美国与欧盟孤儿药研发上市管理制度及对我国的启示

目的通过对美国与欧盟对孤儿药研发上市相关管理政策的分析,为我国孤儿药研发上市管理提供借鉴。方法分析美国和欧盟药政管理部门公开的法规文献和数据库检索数据,总结其对孤儿药的激励政策,分析获得孤儿药资格认定和批准上市的药物特点。结果美国和欧盟对孤儿药研发均颁布实施了诸如市场独占期、政府资助、审评专家对研究方案的指导等相应的激励政策。研发机构应采取及早申请孤儿药认定、多途径发现孤儿药及孤儿药的再开发等研发策略。结论美国和欧盟对孤儿药的研发与上市激励政策,刺激了制药企业对罕见病治疗药物的研发热情,有效缓解了罕见病无药可治的现状,对我国制定相关孤儿药政策提供了有益的借鉴。国内创新型制药企业应尽早布局孤儿药的研发,应重点关注国内已经被大众接受的罕见病和治疗,以及超说明书使用的问题;重点关注生物仿制药如单克隆抗体的研发动态;重点关注国际孤儿药专业公司的研发动态,使孤儿药在国内相关法律法规建立健全后,立即有所响应,尽早抢占孤儿药研发的领先地位和市场地位。     

Drugs for rare diseases: mixed assessment in Europe

(1) Worldwide, there are an estimated 6000 to 7000 rare diseases. Patients face special difficulties in obtaining an accurate diagnosis, adequate information about the disease, and access to qualified specialists. (2) Drug companies do not spontaneously conduct research on drugs for rare diseases, mainly because of the limited market for each indication. Only a few dozen of these drugs were available in France before 2000. (3) In 2000 the European Union adopted a Regulation, based on experience in the United States, aimed at promoting the development of drugs for patients suffering from rare diseases, i.e. 'orphan drugs'. (4) In Europe, orphan drug status can be granted when the prevalence of the disease does not exceed 5 cases per 10 000 inhabitants (or when it is more frequent but profitability is likely to be inadequate). (5) Companies that market an orphan drug receive a variety of financial assistance as well as a 10-year marketing monopoly. (6) Between April 2000 and April 2005, 268 medicinal products received European orphan drug status and 22 were granted European marketing authorization. (7) Access to these drugs varies greatly from one European Union Member State to another, mainly because of the high annual treatment costs (up to 300 000 euros per patient). Worldwide sales of the orphan drug imatinib reached more than two thousand million dollars in 2005. (8) Our systematic analyses (see the New Products column of our French edition la revue Prescrire) show that only 5 drugs which received European orphan drug status before May 2005 were for diseases for which there had previously been no treatment. (9) Clinical evaluation of orphan drugs is hindered by the small number of patients available for clinical trials. Some orphan drugs are adequately tested before being brought to market. Others are not compared to existing treatments. In many cases, surrogate criteria are used instead of clinical endpoints. These methodological flaws are in no way limited to orphan drugs. (10) Not all orphan drugs represent therapeutic advances. Clinical research and evaluation should continue after marketing authorization has been granted. (11) More drugs, with better-documented efficacy and safety, are now available for patients who previously had no effective treatment options. Yet there is too much duplication and too little evaluation, and too many drugs are extremely expensive, meaning that patients in many European countries cannot benefit. And many rare diseases are still neglected.     

Orphan drug development across Europe: bottlenecks and opportunities

With the assignment of the 500th European Union orphan drug designation in 2007, the Regulation on Orphan Medicinal Products truly begins to show its potential for delivering new medicines to patients with rare diseases. Here, we analysed European orphan drug development at a national level and unveil a strong relationship between orphan drug development and pharmaceutical innovation performance in Europe. Moreover, we identify gaps in transition from science into orphan drug development as important bottlenecks that exist in several European countries. Our findings underline the importance of innovation-based policies to enhance the development of orphan drugs in Europe.     

Cross-national comparative study of orphan drug policies in Saudi Arabia,the United States,and the European Union

BackgroundRare diseases are chronic, serious, and life-threatening conditions that have not received sufficient attention from drug developers due to their rarity. Policies have been implemented to encourage research and incentivize the development of orphan drugs. However, the implementation of these policies has been inconsistent worldwide.ObjectiveThe primary aim of this study was to compare orphan drug policies in the United States, Europe, and Saudi Arabia (SA) and assess their impact on the number of approved indications.MethodLists of all drugs granted orphan designations and authorized for marketing in the United States, European Union, and SA were extracted using orphan drug lists available in regulatory body databases. The availability of these drugs, regarding their approval for orphan indication and designation, was assessed and classified using Anatomical Therapeutic Chemical codes.ResultA total of 792 orphan drug designations with at least one authorized indication were identified in this study. Of these, 92% were designated by the Food and Drug Administration (FDA), and 27% were designated by the European Medicine Agency (EMA). The FDA, EMA, and Saudi Food and Drug Authority approved 753, 435, and 253 orphan drugs, respectively.ConclusionFewer orphan drug approvals were found in SA than in the United States and Europe. This highlights the need to focus on rare diseases and orphan drugs and for policies to be created in SA to attract pharmaceutical markets and fulfill unmet orphan drug approval needs.     

健康中国背景下孤儿药创新激励的制度安排

罕见病是一个重要的公共卫生问题,是健康中国战略的重要一环。治疗罕见病的孤儿药较之普通药物,其针对的目标市场狭窄、研发难度大、风险高,使得药企的研发意愿不高。为克服孤儿药研发创新的困境,保障罕见病患者的平等健康权和健康中国战略目标的实现,需要通过制度安排激励孤儿药的创新,以保障罕见药的供应。借鉴美国、欧盟等国家和地区的孤儿药创新激励经验,立足健康中国战略的背景与药事改革的需要,中国应从财税支持、加速审评审批和赋予市场独占权等方面的制度安排激励孤儿药创新。同时应防范创新激励措施可能导致的高价格和安全性方面的负面效应。     

药品全生命周期视角下中国罕见病药物保障政策简析

通过梳理我国国家及地方罕见病药物保障方面的相关政策,从药品全生命周期的角度探析我国罕见病药物保障现状,并提出相应的对策建议.本文通过查阅相关文献,搜索国家及地方政府网站和罕见病相关组织的网络平台,梳理了2015-2020年在罕见病药物研发阶段、注册阶段、定价与报销阶段、供应阶段、上市后监管阶段(药物警戒)与罕见病诊疗等...     

Orphan drugs for rare diseases: is it time to revisit their special market access status?

Orphan drugs are intended for diseases with a very low prevalence, and many countries have implemented legislation to support market access of orphan drugs. We argue that it is time to revisit the special market access status of orphan drugs. Indeed, evidence suggests that there is no societal preference for treating rare diseases. Although society appears to assign a greater value to severity of disease, this criterion is equally relevant to many common diseases. Furthermore, the criterion of equity in access to treatment, which underpins orphan drug legislation, puts more value on health improvement in rare diseases than in common diseases and implies that population health is not maximized. Finally, incentives for the development, pricing and reimbursement of orphan drugs have created market failures, including monopolistic prices and the artificial creation of rare diseases. We argue that, instead of awarding special market access status to orphan drugs, there is scope to optimize research and development (R&D) of orphan drugs and to control prices of orphan drugs by means of, for example, patent auctions, advance purchase commitments, pay-as-you-go schemes and dose-modification studies. Governments should consider carefully the right incentive strategy for R&D of orphan drugs in rare diseases.     

How Far Have We Come? Challenges to Orphan Drug Access in China, 2011-2017

Rare diseases are an important global public health issue. One significant challenge is to ensure the access to orphan drugs for patients with rare disease. This study aims to evaluate the accessibility of orphan drugs in China. Information pertaining to the availability and costs of each orphan drug in each hospital was obtained from the Chinese Medicine Economic Information database during 2011-2017. We measured the accessibility of orphan drugs from 3 aspects: availability, daily costs, and affordability to patients.The market availability rate of orphan drugs in China was 28.8% by June 30, 2017. The median availability rate at the hospital level was less than 15% but was increasing over time. The cost of a defined daily dose of orphan drugs varied significantly with a decreasing trend in all areas. Less than half of all surveyed orphan drugs had a cost of a defined daily dose no more than residents' average daily income.This study reveals the challenges of access to orphan drugs in China. The availability of marketed orphan drugs in China was relatively low and most orphan drugs placed a heavy financial burden on patients with rare disease. It is necessary to develop legislation for orphan drugs and encourage domestic generics.     

Rare diseases, orphan drugs and their regulation: questions and misconceptions

Sustained advocacy efforts driven by patients' organizations to make rare diseases a health priority have led to regulatory and economic incentives for industry to develop drugs for these diseases, known as orphan drugs. These incentives, enacted in regulations first introduced in the United States in 1983 and later in Japan, Europe and elsewhere, have resulted in substantial improvements in the treatment for patients with a range of rare diseases. However, the advent of orphan drug development has also triggered several questions, from the definition of rarity to the pricing of orphan drugs and their impact on health-care systems. This article provides an industry perspective on some of the common questions and misconceptions related to orphan drug development and its regulation, with the aim of facilitating future progress in the field.     

中美政府资助罕见病与罕用药科研基金项目的比较分析

目的:探索中美政府资助罕见病与罕用药科研基金项目差异性。方法:比较分析两国罕见病和罕用药科研项目的管理规定、数量、金额、研究机构和领域五大核心内容。结果:美国出台明确科研资助的罕用药和罕见病法案;2008-2013年间,美国NIH资助37826项罕见病及罕用药科研基金项目,共计约147.3亿美元;同期,中国NSFC资助3132项此类项目,共计约12.9亿元。中美的高校为罕见病及罕用药科研项目的主要承担机构。美国罕见病及罕用药项目的研究领域相对广泛,对重点研究采取持续性资助。结论:我国的罕见病和罕用药科研项目的管理存在定义界定不明确、缺乏专项科研基金项目、管理机构和激励机制,研究经费少和研究领域窄等问题,应针对性进行改进。     

国外罕用药创新激励制度及对我国的启示

罕用药由于具有经济性差、研发过程困难大、流通过程中对制药企业要求较高的特点,制药企业生产、研发这一类药品较少。为了解决这一困境,美国、欧盟、日本等国家和地区颁布实施了相应的罕用药创新激励制度。本文主要梳理了这3个国家和地区的罕用药制度,为我国罕用药制度的建立提供了参考和建议。     

欧盟罕用药管理的成就与经验及其对中国的启示

目的提出我国罕用药制度的建议。方法制度比较分析。结果欧盟通过颁布《罕用药管理规定》以促进罕用药的研发、投产和上市,取得了较为显著的成绩。这得益于欧盟在管理罕用药领域内采取各项行之有效的政策措施,主要体现在夯实主要立法基础、增强制度可操作性、完善特别审批程序以及大力资助研发投入等方面。这些举措给中国未来罕用药管理政策的制定和完善提供了丰富而又宝贵的经验。结论我国需要建立罕用药管理制度、完善特殊审批制度、促进罕用药基础研究的成果向应用领域转化。     

国外罕见病法律和保障体系与我国现状的对比分析

目的：为建立我国罕见病患者医药保障体系提供建议。方法：通过研究国外罕见病药物（孤儿药）研发政策和罕见病患者医药保障法律,找到我国与其他国家罕见病诊治和保障体系之间的差距和不足,并依照我国国情和医疗现状,提出建立我国罕见病患者保障体系的建议。结果：经过系统数据收集和分析后发现,发达国家和地区都有特定的部门负责制定和执行罕见病法律,罕见病的定义明确,制定了孤儿药研发的鼓励性政策并提供经费支持,罕见病的药物研发取得了极大进展,研发的积极性和研发的速度均得到了很大提高。同时,这些国家和地区的孤儿药支付体系比较健全,建立了国家基金、医疗、社会、商业保险等多重渠道不同比例的报销机制。相对来说,我国罕见病患者生存现状不佳,诊治状况不容乐观,用药不规范、依从性低。造成这些现象的原因包括治疗费用高而报销比例低,未引进相关治疗药物,供药不及时或停止供应,误诊率高等等。结论：建立我国罕见病患者保障体系是一项艰巨的工作,应从3个方面展开：一是明确我国罕见病和罕见病用药的定义、完善罕见病立法;二是将孤儿药,特别是通过药品治疗可以治愈的,以及针对儿童罕见病的药品纳入医疗保险,从而提高孤儿药的可及性;三是建立罕见病诊疗流程,提高罕见病的诊疗水平。     

Orphan drug development is progressing too slowly

AIMS: To assess the methodological quality of OMP dossiers and to discuss possible reasons for the small number of products licensed. METHODS: Information about orphan drug designation and approval was obtained from the website of the European Commission-Enterprise and Industry DG and from the European Public Assessment Reports. RESULTS: Out of 255 OMP designations, only 18 were approved (7.1%). Their dossiers often showed methodological limitations such as inappropriate clinical design, lack of active comparator where available and use of surrogate end-points. CONCLUSIONS: The paucity of European incentives for manufacturers and the poor documentation underpinning the applications may have limited the number of new OMP. The over 5000 rare diseases awaiting therapy are an important public health issue.     

Accelerating access to treatments for rare diseases

Changes in regulatory policy and legislative incentives to promote the development of drugs for rare diseases - orphan drugs - have led to increases in the number of orphan drug designations, but the rate of such products reaching the market remains frustratingly flat. This article highlights areas in which novel approaches could facilitate regulatory approval and access to treatments for rare diseases.     

罕见病用药现状分析

罕见病用药指用于治疗、诊断和预防罕见病或罕见症状的药物。近年来罕见病用药的研发逐渐成为一个可获利的研发策略,受到高度关注和重视。从目前国外罕见病药品市场情况、参与罕见病药物研发的公司和重点品种、美国和欧盟等发达国家和地区罕见病药物的指定和批准情况等方面对罕见病用药的现状及发展趋势进行简述。通过借鉴这些国家和地区罕见病药物发展的成功经验,为制定中国罕见病药物开发的刺激措施提出建议,为相关研发人员提供参考。     

Orphan drug development: an economically viable strategy for biopharma R&D

Orphan drug incentives have stimulated research into diseases with significant unmet medical need. Although the targeting of orphan diseases is seen by industry as an attractive strategy, there are limited economic data available to support its use. In this paper we show that the revenue-generating potential of orphan drugs is as great as for non-orphan drugs, even though patient populations for rare diseases are significantly smaller. Moreover, we suggest that orphan drugs have greater profitability when considered in the full context of developmental drivers including government financial incentives, smaller clinical trial sizes, shorter clinical trial times and higher rates of regulatory success. The data support the targeting of rare diseases as an important component of a successful biopharma R&D strategy.     

欧美孤儿药的研究与开发现状

文中对欧美孤儿药开发现状进行了分析。孤儿药研发尽管面临众多困难,但在欧美孤儿药现有制度法规、优惠措施及其他机遇的推动下,取得了较好的成果,促进了对罕见病患者的医疗救治。事实证明,政府完善的政策和采取合理的措施和方法,可解决当前孤儿药研发面临的诸多障碍,保证患者对新治疗方法的可获得性。欧美孤儿药的研发成功经验可为我国孤儿药管理政策和制度的建立提供一定的借鉴。     

英国罕见病药物准入过程中价格谈判机制的实施经验及启示

为我国罕见病药物医保准入过程中谈判机制建立和完善的提供借鉴。本研究通过查阅相关的官网,对英国发布的药品价格谈判相关政策进行深入分析,解读药品价格谈判机制在卫生技术评估与英国国民健康保障体系(National Health Service,NHS)报销中的应用。同时,以实证研究法分析英国国家卫生与临床优化研究所(National Institute for Health and Care Excellence,NICE)于2018年发布的罕见病药物报告,探究价格谈判机制的使用情况。英国对高值罕见病药物的谈判机制主要分为3种,即患者用药可及性方案(Patient Access Scheme,PAS)、商业准入协议(Commercial Access Agreements,CAAs)、管理准入协议(Managed Access Arrangements,MAAs),3种协议在使用过程中,都充分考虑了罕用药的特殊性。英国3种价格谈判机制的应用及其灵活性,对现阶段我国正面临的罕见病药物是否纳入医保问题,以及维护医保基金可持续性均有重要的借鉴价值,也为我国药品价格谈判方案的运行提供实践依据。