitors and other agents representing diverse drug classes and mechanisms of action in myeloproliferative neoplasms (MPNs). In particular, the symptomatic benefits afforded by ruxolitinib have led to the recognition of "clinical improvement" in symptoms and the spleen in international consensus response criteria for MF. Ruxolitinib is also approved for the second-line treatment of polycythemia vera and is being developed for essential thrombocythemia. Appreciation of the universal role of activated JAK/signal transducer and activator of transcription (STAT) signaling in MPNs and improved understanding of the canonical and noncanonical actions of JAK2 have yielded a number of drug targets beyond JAK2 in MPNs, which form the basis for a number of ruxolitinib-based rational combinations that are being explored in MF. Other JAK inhibitors with the potential for significantly less myelosuppression or even improvement of anemia continue to be tested. Finally, agents with very distinct mechanisms of action, such as novel interferon formulations, antifibrotic agents, and telomerase inhibitors, are being pursued in polycythemia vera and MF, respectively. This article reviews the current landscape of clinical drug development in MPNs, focusing on the most promising agents and combinations.

Doxorubicin Conjugated to Immunomodulatory Anticancer Lactoferrin Displays Improved Cytotoxicity Overcoming Prostate Cancer Chemo resistance and Inhibits Tumour Development in TRAMP Mice.

Advanced, metastatic, castration resistant and chemo-resistant prostate cancer has triggered change in the drug development landscape against prostate cancer. Bovine lactoferrin (bLf) is currently attracting attention in clinics for its anti-cancer properties and proven safety profile. bLf internalises into cancer cells via receptor mediated endocytosis, boosts immunity and complements chemotherapy. We employed bLf as an excellent functional carrier protein for delivering doxorubicin (Dox) into DU145 cells, CD44+/EpCAM+ double positive enriched DU145 3D prostaspheres and drug resistant ADR1000-DU145 cells, thus circumventing Dox efflux, to overcome chemo-resistance. Successful bLf-Dox conjugation with iron free or iron saturated bLf forms did not affect the integrity and functionality of bLf and Dox. bLf-Dox internalised into DU145 cells within 6 h, enhanced nuclear Dox retention up to 24 h, and proved significantly effective (p < 0.001) in reducing LC50 value of Dox from 5.3 μM to 1.3 μM (4 fold). Orally fed iron saturated bLf-Dox inhibited tumour development, prolonged survival, reduced Dox induced general toxicity, cardiotoxicity, neurotoxicity in TRAMP mice and upregulated serum levels of anti-cancer molecules TNF-α, IFN-γ, CCL4 and CCL17. The study identifies promising potential of a novel and safer bLf-Dox conjugate containing a conventional cytotoxic drug along with bLf protein to target drug resistance.

Current Trends in Identifying Rapidly Acting Treatments for Depression.

Traditional antidepressant medications generally take weeks-to-months to achieve effect. However, the breakthrough finding of ketamine's rapidly acting antidepressant properties has inspired a decade-and-a-half of progress towards the identification of treatments that work quickly-within hours-to-days. This paradigm-shift in the discovery of antidepressant therapies has significantly changed the current landscape of antidepressant drug development. Building on this, the current review briefly highlights the recent trends in research towards identifying rapidly-acting antidepressants. Specifically, ketamine, GLYX-13, nitrous oxide, metabotropic glutamatergic receptor modulators, scopolamine, opioid-receptor modulators, and low field magnetic stimulation are discussed.

Increasing the odds of effective drug development: Elevating regulatory affairs professionals to strategic partners

AbstractIn today’s globalized drug development landscape, the need for regulatory professionals to be more seamlessly integrated into strategic decisions is evident. Whereas a few companies see the benefit of involving regulatory affairs professionals in strategic business decisions, many still lag behind. Limited literature and scholarly discussion is available on whether regulatory affairs professionals are given the stature and power to make a meaningful contribution during strategy formulation across all stages of the product development, launch, and life-cycle management. This article examines the current business environment for the regulated industries; discusses why it is important that regulatory affairs play an active and strategic role in this sector; and proposes a new educational perspective to facilitate the recognition and acceptance of regulatory affairs professionals as strategic partners.

NMR‐based approach to the analysis of radiopharmaceuticals: radiochemical purity, specific activity, and radioactive concentration values by proton and tritium NMR spectroscopy

Compounds containing tritium are widely used across the drug discovery and development landscape. These materials are widely utilized because they can be efficiently synthesized and produced at high specific activity. Results from internally calibrated (3)H and (1)H nuclear magnetic resonance (NMR) spectroscopy suggests that at least in some cases, this calibrated approach could supplement or potentially replace radio-high-performance liquid chromatography for radiochemical purity, dilution and scintillation counting for the measurement of radioactivity per volume, and liquid chromatography/mass spectrometry analysis for the determination of specific activity. In summary, the NMR-derived values agreed with those from the standard approaches to within 1% to 9% for solution count and specific activity. Additionally, the NMR-derived values for radiochemical purity deviated by less than 5%. A benefit of this method is that these values may be calculated at the same time that (3)H NMR analysis provides the location and distribution of tritium atoms within the molecule. Presented and discussed here is the application of this method, advantages and disadvantages of the approach, and a rationale for utilizing internally calibrated (1)H and (3)H NMR spectroscopy for specific activity, radioactive concentration, and radiochemical purity whenever acquiring (3)H NMR for tritium location.

Biodegradable Particulate Carrier Formulation and Tuning for Targeted Drug Delivery.

Biodegradable micro- and nanoparticles have the potential to reform the drug development landscape by improving drug solubility, changing undesirable pharmacokinetics, realizing the benefits of new molecules arising from genomic and proteomic research, and increasing drug localization in target organs and tissues; i.e., drug targeting. This review provides an overview of the in vivo fate of biodegradable particulate carriers following administration via several routes, as well as how the patient's health state, disease pathophysiology and particle physicochemical properties affect such fates. It also discusses some of the widely used biodegradable polymers, their in vivo biochemical degradation, methods of nanoparticle formulation from such polymers and finally, how such methods could be tailored to achieve targeted delivery to specified tissues both passively and actively.

Our Scope Expansion to Include Biologics

Chemical compounds with relatively low molecular weights, so-called small molecules in pharmaceutical parlance, have been the mainstay of drug-based therapeutics for many decades. More recently, large molecules, known as biologics, have received increasing attention and have become a large segment of drug research and development. Biologics have become an important segment of marketed drugs and are expected to expand further in the future. Most drug discovery and development organizations have shifted their business objectives over the past few years to emphasize protein-based therapeutic agents, such that they will become a greater proportion of their therapeutic pipelines. This transition, a dramatic shift from small-molecule drugs to high-value biopharmaceuticals, has powered a vibrant biotechnology expansion with the concomitant rise of many biopharma enterprises. ACS Medicinal Chemistry Letters recognizes this shift in the landscape of drug discovery and development, as well as the important contributions of medicinal chemists to the field of large-molecule therapeutics. Consequently, the journal is extending its welcome to medicinal chemistry-oriented manuscripts associated with molecular entities that are commonly referred to as “biologics”. Some examples include, but are not limited to, medicinal chemistry aspects of antibody–drug conjugates; protein therapeutics; and passive or active immunotherapies. The Editors encourage the submission of manuscripts pertaining to the identification, synthesis, optimization, and biological characterization of large bioactive molecules and drugs, as a complement to our long-standing emphasis on small molecular entities. As such, our advice to prospective authors has been modified accordingly in Instructions for Authors on our Web site.

Sharing clinical trial data on patient level: opportunities and challenges.

In recent months one of the most controversially discussed topics among regulatory agencies, the pharmaceutical industry, journal editors, and academia has been the sharing of patient-level clinical trial data. Several projects have been started such as the European Medicines Agency´s (EMA) “proactive publication of clinical trial data”, the BMJ open data campaign, or the AllTrials initiative. The executive director of the EMA, Dr. Guido Rasi, has recently announced that clinical trial data on patient level will be published from 2014 onwards (although it has since been delayed). The EMA draft policy on proactive access to clinical trial data was published at the end of June 2013 and open for public consultation until the end of September 2013. These initiatives will change the landscape of drug development and publication of medical research. They provide unprecedented opportunities for research and research synthesis, but pose new challenges for regulatory authorities, sponsors, scientific journals, and the public. Besides these general aspects, data sharing also entails intricate biostatistical questions such as problems of multiplicity. An important issue in this respect is the interpretation of multiple statistical analyses, both prospective and retrospective. Expertise in biostatistics is needed to assess the interpretation of such multiple analyses, for example, in the context of regulatory decision-making by optimizing procedural guidance and sophisticated analysis methods.

From genomic data analysis to drug development: a new generation of trials using molecular marker assessment in breast cance.

With the advent of molecular subtypes in breast cancer, the landscape of clinical trials and drug development is rapidly changing. Molecular screening identifies numerous mutations but actually druggable targets are few and far between. Thus, new clinical trial concepts are needed which are feasible in clinical practice and successful from the point of view of drug development. This article highlights the evolution of the sequencing technologies, the current molecular screening efforts and their impact on drug development as well as novel successful trial designs, focusing on the hormone receptor (HR) positive breast cancer patients. The range of mutations to identify in order to adapt the treatment to each patient and limit the resistance mechanisms is quite wide already, but theoretical or practical restriction may have to be considered to optimize the development of such adaptive combinations of targeted therapies.

The evolving drug development landscape: from blockbusters to niche busters in the orphan drug space.

Strategy, Management and Health Policy Large pharmaceutical companies have traditionally focused on the development of blockbuster drugs that target disease states with large patient populations. However, with large-scale patent expirations and competition from generics and biosimilars, anemic pipelines, escalating clinical trial costs, and global health-care reform, the blockbuster model has become less viable. Orphan drug initiatives and the incentives accompanied by these have fostered renewed research efforts in the area of rare diseases and have led to the approval of more than 400 orphan products. Despite targeting much smaller patient populations, the revenue-generating potential of orphan drugs has been shown to be huge, with a greater return on investment than non-orphan drugs. The success of these "niche buster" therapeutics has led to a renewed interest from "Big Pharma" in the rare disease landscape. This article reviews the key drivers for orphan drug research and development, their profitability, and issues surrounding the emergence of large pharmaceutical firms into the orphan drug space.

An overview of FDA-approved new molecular entities: 1827–2013

The pharmaceutical industry is undergoing fundamental change and its future is unclear. We performed a meta-analysis by cataloging FDA-approved legacy drugs and new molecular entities (NMEs). Objective information regarding scientific, medical and commercial activities was captured and provides insight into processes governing drug development. In this report, we review the rates of NME introduction through to the end of 2013. Recent trends show the emergence of a handful of companies that controls two-thirds of NMEs. We also report growth in the number of NMEs controlled by marketing organizations that have little or no internal drug discovery or development activities. This trend has increased dramatically since 2000 and could raise important questions about the future landscape and viability of drug discovery and development.

Abstract IA06: Adaptive designs and adaptive learning for biomarker-based clinical trials for targeted therapies.

Abstract Rapid advancements in genomics have changed the landscape of target identification and drug development for targeted therapies. Targeted agents work well when drugs are given to patients with the actionable targets. For example, TKI works well for lung cancer patients with EGFR mutation and crizotinib is highly effective for patients with EML4-ALK translocation. Targeted agents, however, do not work for everyone and may not work at all. Hence, the goals for developing target agents include (1) testing the treatment efficacy, (2) identifying prognostic and predictive markers, and (3) providing better treatments to patients enrolled in the trial. Several novel designs have been introduced to achieve these objectives. For example, Bayesian adaptive designs can assign more patients to the more effective treatments based on the available data at the time via the outcome-adaptive randomization. More frequent interim monitoring can drop the ineffective treatments early for futility. New treatments can be added, and effective treatments can graduate for further evaluation. The concepts of the basket design and the N-of-1 design have also been proposed to study the targeted agents based on patients' genomic profiles across different disease sites. Information collected from such trials can be put together to form a continuously updated knowledge database for adaptive learning. Statistical methods such as the hierarchical model and Individual level meta-analysis can be applied to model data collected in the knowledge database to estimate the treatment effect, the marker effect, and their interactions. A platform of a clinical trial infrastructure can be established to facilitate the conduct of such trials. In the talk, pros and cons of various designs will be discussed. Examples and lessons learned from the recently completed BATTLE trial and the on-going BATTLE-2 trial in non-small cell lung cancer will be given. Citation Format: J. Jack Lee. Adaptive designs and adaptive learning for biomarker-based clinical trials for targeted therapies. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr IA06.

The evolving landscape of therapeutic drug development for hepatocellular carcinoma

Currently, only one drug, sorafenib, is FDA approved for the treatment of advanced hepatocellular carcinoma (HCC), achieving modest objective response rates while still conferring an overall survival benefit. Unlike other solid tumors, no oncogenic addiction loops have been validated as clinically actionable targets in HCC. Outcomes of HCC could potentially be improved if critical molecular subclasses with distinct therapeutic vulnerabilities can be identified, biomarkers that predict recurrence or progression early can be determined and key epigenetic, genetic or microenvironment drivers that determine best response to a specific targeting treatment can be uncovered.Our group and others have examined the molecular heterogeneity of hepatocellular carcinoma. We have developed a panel of patient derived xenograft models to enable focused pre-clinical drug development of rationally designed therapies in specific molecular subgroups. We observed unique patterns, including synergies, of drug activity across our molecularly diverse HCC xenografts, pointing to specific therapeutic vulnerabilities for individual tumors. These efforts inform clinical trial designs and catalyze therapeutic development. It also argues for efficient strategic allocation of patients into appropriate enriched clinical trials. Here, we will discuss some of the recent important therapeutic studies in advanced HCC and also some of the potential strategies to optimize clinical therapeutic development moving forward.