美国监管科学发展简介及对我国食品药品科学监管的思考

目的 对美国“监管科学”学科的发展现状进行了简要介绍,为我国该学科的建设及发展提供参考.方法 检索、介绍美国FDA对该学科的研究现状和未来规划;美国的大学和其他学术机构的研究与教学内容;然后,对我国“监管科学”学科的建立和规划提出个人的一些思考.结果与结论 在医用制品快速、大量出现的今天,监管科学在促进食品药品的科学检验和监管中发挥着越来越重要的作用,一些国外药品监管机构（如FDA）甚至把它作为21世纪重点推动的一个学科.我国在构建和发展监管科学学科时,应特别重视：（1）对国外“监管科学”精髓的引进,并根据自己的监管制度形成有特色的学科内容;（2）重视监管科学所需工具的基础性研究投入;（3）重视术语研究和转化的准确性、规范性;（4）重视国外监管法规的学习和引入;（5）设立专项研究基金;（6）重视与大专院校联合,设置相关学科,大力培育人才.     

Treatment sequence network meta-analysis in Crohn’s disease: a methodological case study

Objective: Several biologic therapies are available for the treatment of mild-to-moderate Crohn’s disease (CD). This network meta-analysis (NMA) aimed to assess the comparative efficacy of ustekinumab, adalimumab, vedolizumab and infliximab in the maintenance of clinical response and remission after 1?year of treatment.

Methods: A systematic literature search was performed to identify relevant randomized controlled trials (RCTs). Key outcomes of interest were clinical response (CD activity index [CDAI] reduction of 100 points; CDAI-100) and remission (CDAI score under 150 points; CDAI < 150). A treatment sequence Bayesian NMA was conducted to account for the re-randomization of patients based on different clinical definitions, the lack of similarity of the common comparator for each trial and the full treatment pathway from the induction phase onwards.

Results: Thirteen RCTs were identified. Ustekinumab 90?mg q8w was associated with statistically significant improvement in clinical response relative to placebo and vedolizumab 300?mg. For clinical remission, ustekinumab 90?mg q8w was associated with statistically significant improvement relative to placebo and vedolizumab 300?mg q8w. Findings from sub-population analyses had similar results but were not statistically significant.

Conclusions: The NMA suggest that ustekinumab is associated with the highest likelihood of reaching response or remission at 1?year compared with placebo, adalimumab and vedolizumab. Results should be interpreted with caution because this is a novel methodology; however, the treatment sequence analysis may be the most methodologically sound analysis to derive estimates of comparative efficacy in CD in the absence of head-to-head evidence.     

Disabling inflammatory pathways with biologics and resulting clinical outcomes in severe asthma

Introduction: Patients with severe asthma have a significant unmet need with persistent symptoms and/or frequent exacerbations despite high intensity treatment. These severe unrelenting symptoms have a huge impact on heathcare resources due to frequent hospital admissions and requirement for intensive and expensive medications. There is a compelling need for more effective and safer therapies to help severe asthma sufferers to achieve adequate control of their disease.

Areas covered: Expanding knowledge of innate and adaptive immune responses has led to development of new biologic approaches for severe asthma. Here, the authors will review the existing efficacy and safety data from clinical trials of some of the new biologic therapies that are in development for severe asthma. Their specific role in distinctively targeted subpopulations of severe asthmatics will be also discussed.

Expert opinion: Defining and phenotyping severe asthma patients will become increasingly important as some patients who were previously classified as having severe asthma may become well-controlled with a targeted phenotype-specific treatment. However, pharmacoeconomic concerns should also be taken into account given the elevated acquisition costs of recombinant human monoclonals and of the diagnostic screening procedures for the identification of potential responders.     

Shark variable new antigen receptor biologics – a novel technology platform for therapeutic drug development

Introduction: Biologics drugs have succeeded in achieving a commercial dominance in the global market for new therapies and large pharmaceutical companies' interest remains strong through a continued commitment to pipeline development. It is not surprising, therefore, that next-generation biologics, particularly antibody-like scaffolds that offer many of the advantages of the original biologic drugs but in simplified formats, have entered the clinic as competing substitute therapeutic products, to capture market share.

Areas covered: Specifically, this paper will position shark-derived variable new antigen receptors (VNARs) within an overview of the existing biologics landscape including the growth, diversity and success to date of alternative scaffolds. The intention is not to provide a comprehensive review of biologics as a whole but to discuss the main competing single-domain technologies and the exciting therapeutic potential of VNAR domains as clinical candidates within this context.

Expert opinion: The inherent ability to specifically bind target and intervene in disease-related biological processes, while reducing off-site toxicity, makes mAbs an effective, potent and now proven class of therapeutics. There are, however, limitations to these ‘magic bullets’. Their size and complexity can restrict their utility in certain diseases types and disease locations. In contrast, a number of so-called alternative scaffolds, derived from both immunoglobulin- and non-immunoglobulin-based sources have been developed with real potential to overcome many of the shortcomings documented for mAb treatments. Unlike competing approaches such as Darpins and Affibodies, we now know that shark VNAR domains (like camel VHH nanobody domains), are an integral part of the adaptive immune system of these animals and have evolved naturally (but from very different starting molecules) to exhibit high affinity and selectivity for target. In addition, and again influenced by the environment in which they have evolved naturally, their small size, simple architecture, high solubility and stability, deliver additional flexibility compared to classical antibodies (and many non-natural alternative scaffolds), thereby providing an attractive basis for particular clinical indications where these attributes may offer advantages.     

Primary care of asthma: new options for severe eosinophilic asthma

Objective: Asthma is a common heterogeneous disease characterized by airway inflammation and bronchoconstriction. Current treatment guidelines provide recommendations for categorizing disease severity, asthma control and management. This paper reviews asthma assessment in primary care and describes the pathophysiology, clinical characteristics and new targeted treatments available for patients with severe eosinophilic asthma.

Methods: A non-systematic PubMed literature search was conducted and articles, primarily from the last 5?years, were selected based on relevance to primary care practice, asthma pathophysiology and biologic therapies.

Results: Despite optimal therapy including high-dose inhaled corticosteroids (ICS), long-acting β2-agonists and tiotropium, ～4–10% of all patients with severe asthma continue to have poor asthma control. These patients have impaired quality of life, frequent exacerbations and are exposed to the side effects of repeated courses of oral steroids. Approximately 50% of patients with severe uncontrolled asthma have eosinophilic asthma, with increased airway expression of type 2 cytokines IL-4, IL-5 and IL-13. Eosinophilic asthma is identified in primary care by having eosinophils ≥150–300 cells/μL on a complete blood count with differential.

Conclusions: A new class of agents is available for patients with moderate to severe eosinophilic asthma. Four biologic therapies – mepolizumab, reslizumab, benralizumab and dupilumab – that interfere with the regulation and activity of eosinophils have been approved by the FDA for patients with moderate to severe asthma with an eosinophilic phenotype. Primary care physicians should be familiar with these medications to explain part of the rationale for referral to specialist care and manage patient expectations for treatment.     

Parents’ Willingness to Pay for Biologic Treatments in Juvenile Idiopathic Arthritis

BackgroundBiologic therapies are considered the standard of care for children with the most severe forms of juvenile idiopathic arthritis (JIA). Inconsistent and inadequate drug coverage, however, prevents many children from receiving timely and equitable access to the best treatment.ObjectiveThe objective of this study was to evaluate parents’ willingness to pay (WTP) for biologic and nonbiologic disease-modifying antirheumatic drugs (DMARDs) used to treat JIA.MethodsUtility weights from a discrete choice experiment were used to estimate the WTP for treatment characteristics including child-reported pain, participation in daily activities, side effects, days missed from school, drug treatment, and cost. Conditional logit regression was used to estimate utilities for each attribute level, and expected compensating variation was used to estimate the WTP. Bootstrapping was used to generate 95% confidence intervals for all WTP estimates.ResultsParents had the highest marginal WTP for improved participation in daily activities and pain relief followed by the elimination of side effects of treatment. Parents were willing to pay $2080 (95% confidence interval $698–$4065) more for biologic DMARDs than for nonbiologic DMARDs if the biologic DMARD was more effective.ConclusionsParents’ WTP indicates their preference for treatments that reduce pain and improve daily functioning without side effects by estimating the monetary equivalent of utility for drug treatments in JIA. In addition to evidence of safety and efficacy, assessments of parents’ preferences provide a broader perspective to decision makers by helping them understand the aspects of drug treatments in JIA that are most valued by families.     

Current challenges and emerging drug delivery strategies for the treatment of psoriasis

ABSTRACT

Introduction: Psoriasis is a common skin disorder associated with physical, social, psychological and financial burden. Over the past two decades, advances in our understanding of pathogenesis and increased appreciation for the multifaceted burden of psoriasis has led to new treatment development and better patient outcomes. Yet, surveys demonstrate that many psoriasis patients are either undertreated or are dissatisfied with treatment. There are many barriers that need be overcome to optimize patient outcomes and satisfaction.

Areas covered: This review covers the current challenges associated with each major psoriasis treatment strategy (topical, phototherapy, oral medications and biologics). It also reviews the challenges associated with the psychosocial aspects of the disease and how they affect treatment outcomes. Patient adherence, inconvenience, high costs, and drug toxicities are all discussed. Then, we review the emerging drug delivery strategies in topical, oral, and biologic therapy.

Expert opinion: By outlining current treatment challenges and emerging drug delivery strategies, we hope to highlight the deficits in psoriasis treatment and strategies for how to overcome them. Regardless of disease severity, clinicians should use a patient-centered approach. In all cases, we need to balance patients’ psychosocial needs, treatment costs, convenience, and effectiveness with patients’ preferences in order to optimize treatment outcomes.     

Advances in pharmacotherapy for primary biliary cirrhosis

Introduction: Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease mostly seen in middle-aged women characterized by progressive nonsuppurative destruction of small bile ducts resulting in intrahepatic cholestasis, parenchymal injury and ultimately end-stage liver disease. Despite major breakthroughs in our understanding of PBC, there remains only one FDA-approved agent for treatment: ursodeoxycholic acid (UDCA) to which one-third of patients are unresponsive.

Areas covered: Biochemical response to treatment with UDCA is associated with excellent survival rates in PBC patients. However, there is a need for alternative treatments for nonresponders. Results from human epidemiological and genetic studies as well as preclinical studies in PBC animal models have provided a strong impetus for the development of new therapeutic agents. In this review, we discuss the recent advances in translational research in PBC focusing on promising therapeutic approaches, namely immune-based targeted therapies and agents targeting the synthesis and circulation of bile acids.

Expert opinion: We are in a new era for the development of novel therapies for PBC. Data on fibrates, budesonide and obeticholic acid offer encouragement for nonresponders to UDCA.     

ABP 501 for the treatment of rheumatoid arthritis

Introduction: Rheumatoid arthritis (RA) is an autoimmune disease, which has a negative impact on the ability to perform activities daily. Tumour necrosis factor α (TNF) is a cytokine with diverse cellular effects, and a key regulator of the inflammatory response. ABP 501 is a biosimilar to adalimumab, a TNF inhibitor.

Areas covered: In this review, we examined ABP 501, as a biosimilar candidate to adalimumab in the treatment of RA focusing on the available data. Current data indicate that ABP 501 is a highly similar alternative to adalimumab in terms of safety, efficacy, tolerability and immunogenicity. ABP 501 has already been approved by health authorities in Europe and the United States of America, as a subcutaneous (s.c.) therapy option for the treatment of patients with RA, but also for the full spectrum approved for its bio-originator adalimumab.

Expert opinion: Current body of evidence suggests that all biologic activities have been demonstrated to be equivalent between ABP 501 and the originator, including binding rates and affinity to TNF, and also the effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC). Therefore, it is fully expected to have same efficacy and safety in all indications.     

An overview of the efficacy and safety of systemic treatments for psoriasis in the elderly

Introduction: Psoriasis in elderly patients is considered to be of emerging clinical relevance because of the increase in the aged segment of the population. Psoriasis in such a group raises significant management challenges. There is an age-related immunosuppression, a high frequency of comorbidities, and polypharmacy, which enhances the potential risk of drug interactions or side effects when an additional systemic treatment must be administered. Despite the aging of the general population, clinical studies focusing on treatment of geriatric psoriasis are limited. Patients > 65 years are often not included in randomized clinical trials. As a result, the geriatric population affected by moderate-to-severe psoriasis is usually under-treated.

Areas covered: This review focuses on the use of systemic treatments in elderly psoriatic patients and their efficacy and safety data, analyzing the available literature evidences.

Expert opinion: Conventional agents should be carefully evaluated in each patient considering the possible organ impairment, comorbidities, concomitant medications and contraindications. Apremilast is an appropriate treatment for elderly patients. Biologics represent a safe option for a long-term management of psoriasis. Etanercept, adalimumab, ustekinumab, secukinumab, ixekizumab, and brodalumab have not been associated to a higher risk of adverse events in the elderly.