Clinical assessment in juvenile dermatomyositis

Juvenile dermatomyositis (JDM) is a multisystem inflammatory disease of unknown etiology that affects primarily the skin and muscles. Although the prognosis of JDM has improved considerably in the last three decades, a number of patients may develop irreversible damage due to the disease activity or its treatment. This damage may cause permanent disability and affect the quality of life of patients and their families. In the clinical management of patients with JDM, there is, therefore, the need of monitoring the level of disease activity, the accrual of organ damage, and the impact of the illness on patients' daily living. A reliable assessment of these different aspects of disease requires the availability of well-designed and standardized clinical tools. In the recent years, there has been increasing collaborative effort to devise new assessment measures and these measures have been included into disease activity and damage core sets of outcome variables that have been developed through international consensus. In addition, preliminary definitions of clinical improvement for patients with JDM and other idiopathic inflammatory myopathies have been created. In this review, the latest advances in the development of standardized instruments for the clinical assessment of JDM patients are illustrated and the recent international efforts that have led to the development of core sets of outcome measures and to preliminary definitions of improvement for JDM clinical trials are summarized.     

Data sharing to advance gene-targeted therapies in rare diseases

Recent advancements in gene-targeted therapies have highlighted the critical role data sharing plays in successful translational drug development for people with rare diseases. To scale these efforts, we need to systematize these sharing principles, creating opportunities for more rapid, efficient, and scalable drug discovery/testing including long-term and transparent assessment of clinical safety and efficacy. A number of challenges will need to be addressed, including the logistical difficulties of studying rare diseases affecting individuals who may be scattered across the globe, scientific, technical, regulatory, and ethical complexities of data collection, and harmonization and integration across multiple platforms and contexts. The NCATS/NIH Gene-Targeted Therapies: Early Diagnosis and Equitable Delivery meeting series held during June 2021 included data sharing models that address these issues and framed discussions of areas that require improvement. This article describes these discussions and provides a series of considerations for future data sharing.     

Challenges of developing and conducting clinical trials in rare disorders

Rare disease drug development is a rapidly expanding field. Clinical researchers in rare diseases face many challenges when conducting trials in small populations. Disease natural history is often poorly understood and the ability to detect clinically meaningful outcomes requires understanding of their rate of occurrence and variability, both of which contribute to difficulties in powering a study. Standard trial designs are not optimized to obtain adequate safety and efficacy data from small numbers of patients, so alternative designs (enrichment, crossover, adaptive, N‐of 1) need to be considered. The affected patients can be hard to identify, especially early in the course of their disease, are generally geographically dispersed, and are often children. Trials are frequently conducted on an international scale and may be subject to complex or multiple regulatory agency oversights and may be affected by local customs, cultures, and practices. A basic understanding of the FDA programs supporting development of drugs for rare diseases is provided by this review and the role of early consultation with the FDA is emphasized. Of recent FDA New Molecular Entities (NME) approvals, 41% (17 approvals) in 2014, 47% (21 approvals) in 2015, and 41% (9 approvals) in 2016 were for rare disease indications. Through effective interactions and collaborations with physicians, institutions, and patient groups, sponsors have been successful in bringing new treatments to market for individuals affected by rare diseases. Challenges to drug development have been overcome through the focused efforts of patients/families, non‐profit patient advocacy groups, drug developers, and regulatory authorities.

     

ObituaryDonato Alarcon-Segovia✠, M.D.Mexico City,May 6, 1935–December 21, 2004

Juvenile dermatomyositis (JDM) is a multisystem inflammatory disease of unknown etiology that affects primarily the skin and muscles. Although the prognosis of JDM has improved considerably in the last three decades, a number of patients may develop irreversible damage due to the disease activity or its treatment. This damage may cause permanent disability and affect the quality of life of patients and their families. In the clinical management of patients with JDM, there is, therefore, the need of monitoring the level of disease activity, the accrual of organ damage, and the impact of the illness on patients' daily living. A reliable assessment of these different aspects of disease requires the availability of well-designed and standardized clinical tools. In the recent years, there has been increasing collaborative effort to devise new assessment measures and these measures have been included into disease activity and damage core sets of outcome variables that have been developed through international consensus. In addition, preliminary definitions of clinical improvement for patients with JDM and other idiopathic inflammatory myopathies have been created. In this review, the latest advances in the development of standardized instruments for the clinical assessment of JDM patients are illustrated and the recent international efforts that have led to the development of core sets of outcome measures and to preliminary definitions of improvement for JDM clinical trials are summarized.     

Pharmacological treatments for eosinophilic esophagitis: current options and emerging therapies

ABSTRACT

Introduction: The epidemiology of eosinophilic esophagitis (EoE) has increased rapidly to represent a common cause of chronic and recurrent esophageal symptoms. Current treatment options have limitations so the development of novel therapies is a matter of growing interest.

Areas covered: This article provides an up-to-date discussion of current therapies and investigational options for EoE. Established anti-inflammatory treatments for EoE at present include dietary therapy, proton pump inhibitors and swallowed topic steroids, which should be combined with endoscopic dilation in case of strictures. Refractoriness, high recurrence rates, and need for long-term therapies have promoted the investigation of novel, esophageal-targeted formulas of topic corticosteroids, and monoclonal antibodies (including mepolizumab, reslizumab, QAX576, RPC4046, dupilumab, omalizumab, infliximab, and vedolizumab) for EoE, with some having been demonstrated as effective and safe in the short term. Several additional promising therapies are also discussed.

Expert opinion: Several therapeutic targets have shown efficacy and will be approved to treat EoE, especially corticosteroid-sparing options and those for patients with multiple Th2-associated diseases. Personalized therapeutic strategies for initial and maintenance treatments of EoE must be rationally designed, to reduce the burden of disease and answer meaningfully the needs of all stakeholders involved in EoE.     

Ethical challenges for a new generation of early-phase pediatric gene therapy trials

After decades of setbacks, gene therapy (GT) is experiencing major breakthroughs. Five GTs have received US regulatory approval since 2017, and over 900 others are currently in development. Many of these GTs target rare pediatric diseases that are severely life-limiting, given a lack of effective treatments. As these GTs enter early-phase clinical trials, specific ethical challenges remain unresolved in three domains: evaluating risks and potential benefits, selecting participants fairly, and engaging with patient communities. Drawing on our experience as clinical investigators, basic scientists, and bioethicists involved in a first-in-human GT trial for an ultrarare pediatric disease, we analyze these ethical challenges and offer points to consider for future GT trials.     

Conduct of device clinical trials: the need for collaboration in response to a changing health care environment

Prior to initiating a clinical trial, many issues need to be discussed to insure an adequate understanding of the investigators' and sponsors' limitations, capabilities, and expectations. Many of these issues are addressed in contracts and agreements, the formats for which have evolved over many years. In these documents, issues such as publication rights, access to results, confidentiality, conditions for termination, compensation, and indemnification are covered. However, other essential, although noncontractual issues that reflect upon trends in and the climate of the health care system, need to be discussed. Issues such as the development of collaborative cost-effectiveness studies, public relations plans, content of a cost-benefit analysis, results of other trials, reimbursement strategies, and the development of resources that contribute to the ease, safety, and efficacy of device use. With the increasing expense, oversight, and administrative burden for the conduct and participation in clinical trials, there is a correspondingly greater need for sponsor and investigator communication, collaboration, and risk and cost sharing to ensure the successful outcome of clinical trials today.     

Clinical pharmacology and clinical trials in Japan

Clinical pharmacology is the pursuit of rational therapeutics by following the scientific principles of medicine and pharmacology. In Japan the roles for clinical pharmacology and clinical pharmacologists have been evolving since the discipline appeared in the 1950s. Clinical pharmacology and clinical trials for drug development depend on each other, and clinical pharmacologists play an important role in drug development in Japan. As the discipline becomes more important and complicated, many issues regarding drug therapeutics and clinical trials in Japan have been raised, and several points of view have been expressed. The following suggestions have been made to improve clinical pharmacology in Japan: (a) Medical education in the field of clinical pharmacology must be improved by creating or improving clinical pharmacology programs in medical schools. (b) The appropriate infrastructure for clinical trials must be established so that the physicians' workload is reduced, and patients' participation in clinical trials becomes much easier. (c) Scientific and ethical standards of the pharmaceutical industry must be improved, and the effort should be made to produce drugs with new mechanisms of action or with significant expected benefits. (d) The regulatory agency must provide stronger support, encompassing all the various points of view of academic institutes and the pharmaceutical industry. In light of the enthusiasm demonstrated by the government, physicians, and pharmaceutical industry in Japan for continued progress in clinical pharmacology, it seems likely that all its challenges will be overcome in the near future. Hence, despite the various problems discussed here the future seems promising for the continued development of clinical pharmacology.Abbreviations GCP Good clinical practice - JSCPT Japanese Society of Clinical Pharmacology and Therapeutics     

Biological Therapies for Eosinophilic Esophagitis: Where Do We Stand?

Eosinophilic esophagitis (EoE) is an immune-mediated, chronic esophageal disease characterized by esophageal symptoms and esophageal eosinophilia. It is triggered by foods and possibly by environmental allergens. Currently, there are no FDA-approved therapies for EoE. Commonly used treatments include dietary restrictions and topical corticosteroids. Many of these therapies are suboptimal in their efficacy, have side effects, or diminish patients’ quality of life. Biologic therapies for EoE have therefore been sought as an alternative. The mechanism by which food allergens trigger EoE is thought to be a T helper type 2 (Th2) reaction, resulting in secretion of the cytokines IL-4, IL-5, and IL-13. IL-5 induces eosinophil production and trafficking to the esophagus, and IL-13 induces esophageal epithelial cells to secrete eotaxin-3, which drives eosinophil chemotaxis and activation. Mepolizumab and reslizumab, two anti-IL-5 antibodies, were studied in children and adults with EoE and resulted in reduction of esophageal tissue and blood eosinophils, but no significant reduction in symptoms. QAX576, an anti-IL-13 antibody, was studied in adults with EoE and showed a decrease in the esophageal eosinophil load and a trend towards clinical improvement. Since in situ IgE production was demonstrated in the EoE esophagus, omalizumab, an anti-IgE antibody, was studied in patients with EoE and not found to be overall beneficial. Furthermore, given the increased esophageal epithelial cell TNF-α expression in EoE, infliximab, an anti-TNF-α antibody, was studied in patients with EoE, with lack of success both clinically and histologically. In summary, although none of the biologicals studied so far in EoE have been highly effective, many demonstrated some histological benefit, especially those that targeted the Th2 axis. Therefore, the future for biologicals is promising as the pathophysiology of EoE is better understood, clinical assessment tools are validated, identification of patient subsets that respond best to biologicals is made, and dosages of biologicals are optimized.     

Biomarkers in clinical trials for neurodegenerative diseases: Regulatory perspectives and requirements

Biomarkers might play comprehensive roles in drug development for neurodegenerative diseases and particularly Alzheimer's disease (AD) and other dementias. Biomarkers can already be used to better define homogeneous study populations (e.g. enriched population at risk for AD) and to select the most promising drug candidates in their effective dosages for phase III clinical trials, so some biomarkers are currently in the process of implementation as primary, co-primary or secondary outcome variables into regulatory guideline documents, e.g. regarding phase II in drug development programs as outcome measures in proof of concept or dose finding studies. There are specific biomarkers available depending on the hypothesized mechanism of action of a medicinal product, e.g. impact on the amyloidogenic cascade or on tau-hyperphosphorylation. However, further validation of specific biomarkers in large-scale international controlled multicenter studies is necessary before they can be accepted as primary outcome measures in pivotal phase III clinical trials. There is an even stronger need for rigorous co-development of biological trait- and state marker candidates to provide evidence that a medicinal product affects the underlying disease process, which, together with clinical improvement, will be a precondition for a label of disease modification. Until now no biomarker has been sufficiently validated to be acceptable as a surrogate endpoint. Establishing of surrogate endpoints is an important goal in neurodegenerative diseases, particularly in their early (preclinical, presymptomatic) stages, as traditional clinical outcome measures might be too insensitive to change or need unfeasible treatment durations for clinical trial conditions. Improvements can only be accomplished by active synergistic collaboration between academic, industrial and regulatory partners.     

Phenotypes and endotypes in eosinophilic esophagitis

ObjectiveTo improve understanding of the heterogeneous presentation of eosinophilic esophagitis (EoE), and its different potential phenotypes and endotypes.Data SourcesWe reviewed studies addressing EoE genetics, risks, natural history, treatment, phenotype, or endotype to assess data relating to differences in the presentation of EoE in children and adults. This review was restricted to articles in the English language.Study SelectionsData source abstracts, pertinent articles, and book chapters meeting the objectives were critically reviewed.ResultsData to support differing phenotypes and endotypes in EoE are emerging, but findings are based on multiple studies and therefore sometimes incomparable. Like other atopic disorders EoE is a complex disease with diverse clinical presentations (phenotypes) based on response to therapy, natural history, and association with atopic comorbidities. Different pathogenetic mechanisms (endotypes) may drive the multiple phenotypes. T Helper type 2 inflammation, epithelial barrier defects, enhanced fibrosis, and association with rare monogenetic diseases are the most described endotypes in EoE.ConclusionEosinophilic esophagitis is an atopic disorder that is increasing in prevalence and can be difficult to treat. Better understanding of phenotypes and endotypes in EoE may enable future care to be individualized more effectively, resulting in shorter time to remission and fewer endoscopies.     

The implications for europe of revised FDA guidelines for clinical trials with anti-infective agents

This article summarizes the current collaborative effort between the US Food und Drug Administration and the Infectious Diseases Society of America for the purpose of generating new General and Disease/Organism Specific Guidelines for the evaluation of anti-infective agents. Examples of proposed changes from draft documents are presented. The final documents may assist European colleagues in their efforts to establish a standardized new drug registration process by 1992. An area of mutual interest is the acceptability of safety and efficacy data from international clinical trials. In the interest of human and financial economies, both US and European Guidelines need to clarify the conditions, or criteria, for the conduct of valid off-shore clinical trials.     

Pathophysiology of eosinophilic esophagitis: recent advances and their clinical implications

Introduction: Diagnostic and therapeutic strategies in eosinophilic esophagitis (EoE) are evolving. New knowledge regarding the pathophysiology of EoE has been the foundation for updated diagnostic recommendations and new therapeutic trials.

Areas covered: We performed structured literature searches in Medline and PubMed, Cochrane meta-analyses, and abstracts of international congresses to review therapeutic approaches for EoE in July 2018. Additional articles were obtained by perusing the references of articles identified in the original PubMed search. Articles were excluded if they did not focus on the mechanism of disease, diagnosis, or treatment of humans with EoE.

Expert commentary: Recent advances in the understanding of mechanisms underlying the pathology of EoE have resulted in significant change in the diagnostic algorithm for EoE, and are identifying promising potential targets for personalized medicine. There is a clinical need for improved targeted therapy for EoE, and better understanding the underlying pathophysiology of EoE will help to determine therapeutic targets. In this review, we highlight key mechanisms in the pathophysiology of EoE and how they are being utilized to change therapy in EoE.     

A global research agenda for leptospirosis

Leptospirosis is a zoonotic spirochetal disease of global importance. This disease continues to have a major impact on people living in urban and rural areas of developing countries with inestimable morbidity and mortality. Funding for research and control efforts is currently haphazard, not organized and not effective for public health efforts, primarily because there are no concerted, ongoing international efforts to assess the impact of leptospirosis on human health. Major issues in the field need to be addressed to develop strategies of control, amelioration and treatment. These include the following: mechanisms of naturally acquired and vaccine-induced protective immunity against clinical leptospirosis; mechanisms of severe leptospirosis pathogenesis; standardized, precise and simplified taxonomy of Leptospira relevant to disease manifestations, transmission and control; effective adjunct treatments in addition to antimicrobials; and environmental assessment for risk of leptospirosis transmission and relevant mammalian reservoirs. Once effective ongoing, collaborative international efforts to assess the impact of leptospirosis on human and veterinary health are underway, appropriate mobilization of clinical and public health research funding will follow.     

Biomarkers in clinical trials for neurodegenerative diseases: regulatory perspectives and requirements

Biomarkers might play comprehensive roles in drug development for neurodegenerative diseases and particularly Alzheimer's disease (AD) and other dementias. Biomarkers can already be used to better define homogeneous study populations (e.g. enriched population at risk for AD) and to select the most promising drug candidates in their effective dosages for phase III clinical trials, so some biomarkers are currently in the process of implementation as primary, co-primary or secondary outcome variables into regulatory guideline documents, e.g. regarding phase II in drug development programs as outcome measures in proof of concept or dose finding studies. There are specific biomarkers available depending on the hypothesized mechanism of action of a medicinal product, e.g. impact on the amyloidogenic cascade or on tau-hyperphosphorylation. However, further validation of specific biomarkers in large-scale international controlled multicenter studies is necessary before they can be accepted as primary outcome measures in pivotal phase III clinical trials. There is an even stronger need for rigorous co-development of biological trait- and state marker candidates to provide evidence that a medicinal product affects the underlying disease process, which, together with clinical improvement, will be a precondition for a label of disease modification. Until now no biomarker has been sufficiently validated to be acceptable as a surrogate endpoint. Establishing of surrogate endpoints is an important goal in neurodegenerative diseases, particularly in their early (preclinical, presymptomatic) stages, as traditional clinical outcome measures might be too insensitive to change or need unfeasible treatment durations for clinical trial conditions. Improvements can only be accomplished by active synergistic collaboration between academic, industrial and regulatory partners.     

Standardization of early drug trials in allergic diseases (with reference to a trial of doxantrazole)

Attention is drawn to the long wait in certain countries before new drugs and other therapies for the treatment of allergic diseases are approved by the local authorities, even when good trials with them have been carried out elsewhere. The main reasons for requiring repeat trials are poor original case selection and inadequate parameters of assessment, particularly environmental variations. The results of re-assessing patients who in the previous year had undergone a trial of a new chromoglycate-like drug (Doxantrazole) are used to illustrate the need to introduce standard basic requirements when new drugs and other agents are being tested in allergic diseases. A suggested format of such requirements is presented.     

Building collaborative networks for HIV/AIDS vaccine development: the AVIP experience

The need for an effective HIV/AIDS vaccine is imperative to halt a pandemic that involves more than 40 million individuals worldwide as of 2005 and is causing enormous socio-economic losses, especially in developing countries (DC). The overall failure of more than two decades of HIV vaccine research justifies the demands for a concerted effort for the rapid development of new and efficacious vaccines against HIV/AIDS. In this context, building international collaborative networks is a must for speeding up scientific research and optimizing the use of funding in a synergistic fashion, as resources for HIV/AIDS are limited and do not involve most of the biggest Pharmas that are more interested in drug discovery. The AIDS Vaccine Integrated Project (AVIP) consortium is an example of synergistic partnership of international European Union and DC experts with a common research goal. AVIP is a European Commission-funded (FP-6), consortium-based, 5-year program directed to the fast development of new HIV/AIDS vaccine candidates to be tested in phase I clinical trials in Europe for future advancement to phase II/III testing in DC. To ensure their rapid development, AVIP novel combined vaccines include both regulatory and structural HIV antigens, which have already been tested, as single components, in phase I clinical trials. In particular, such combination vaccines may be superior to earlier vaccine candidates, the vast majority of which are based only on either structural or regulatory HIV products. In fact, the generation of immune responses to both types of viral antigens expressed either early (regulatory products) or late (structural products) during the viral life cycle can maximize immune targeting of both primary or chronic viral infection. Further, the rational design of combined vaccines allows exploitation of immunomodulatory functions of HIV regulatory proteins, which can improve immunity against structural vaccine components. The building of the AVIP consortium and its scientific strategy will be reviewed in this paper as an example of the establishment of a consortium regulated by a specific intellectual property agreement.     

Eosinophilic esophagitis

ObjectiveTo review the understanding of the pathogenesis of eosinophilic esophagitis (EoE) and the role of the immune system in the disease process.Data SourcesPeer-reviewed articles on EoE from PubMed searching for “Eosinophilic Esophagitis and fibrosis” in the period of 1995 to 2013.Study SelectionsStudies on the clinical and immunologic features, pathogenesis, and management of EoE.ResultsRecent work has revealed that thymic stromal lymphopoietin and basophil have an increased role in the pathogenesis of disease. Additional understanding on the role of fibrosis in EoE is emerging.ConclusionThe incidence of EoE is increasing like most atopic disease. Similar to other allergic diseases, EoE is treated with topical steroids and/or allergen avoidance.