Landscape Of Drug Development Research Articles

Abstract IA16: Accelerating innovation for children with cancer in the new regulatory environment

Abstract Over the last 20 years, several pieces of regulation have been launched, in the US and in Europe, to mandate and incentivize the development of safe and effective medicines for children. It has been a success in several pediatric specialties such as rheumatology, infection diseases, cardiovascular diseases, allergy, and several rare pediatric diseases. In oncology, the landscape of pediatric drug development has significantly changed, but very few new anticancer medicines have been approved for the treatment of pediatric malignancies over the last 10 years as compared to the high number of anticancer drugs approved for the treatment of cancer in adults: dinutuximab for neuroblastoma, blinatumomab and tisagenlecleucel for acute lymphoblastic leukemia, and larotrectinib for NTRK positive malignancies. So far, the regulations mandated the pediatric development of any drug if the indicated disease in adults occurred in children. If not, a waiver was issued and the company did not have to study the drug in children. In oncology, malignancies in children and in adults are different, but the same drugs are used to treat both, and often the same biologic alterations (targets) are found in both adult and pediatric malignancies. Too many oncology drugs have been waived. In addition, the pediatric trials of oncology products as part of Pediatric Investigation Plans and Pediatric Study Plans started late in the life cycle of product development and often close to or after the marketing authorization. There is a crucial need to improve and accelerate new drug development for children and adolescents with cancer. The goal is to drive pediatric oncology drug developments through science (using biology, preclinical evaluation, and precision medicine), to better meet patients’ unmet medical needs and to facilitate prioritization among all compounds in development. The FDA Race for Children Act is setting a new regulatory environment that will improve the situation by asking pediatric development of oncology products if their target is “directed at a molecular target that the Secretary determines to be substantially relevant to the growth or progression of a pediatric cancer.” In addition, over the last 5 years, the value of having all stakeholders, i.e. academia, parents, industry and regulators, working together has been demonstrated by ACCELERATE, the international multistakeholder platform (www.accelerate-platform.org). Accelerating innovation for pediatric cancers is urgently needed and feasible in the new regulatory environment and requires international cooperation of all stakeholders. Citation Format: Gilles Vassal. Accelerating innovation for children with cancer in the new regulatory environment [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA16.

Potential Statistical Issues Between Designers and Regulators in Confirmatory Basket, Umbrella, and Platform Trials.

Platform and basket trial have the potential to alter the landscape of drug development in many disease areas. Although these trials create many efficiencies compared with simple trials, they also create new statistical challenges for regulators. I highlight some of these new issues and discuss the regulatory challenges emerging from these trials. I highlight some critical points made by Collignon et al.,1 while providing some conflicting views on these statistical challenges.

Coronavirus Disease 2019 (COVID-19) – An Overview

The coronavirus disease 2019 (COVID-19) is now a pandemic with a massive death toll across the world. The knowledge and understanding of this novel coronavirus transmission and pathogenesis are evolving. Although the landscape of vaccine and drug development is changing at an unprecedented pace, currently, there is no specific effective treatment. Proper and timely management of severe and critically ill COVID-19 patients is crucial to reduce deaths in the ongoing pandemic. Ramping up testing capacity alongside a test strategy in place, ensuring adequate resources, i.e., protective gear, O2 supply, ICU facilities are essential requirements in the fight against COVID-19. Infection prevention and control measures at a personal level (e.g., handwashing, wearing masks, proper donning and doffing of personal protective equipment), and at hospital settings (e.g., hospital cleanliness, safe handling, and disposal of waste) are extremely important to reduce the risk of infection. COVID-19 pandemic has caused a global crisis that requires a multidisciplinary response and concerted effort to ensure resilience in health systems.
 J Bangladesh Coll Phys Surg 2020; 38(0): 84-90

Immune checkpoint blockade in solid organ tumours: Choice, dose and predictors of response.

Immune checkpoint blockade has transformed outcomes across solid organ tumours. Monoclonal antibodies targeting the negative inhibitory cytotoxic T lymphocyte-associated protein 4 and programmed-death 1/programmed death-ligand 1 axis can lead to deep and durable responses across several tumour streams in the advanced setting. This immunotherapy approach is increasingly used earlier in the treatment paradigm. A rapidly evolving regulatory, reimbursement and drug development landscape has accompanied this novel class of immunotherapy. Unfortunately, only a small proportion of patients respond meaningfully to these agents. Here we review how the underlying tumoural genomic, histological and immunological characteristics interact within various patient phenotypes, leading to variations in response to checkpoint blockade. Concurrently, we outline the clinical trial and real-world evidence that allows for appropriate selection of agent, dose and schedule in solid organ malignancies. An exploration of current trends in basic and translational research in immune checkpoint blockade accompanies a commentary on future clinical directions for checkpoint blockade in oncology.

The Use of Conformational Restriction in Medicinal Chemistry.

During the early preclinical phase, from hit identification and optimization to a lead compound, several medicinal chemistry strategies can be used to improve potency and/or selectivity. The conformational restriction is one of these approaches. It consists of introducing some specific structural constraints in a lead candidate to reduce the overall number of possible conformations in order to favor the adoption of a bioactive conformation and, as a consequence, molecular recognition by the target receptor. In this work, we focused on the application of the conformational restriction strategy in the last five years for the optimization of hits and/or leads of several important classes of therapeutic targets in the drug discovery field. Thus, we recognize the importance of several kinase inhibitors to the current landscape of drug development for cancer therapy and the use of G-protein Coupled Receptor (GPCR) modulators. Several other targets are also highlighted, such as the class of epigenetic drugs. Therefore, the possibility of exploiting conformational restriction as a tool to increase the potency and selectivity and promote changes in the intrinsic activity of some ligands intended to act on many different targets makes this strategy of structural modification valuable for the discovery of novel drug candidates.

Defining, Identifying, and Understanding "Exceptional Responders" in Oncology Using the Tools of Precision Medicine.

Widely available molecular profiling technology, including next-generation sequencing has changed the landscape of drug development in cancer. An increasing number of clinical trials in early drug development require patient selection based on molecular alterations. Concurrently, efforts to identify molecular alterations in tumors that exhibited exceptional response after systemic treatment with standard or investigational agents have been published or are in progress. These discoveries may ultimately serve as predictive markers or "actionable mutations" for future therapies. To test the feasibility of collecting the archival tissues from proposed exceptional responder patients and successful subsequent molecular profiling, the National Cancer Institute opened a nationwide exceptional responder initiative protocol in 2014. In addition, an increasing number of exceptional responder cases have been identified and published from academia institutions. The Network of Enigmatic Exceptional Responders study uses crowdsourcing to identify exceptional responders and will molecularly profile tumors to discern molecular correlates with exceptional response. In this review, we discuss the potential role of exceptional responder molecular analysis in new biomarker discovery efforts to further advance precision medicine in oncology therapeutics.

Engineering Microfluidic Organoid-on-a-Chip Platforms.

In vitro cell culture models are emerging as promising tools to understand human development, disease progression, and provide reliable, rapid and cost-effective results for drug discovery and screening. In recent years, an increasing number of in vitro models with complex organization and controlled microenvironment have been developed to mimic the in vivo organ structure and function. The invention of organoids, self-organized organ-like cell aggregates that originate from multipotent stem cells, has allowed a whole new level of biomimicry to be achieved. Microfluidic organoid-on-a-chip platforms can facilitate better nutrient and gas exchange and recapitulate 3D tissue architecture and physiology. They have the potential to transform the landscape of drug development and testing. In this review, we discuss the challenges in the current organoid models and describe the recent progress in the field of organoid-on-a-chip.

Treatment Combinations for Alzheimer's Disease: Current and Future Pharmacotherapy Options.

Although Alzheimer’s disease (AD) is the world’s leading cause of dementia and the population of patients with AD continues to grow, no new therapies have been approved in more than a decade. Many clinical trials of single-agent therapies have failed to affect disease progression or symptoms compared with placebo. The complex pathophysiology of AD may necessitate combination treatments rather than monotherapy. The goal of this narrative literature review is to describe types of combination therapy, review the current clinical evidence for combination therapy regimens (both symptomatic and disease-modifying) in the treatment of AD, describe innovative clinical trial study designs that may be effective in testing combination therapy, and discuss the regulatory and drug development landscape for combination therapy. Successful combination therapies in other complex disorders, such as human immunodeficiency virus, may provide useful examples of a potential path forward for AD treatment.

Commentary on “Statistics at FDA: Reflections on the Past Six Years”

We thank Dr. LaVange for the insightful overview of her tenure at the United States Food and Drug Administration (FDA). We enjoyed the broad discussion of statistical topics arising from her regulatory practice, emphasizing the constant need to drive for innovation in a rapidly evolving drug development landscape. We have made similar experiences in our daily practice, and it is a great pleasure to discuss this article and share some of our thoughts. Although we would like to address all the issues raised by Dr. LaVange, space limitations force us to focus on some selected topics: (i) estimands and treatment effect measures, (ii) considerations on multiplicity across individual studies, and (iii) statistical leadership in the digital age.

Adaptive designs in clinical trials: from scientific advice to marketing authorisation to the European Medicine Agency

BackgroundIn recent years, experience on the application of adaptive designs in confirmatory clinical trials has accumulated. Although planning such trials comes at the cost of additional operational complexity, adaptive designs offer the benefit of flexibility to update trial design and objectives as data accrue. In 2007, the European Medicines Agency (EMA) provided guidance on confirmatory clinical trials with adaptive (or flexible) designs. In order to better understand how adaptive trials are implemented in practice and how they may impact medicine approval within the EMA centralised procedure, we followed on 59 medicines for which an adaptive clinical trial had been submitted to the EMA Scientific Advice (SA) and analysed previously in a dedicated EMA survey of scientific advice letters. We scrutinized in particular the submission of the corresponding medicines for a marketing authorisation application (MAA). We also discuss the current regulatory perspective as regards the implementation of adaptive designs in confirmatory clinical trials.MethodsUsing the internal EMA MAA database, the AdisInsight database and related trial registries, we analysed how many of these 59 trials actually started, the completion status, results, the time to trial start, the adaptive elements finally implemented after SA, their possible influence on the success of the trial and corresponding product approval.ResultsOverall 31 trials out of 59 (53%) were retrieved. Thirty of them (97%) have been started and 23 (74%) concluded. Nine of these trials (39% out of 23) demonstrated a significant treatment effect on their primary endpoint and 4 (17% out of 23) supported a marketing authorisation (MA). An additional two trials were stopped using pre-defined criteria for futility, efficiently identifying trials on which further resources should not be spent. Median time to trial start after SA letter was given by EMA was 5 months. In the investigated trial registries, at least 18 trial (58% of 31 retrieved trials) designs were implemented with adaptive elements, which were predominantly dose selection, sample size reassessment (SSR) and stopping for futility (SFF). Among the 11 completed trials including adaptive elements, 6 demonstrated a significant treatment effect on their primary endpoint (55%).ConclusionsAdaptive designs are now well established in the drug development landscape. If properly pre-planned, adaptations can play a key role in the success of some of these trials, for example to help successfully select the most promising dose regimens for phase II/III trials. Interim analyses can also enable stopping of trials for futility when they do not hold their promises. Type I error rate control, trial integrity and results consistency between the different stages of the analyses are fundamental aspects to be discussed thoroughly. Engaging early dialogue with regulators and implementing the scientific advice received is strongly recommended, since much experience in discussing adaptive designs and assessing their results has been accumulated.

Immunomodulatory Effects of Current Targeted Therapies on Hepatocellular Carcinoma: Implication for the Future of Immunotherapy.

Multikinase inhibitors with antiangiogenic properties used to be standard therapy for patients with advanced hepatocellular carcinoma (HCC). Recently, several antiangiogenic agents (lenvatinib, cabozantinib, and ramucirumab) have demonstrated antitumor activity for advanced HCC in randomized controlled trials. However, the landscape of drug development for HCC may change dramatically with the advent of immune checkpoint inhibitor therapy, particularly the anti-programmed cell death-1 (anti-PD1) agents. In addition, early-phase clinical trials of combination of anti-PD-1 and antiangiogenic agents have shown very promising anti-tumor activity in patients with advanced HCC. Therefore, the critical research questions at present are whether this combination strategy will be the next generation of standard therapy and which antiangiogenic agents will be the optimal partner for the combination. All of the 4 multikinase inhibitors for HCC (sorafenib, regorafenib, lenvatinib, and cabozantinib) have been reported to have immune modulatory effects. The authors systematically reviewed the pre-clinical evidence of their immune modulatory effects to explore whether these effects were mediated by angiogenesis inhibition or by other "off-target" effects on the tumor microenvironment. Studies of sorafenib comprised the majority (58 of the 71) of the research articles reviewed. Potentially beneficial effects on anti-tumor immunity may result from increased M1 polarization of macrophages and stimulation of CD8 T cell function. On the other hand, high dosage of the kinase inhibitors in pre-clinical models and hypoxia associated with angiogenesis may contribute to immune suppression in the tumor microenvironment. Sorafenib and other multikinase inhibitors may promote anti-tumor immunity through modulation of multiple immune cell types as well as the tumor microenvironment. The optimal immune modulatory dosage should be defined to facilitate design of future combination regimens.

Developments in anti-complement therapy; from disease to clinical trial

The complement system is well known for its role in innate immunity and in maintenance of tissue homeostasis, providing a first line of defence against infection and playing a key role in flagging apoptotic cells and debris for disposal. Unfortunately complement also contributes to pathogenesis of a number of diseases; in some cases driving pathology, and in others amplifying or exacerbating the inflammatory and damaging impact of non-complement disease triggers. The role of complement in pathogenesis of an expanding number of diseases has driven industry and academia alike to develop an impressive arsenal of anti-complement drugs which target different proteins and functions of the complement cascade. Evidence from genetic and biochemical analyses, combined with improved identification of complement biomarkers and supportive data from sophisticated animal models of disease, has driven a drug development landscape in which the indications selected for clinical trial cluster in three ‘target’ tissues: the kidney, eye and vasculature. While the disease triggers may differ, complement activation and amplification is a common feature in many diseases which affect these three tissues. An abundance of drugs are in clinical development, some show favourable progression whereas others experience significant challenges. However, these hurdles in themselves drive an ever-evolving portfolio of ‘next-generation’ drugs with improved pharmacokinetic and pharmacodynamics properties. In this review we discuss the indications which are in the drug development ‘spotlight’ and review the relevant indication validation criteria. We present current progress in clinical trials, highlighting successes and difficulties, and look forward to approval of a wide selection of drugs for use in man which give clinicians choice in mechanistic target, modality and route of delivery.

Report of the 14th International Conference on Malignant Lymphoma (ICML) Closed Workshop on Future Design of Clinical Trials in Lymphomas.

The 14th ICML held in Lugano in June 2017 was preceded by a closed workshop (organized in collaboration with the American Association for Cancer Research and the European School of Oncology) where experts in preclinical and clinical research in lymphomas met to discuss the current drug development landscape focusing on critical open questions that need to be addressed in the future to permit a more efficient drug development paradigm in lymphoma. Topics discussed included both preclinical models that can be used to test new drugs and drug combinations, as well as the optimal design of clinical trials and the endpoints that should be used to facilitate accelerated progress. This report represents a summary of the workshop. Clin Cancer Res; 24(13); 2993-8. ©2018 AACR.

Tumor-Agnostic Drug Development.

Therapies designed to target cancers that harbor specific molecular signatures have reshaped the landscape of oncologic drug development, and advances in next generation sequencing have led to an increase in the identification of these alterations across tumor types. Tumor-agnostic trial designs, such as the "basket trial," have been developed as an approach to study the efficacy of these treatments and increase patient access, especially for patients whose tumors carry these alterations infrequently. We review key aspects of these genomically enriched trial strategies and their impact on drug development and approval.

The current landscape of early drug development for patients with sarcoma in the immunotherapy era.

Immunotherapy has changed the treatment paradigm of melanoma and other malignancies. Recently, trials of checkpoint inhibition in sarcomas have been far from outstanding, although specific sarcoma subtypes appear to benefit from these novel therapies. The next steps involve combining immune checkpoint inhibition with classic cancer therapies in order to increase immunogenicity and also potentially complex immunotherapy techniques such as adoptive cell therapy. Currently, numerous clinical trials are exploring different immunotherapies in the sarcomas. Herein, we describe some of the preclinical and clinical data that have laid the groundwork for the use of immunotherapies in sarcomas, as well as the current and future studies that could make immunotherapy a therapeutic option for patients with sarcoma.

Joint adolescent–adult early phase clinical trials to improve access to new drugs for adolescents with cancer: proposals from the multi-stakeholder platform—ACCELERATE

The impressive progress recently observed in adult cancers through the introduction of new drugs has not yet been translated to adolescents 12-17 years of age [defined according to the International Conference on Harmonization (ICH) E11]. The current drug development landscape separates adult and paediatric drug development (Table 1). Adolescents are grouped with children, leading to a mismatch with a lack of trials for adolescents with relapsed cancer and delayed access to new, effective drugs already available for adults.

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.