罕见病药品贝林妥欧单抗临床研发和风险获益评估及启示

贝林妥欧单抗（通用名blinatumomab、中文商品名贝利妥、英文商品名Blincyto）于2014年获美国食品药品管理局（FDA）批准上市，是全球首个治疗急性淋巴细胞白血病（ALL）的双靶点抗体药物，持证商为美国安进公司（Amgen）。作为创新生物制品，其上市申请、审评和批准过程分别经历了FDA孤儿药（orphan drug）资格认定、突破性治疗药品（breakthrough therapy）资格认定、优先审评（priority review）资格认定、附条件批准（accelerated approval）等创新药的优先和特殊政策。通过文献研究法，收集、整理、分析了FDA首次批准贝林妥欧单抗的审评报告及相关文献，在全面了解该品种特点及审评审批过程的基础上，以有效性研究评价模式为切入点，尝试总结“以患者需求为核心，以临床价值为导向”的创新药物审评审批理念的具体实践经验，以期为我国新药研发和审评提供借鉴。     

Orphan drug development: The impact of regulatory and reimbursement frameworks

The enactment of orphan drug-specific legislation pioneered by the USA was subsequently followed by many regions, including the European Union (EU), Australia, Japan, and Taiwan. Here, we discuss the associated regulations established and their impacts in the aforementioned regions, which are among the first with frameworks specific for orphan drugs. Varied scopes of rare diseases or orphan drugs, diverse incentives, and heterogeneous types of reimbursement systems imply the prioritization of the agencies concerned. The numbers of designated and approved drugs reflect the impact of the regulatory and reimbursement frameworks. A comparison of the frameworks and their impact in the respective regions could provide valuable information for developing and improving related frameworks for countries worldwide.     

High prevalence rates of tobacco, alcohol and drug use in adolescents and young adults in France: results from the GAZEL Youth study

BACKGROUND: Rates of substance use among adolescents have increased in the 1990s, however little is known about current patterns of substance use among youths entering adulthood. METHODS: We studied sex and age-specific rates of substance use (tobacco, alcohol, cannabis, other illicit drugs, inhalants and psychotropic medications) in a large sample of French youths aged 12-26 years (the GAZEL Youth study, n=1333). RESULTS: Prevalence rates of substance use were high and varied with age and sex. Tobacco, cannabis and polysubstance use were most frequent among 19-21 year-olds (regular tobacco use: 41.5% in males, 39.9% in females; regular cannabis use: respectively 23.9% and 10.9%; tobacco+alcohol+cannabis: respectively 9.9% and 4.6%). Regular alcohol use was most frequent among 22-26 year-olds (29.8% in males, 15.6% in females). Across successive birth cohorts, the age of initiation of tobacco and cannabis use decreased. Males were consistently more likely to use psychoactive substances than females (except for tobacco and psychotropic medications). CONCLUSIONS: Rates of substance abuse peak in late adolescence but remain high among a subgroup of young adults. Moreover, substance use initiation appears to be occurring at increasingly younger ages.     

Positron emission tomography microdosing: a new concept with application in tracer and early clinical drug development

The realisation that new chemical entities under development as drug candidates fail in three of four cases in clinical trials, together with increased costs and increased demands of reducing preclinical animal experiments, have promoted concepts for improvement of early screening procedures in humans. Positron emission tomography (PET) is a non-invasive imaging technology, which makes it possible to determine drug distribution and concentration in vivo in man with the drug labelled with a positron-emitting radionuclide that does not change the biochemical properties. Recently, developments in the field of rapid synthesis of organic compounds labelled with positron-emitting radionuclides have allowed a substantial number of new drug candidates to be labelled and potentially used as probes in PET studies. Together, these factors led to the logical conclusion that early PET studies, performed with very low drug doses—PET-microdosing—could be included in the drug development process as one means for selection or rejection of compounds based on performance in vivo in man. Another important option of PET, to evaluate drug interaction with a target, utilising a PET tracer specific for this target, necessitates a more rapid development of such PET methodology and validations in humans. Since only very low amounts of drugs are used in PET-microdosing studies, the safety requirements should be reduced relative to the safety requirements needed for therapeutic doses. In the following, a methodological scrutinising of the concept is presented. A complete pre-clinical package including limited toxicity assessment is proposed as a base for the regulatory framework of the PET-microdosing concept.     

The impact of molecular targets in cancer drug development: major hurdles and future strategies

The last decades were characterized by enormous technological advances resulting in a better understanding of disease pathologies and improvement of treatment strategies. The development of targeted drugs, whose beginning can be traced back to Paul Ehrlich’s theory of the ‘magic bullet’ approximately 100 years ago, is today widely appraised as a promising strategy to combat benign, as well as malignant, diseases. Over 40 years after US President Nixon declared the ‘war on cancer’, treatment outcome, especially of solid tumors in the advanced stages of disease, still lies far behind expectations. In this perspective article, the authors discuss the recent development of targeted cancer drugs and identify major hurdles. The authors further highlight future strategies that might improve and accelerate the drug-development process.     

Tumor vasculature directed drug targeting: applying new technologies and knowledge to the development of clinically relevant therapies

Recognition of the dependence of solid tumor growth on the formation of new blood vessels has ignited an enormous research effort aimed at the development of new therapeutic strategies for cancer. Besides direct application of drugs inhibiting endothelial cell function during angiogenesis, tumor vasculature directed drug-targeting strategies have been investigated for this purpose. In animal models of disease, proof of principle regarding the potential of selective interference with tumor blood flow as a powerful tumor therapy has been generated to its full extent. The challenge for the coming years will be to develop these strategies into clinically applicable ones. New insights into the molecular mechanisms prevailing in the endothelium during angiogenesis and into the mechanism(s) of action of drugs with anti-angiogenic activities, as well as new techniques to identify useful tumor endothelium specific target epitopes have in recent years been exploited to meet this challenge. This review summarizes vasculature directed therapeutic strategies proven to be successful in pre-clinical models and new (drug targeting) technologies enabling the development of more effective therapeutics for the treatment of cancer.     

Isoniazid–phytochemical conjugation: A new approach for potent and less toxic anti‐TB drug development

Mycobacterium tuberculosis (Mtb) causes one of the most grievous pandemic infectious diseases, tuberculosis (TB), with long‐term morbidity and high mortality. The emergence of drug‐resistant Mtb strains, and the co‐infection with human immunodeficiency virus, challenges the current WHO‐TB stewardship programs. The first‐line anti‐TB drugs, isoniazid (INH) and rifampicin (RIF), have become extensively obsolete in TB control from chromosomal mutations during the last decades. However, based on clinical trial statistics, the production of well‐tolerated anti‐TB drug(s) is miserably low. Alternately, semi‐synthesis or structural modifications of first‐line obsolete antitubercular drugs remain as the versatile approach for getting some potential medicines. The use of any suitable phytochemicals with INH in a hybrid formulation could be an ideal approach for the development of potent anti‐TB drug(s). The primary objective of this review was to highlight and analyze available INH–phytochemical hybrid research works. The utilization of phytochemicals through chemical conjugation is a new trend toward the development of safer/non‐toxic anti‐TB drugs.     

Blood–brain barrier models and their relevance for a successful development of CNS drug delivery systems: A review

During the research and development of new drugs directed at the central nervous system, there is a considerable attrition rate caused by their hampered access to the brain by the blood–brain barrier. Throughout the years, several in vitro models have been developed in an attempt to mimic critical functionalities of the blood–brain barrier and reliably predict the permeability of drug candidates. However, the current challenge lies in developing a model that retains fundamental blood–brain barrier characteristics and simultaneously remains compatible with the high throughput demands of pharmaceutical industries. This review firstly describes the roles of all elements of the neurovascular unit and their influence on drug brain penetration. In vitro models, including non-cell based and cell-based models, and in vivo models are herein presented, with a particular emphasis on their methodological aspects. Lastly, their contribution to the improvement of brain drug delivery strategies and drug transport across the blood–brain barrier is also discussed.     

Translation,cross-cultural adaptation and validation of the revised Patients’ Attitudes Towards Deprescribing (rPATD) questionnaire to Portuguese: Older adults version

BackgroundDeprescribing is a patient-centered approach to managing inappropriate polypharmacy that faces several barriers, including patients' attitudes and beliefs about medications that need to be considered. For this purpose, the revised Patients' Attitudes Towards Deprescribing (rPATD) questionnaire is a helpful instrument, but until now, there is no Portuguese version.ObjectivesTo translate and validate the rPATD questionnaire (older adults version) to Portuguese.MethodsThe rPATD questionnaire was translated and cross-culturally adapted using forward-backward translation and pre-testing. A cross-sectional study with 192 older adults aged ≥65 years taking at least 1 regular medication was conducted for validity assessment. Participants were recruited by convenience sampling in 3 Portuguese outpatient rehabilitation medicine clinics. Psychometric properties were evaluated through face and content validity; construct validity, by assessing structural validity through exploratory factor analysis, hypotheses testing, including concurrent validity and cross cultural validity; reliability with internal consistency; and item-total correlation. Floor and ceiling effects were examined.ResultsThe exploratory factor analysis (EFA) revealed a 4-factor structure that explains 51.08% of the total variance, as in the original rPATD. These 4 factors are related to the level of involvement in medication management, beliefs in the appropriateness of medication, perceived burden of medication, and concerns about stopping medications. Factor loadings ranged from 0.226 to 0.800; 2 items scored <0.3, and no cross-loading was found. The exclusion of the 2 items loading <0.3 in the EFA showed no significant improvement in factor loading or internal consistency, so the item structure was maintained. In hypothesis testing, 78% of the correlations were correctly predicted. The 4 factors internal consistency was generally acceptable, with Cronbach's alpha ranging from 0.638 to 0.830. The item-total correlation ranged between 0.223 and 0.7.ConclusionThe Portuguese rPATD questionnaire for older adults presents globally good or acceptable psychometric properties.