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孤儿药（英语：Orphan drug，亦称为罕用药）指的是专门用于治疗罕见疾病的药物。[1]因为其孤苦无依且乏人重视的印象，这些罕见疾病有时也被称为孤儿病。[2]由于孤儿药的市场需求太小，正常情况下药物开发上难以收回成本，因此许多国家将罕见疾病的定义以及孤儿药的开发列为重要的政策，透过给予补贴、延长厂商对孤儿药的专卖权（英语：Exclusive right）等优惠以鼓励开发商投入资源开发此类药物。[3][4][5][6]此外，孤儿药在许多国家比起一般药物更容易取得上市许可（英语：marketing authorisation）。[3][4][5][6]各国对于认定罕见疾病的标准并不一致，因此甲地的孤儿药在乙地有可能被视为一般药物，各国的孤儿药种类多寡也可能有数倍的差距。[7]

定义[编辑]

更多信息：罕见疾病

药物开发（英语：Drug development）的过程费时[注 1][8]、昂贵[注 2][8]、而且困难[注 3][9]，因此开发治疗罕见疾病的药物对药厂而言难以回收成本。虽然详细的规定在各国有所不同，但一般而言孤儿药指的就是这类公共卫生上有需求，但因为市场规模问题，药商不愿投入开发或生产的药物[10]。虽然多数孤儿药用于治疗罕见疾病，但这个问题并不仅限于罕见疾病用药，有时候即使是治疗常见疾病的药物也有可能“孤儿化”。举例来说，苄青霉素是唯一可以预防及治疗梅毒垂直传染的药物，但由于其价格低廉，对药商而言生产贩售苄青霉素没有获利空间，因此苄青霉素短缺的问题长期无法解决[11]。

政策[编辑]

规范概论[编辑]

从公共卫生的角度而言，罕见疾病以及孤儿药问题的处理带来许多挑战。美国为了解决这些问题在1983年通过孤儿药法案（英语：Orphan Drug Act of 1983）[12]，孤儿药法案所采取的策略包括直接补贴孤儿药的研究开发与临床试验、优先上市审查、延长药物专卖权、以及租税优惠等等。由于这些优惠有效的促进了孤儿药的开发[注 4][13]，稍后各国陆续采取的政策也常使用相似的策略[14][15]。下表中之相关规范与政策，罕见疾病及孤儿药当地法规规定需登记者，在表格中会列出已登记罕见疾病及孤儿药之数量，如果未特别规范则标为不表列。

台湾 新加坡 中国 日本 大韩民国 澳大利亚 欧盟 美国
相关规范 罕见疾病防治
及药物法[16]		 孤儿药条例[注 5][17] 无[18] 药事法（：医薬品、医療機器等の品質、有効性及び安全性の確保等に関する法律）
第七十七条
第二款[18][19][20]		 孤儿药管理
条款[注 6][21]		 孤儿药
计划[22][注 7]		 欧洲孤儿药
规范[23]		 孤儿药法案（英语：Orphan Drug Act of 1983）
主管机关 卫生福利部 卫生科学局（英语：Health Sciences Authority） 卫生部 厚生劳动省 食药安全部（英语：Ministry of Food and Drug Safety）[21] 药物管理局（英语：Therapeutic Goods Administration）[24] 欧洲药品
管理局[25]		 食品药物管理局
罕见疾病定义 发生率少于
1/10,000[26]		 患病者少于
20,000人[27]		 政府核定[注 8][5] 患病者少于
50,000人[28]		 患病者少于
20,000人[21]		 发生率少于
1/2,000[29]		 发生率少于
1/2,000[15]		 发生率少于
3/4,000[15]
罕见疾病种类 220[30] 不表列[27] 121[注 8][31] 331[32] 不表列 不表列[24] 不表列 不表列
孤儿药种类 235[33] 不表列[27] 不表列[34] 417[35] 158[36][注 9] 287[37] 1627[38] 4846[39]
研究或临床试验补助 无[注 10][40] 无[17] 无 补助研发费用[28] 申请费减免
50 %[21]		 免申请费[24] 各国自主[18] 补助研究费用
免申请费[18]
优先审查 加速核准[注 11][41] 若经处方进口
不须审查[27][18]		 小型或豁免
临床试验[18][34]		 独立审查窗口[28] 不需复审[21] 无[24] 有[15] 优先审查（英语：priority review）
速审（英语：fast track）
突破性新疗法（英语：breakthrough therapy）
专卖权 10年[18] 10年[18] 无 10年[28] 无[21] 无[18] 10年[18] 7年[15]
税务优惠 同一般新药[注 12][42] 无[17] 无 税务减免[28] 无[21] 无[18] 各国自主[18] 税务减免[18]


规范个论与历史[编辑]

台湾[编辑]

行政院在1997年提案的罕见疾病防治及药物法[16][注 13]是世界上第五部专门用来管理罕见疾病及药品的法律[43]。依照该法规定，卫生福利部应该设立由政府代表、医疗人员、以及社会公正人士组成的罕见疾病及药物审议委员会。这个委员会主要负责审批孤儿药与提供罕见疾病防治与治疗相关政策的建议[16]。以盛行率万分之一以标准，治疗照护困难又不受全民健康保险给付的疾病可以登记为罕见疾病[26]，罕见疾病患者的诊断、治疗与照护均可以申请补助[44]。

有研究支持可用于预防、诊断或治疗罕见疾病的药物，在申请登记为孤儿药时需要再提供。安全性试验报告及临床试验报告[45]。成功登记孤儿药的药商在登记的有效期间可以享有最长十年的专卖期[16]。卫生福利部如果有计划鼓励药商投入进口、生产、或是开发孤儿药，罕见疾病及药物审议委员会也要负责评估药商是否符合奖励标准[46]。

新加坡[编辑]

新加坡在1991年通过孤儿药条例，该法定义孤儿药用于治疗有生命危险且对日常生活有极大影响的疾病[17]。符合该条件的药物如果在他国已取得许可，但在新加坡尚未核准，则可以提出专案申请进口该项药物。新加坡不补助孤儿药的开发，但孤儿药核准后享有十年专卖权[17][18]。

中国[编辑]

中国虽然没有针对孤儿药与罕见疾病的特别法规。[47]，但于2015年国务院曾指示应加速审查孤儿药[48]。2017年时国家食品药品监督管理总局提出了相应的意见稿，其中指出孤儿药应该优先审批[49]。2018年8月，国家卫生健康委员会与其他机关发布《第一批罕见病目录》，其收录121种疾病，但尚未将治疗这些疾病的药物列入中华人民共和国医疗保险范围当中[47]。

日本[编辑]

欧盟[编辑]

欧洲共同体在2000年[23]通过鼓励孤儿药开发的相关法规。该法案的立法宗旨与美国孤儿药法案相似，但孤儿药的定义较广，除罕见疾病外，治疗被忽视的热带病也被归为孤儿药[50]。厂商在药物研发过程中可以向欧洲药物管理局所属的孤儿药物医材委员会（Committee on Orphan Medicinal Products）申请登记为孤儿药，成功登记为孤儿药的药物在开发过程中会得到技术支援，上市审查的过程则可以透过欧洲药物管理局的单一窗口负责办理。核准上市之后，开发商享有自核准日起十年的专卖权，另外还有行政规费的减免与研发经费的支援等[51]。2007年下半年，美国食品药物管理局与欧洲药物管理局为方便厂商提出申请，决定将孤儿药申请流程一致化[52]。虽然欧美的孤儿药登记流程是相同的，但审核仍然独立进行[52]。

美国[编辑]

在美国罕见疾病组织为首的罕见疾病支持团体的推动下，孤儿药法案（英语：Orphan Drug Act of 1983）于1983年通过[53]。订定孤儿药法案的目的是鼓励药商开发市场较小的药物[54]。根据孤儿药法案的规定，如果药品、疫苗及检验器材的适应症在美国境内的病人数少于20万或或者新药的预期收入不足以收回研发成本均可登记为孤儿药[55]。为了刺激孤儿药的研究，孤儿药的研发厂商将获得7年的专卖权、最高50 %研发费用可抵免税金、研究经费补助、美国食品药物管理局行政规费减免、以及申请流程咨询与协助等[55]。孤儿药的开发商可以在提出上市许可前向孤儿药开发办公室申请，将开发中的药品登记为孤儿药[56]。申请时开发商需要说明该药物预计治疗的疾病的盛行率以及支持该药物治疗目标疾病的科学证据[13][57][注 14]。2002年罕见疾病法案（英语：Rare Diseases Act of 2002）通过，该法案的内容包括设立罕见疾病办公室（英语：Office of Rare Diseases Research）以及进一步增加投入孤儿药开发的预算。[58]

除了政府机关的投入，学术机构也对孤儿药的开发扮演重要角色。举例来说，明尼苏达大学药学院设立于2005年的马奎尔转译医学中心在2007年更名为孤儿药研究中心（英语：Center for Orphan Drug Research），致力于协助专业知识与资源较少的小公司进行药物合成、调配（formulation）、定量药理分析（英语：Pharmacometrics）、以及生物处理（英语：Bioprocess）[59]。凯克应用生命科学研究所的罕见疾病疗法中心则以协助分析潜在药物的调配与生物处理特性来让更多潜在的孤儿药能够成功上市。[59]

在关注罕见疾病权益的倡议组织方面，除了推动孤儿药法案的美国罕见疾病组织外，还有全球基因（英语：Global Genes）[60]、弗里德希氏共济失调研究连线（英语：Friedreich's Ataxia Research Alliance）[61]等团体以促进罕见疾病患者权益为宗旨。

成效[编辑]

According to Thomson Reuters in their 2012 publication "The Economic Power of Orphan Drugs," there has been increased investing in orphan drug research and development partly due to the U. S. Orphan Drug Act of 1983 (ODA) and similar acts in other regions of the world and also driven by "high-profile philanthropic funding."[62][63]

Per the trade journal Drug Discovery Today between 2001 and 2011 was the "most productive period in the history of orphan drug development, in terms of average annual orphan drug designations and orphan drug approvals."[63]:660 For the same decade the compound annual growth rate (CAGR) of the orphan drugs was an "impressive 25.8 percent, compared to only 20.1 percent for a matched control group of non-orphan drugs."[62]:6 By 2012, the market for orphan drugs was worth USD$637 million compared to the USD$638 million matched control group of non-orphan drugs.[62]

By 2012,

"the revenue-generating potential of orphan drugs [was] 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."

——Gaze and Breen 2012

According to a 2014 report, the orphan drug market has become increasingly lucrative for a number of reasons: The cost of clinical trials for orphan drugs is substantially lower than for other diseases —trial sizes are naturally much smaller than for more common diseases with larger numbers of patients. Small clinical trials and little competition place orphan agents at an advantage in regulatory review.[64]

Tax incentives reduce the cost of development. On average the cost per patient for orphan drugs is "six times that of non-orphan drugs, a clear indication of their pricing power". The cost of per-person outlays are huge and are expected to increase with wider use of public subsidies.[64]

The 2014 Orphan Drug report stated that the percentage of orphan drug sales as part of all prescription drug sales had been increasing at rapid rate. By 2020 the total was predicted to be $176 billion.[64] Although orphan disease populations are the smallest, the cost of per-patient outlays have been the largest. There pressure on pharmaceuticals which "represent the biggest budgetary drain" has been predicted to increase particularly as more people with rare diseases will be eligible for subsidies —in the United States for example through the Affordable Care Act.[64]


A 2015 study of "34 key Canadian stakeholders including drug regulators, funders, scientists, policy experts, pharmaceutical industry representatives, and patient advocates" investigated contributing factors to the growing interest of the pharmaceutical industry in "niche markets" such as orphan drugs.[65]

例如治疗庞贝氏症的药物Myozyme便是一例，发展出该药的中央研究院生物医学科学研究所所长陈垣崇便是投入研究数十年，也放弃了许多收入更高的工作机会。

现况与展望[编辑]

截至2014年 (2014-Missing required parameter 1=month!), there were 281 marketed orphan drugs and more than 400 orphan designated drugs in clinical trials. More than 60% of orphan drugs were biologics. The US dominated the development of orphan drugs with more than 300 orphan drugs in clinical trial process, followed by Europe. Cancer treatment was the indication in more than 30% for orphan drug clinical trials.[66]

  • Number of orphan drugs in clinical trials: 600[66]
  • Number of orphan drugs in Phase-2 Trial: 231[66]
  • Number of orphan drugs in US clinical trials: 350 in the pipeline from research until registration[66]
  • Key Market: US (Sales more than US$40 billion)[66]

Numbers of new drugs[编辑]

Under the ODA and EU legislation, many orphan drugs have been developed, including drugs to treat glioma, multiple myeloma, cystic fibrosis, phenylketonuria, snake venom poisoning, and idiopathic thrombocytopenic purpura.[来源请求]

The Pharmaceitical Executive opines, that the "ODA is nearly universally acknowledged to be a success".[67]

Before the United States Congress enacted the ODA in 1983, only 38 drugs were approved in the USA specifically to treat orphan diseases.[68] In the USA, from January 1983 to June 2004, the Office of Orphan Products Development 249 orphan drugs received marketing authorization and granted 1,129 different orphan drug designations, compared to fewer than ten such products in the decade prior to 1983. From 1983 until May 2010, the FDA approved 353 orphan drugs and granted orphan designations to 2,116 compounds. As of 2010, 200 of the roughly 7,000 officially designated orphan diseases have become treatable.[67]

Critics have questioned whether orphan drug legislation was the real cause of this increase, claiming that many of the new drugs were for disorders which were already being researched anyway, and would have had drugs developed regardless of the legislation, and whether the ODA has truly stimulated the production of non-profitable drugs; the act also has been criticised for allowing some pharmaceutical companies to make a large profit of drugs which have a small market but sell for a high price.[54]

While the European Medicines Agency grants orphan drugs market access to all member states, in practice, they only reach the market when a member state decides that its national health system will reimburse for the drug. For example, in 2008, 44 orphan drugs reached the market in the Netherlands, 35 in Belgium, and 28 in Sweden, while in 2007, 35 such drugs reached the market in France and 23 in Italy.[69]

Though not technically an orphan disease, the research and development into the treatment for AIDS has been heavily linked to the Orphan Drug Act. In the beginning of the AIDS epidemic the lack of treatment for the disease was often accredited to a believed lack of commercial base for a medication linked to HIV infection. This encouraged the FDA to use the Orphan Drug Act to help bolster research in this field, and by 1995 13 of the 19 drugs approved by the FDA to treat AIDS had received orphan drug designation, with 10 receiving marketing rights. These are in addition to the 70 designated orphan drugs designed to treat other HIV related illnesses.[70]

Examples for selected diseases[编辑]

In the 1980s, people with cystic fibrosis rarely lived beyond their early teens. Drugs like Pulmozyme and tobramycin, both developed with aid from the ODA, revolutionized treatment for cystic fibrosis patients by significantly improving their quality of life and extending their life expectancies. Now, cystic fibrosis patients often survive into their thirties and some into their fifties.

The 1985 Nobel Prize for medicine went to two researchers for their work related to familial hypercholesterolemia, which causes large and rapid increases in cholesterol levels. Their research led to the development of statin drugs which are now commonly used to treat high cholesterol.[71]

Penicillamine was developed to treat Wilson's disease, a rare hereditary disease that can lead to a fatal accumulation of copper in the body. This drug was later found to be effective in treating arthritis.[71] Bis-choline tetrathiomolybdate is currently under investigation as a therapy against Wilson's disease.

Cost[编辑]

According to a 2015 report published by EvaluatePharma, the economics of orphan drugs mirrors the economics of the pharmaceutical market as a whole but has a few very large differences.[72] The market for orphan drugs is by definition very small, but while the customer base is drastically smaller the cost of research and development is very much the same as for non orphan drugs. This, the producers have claimed, causes them to charge extremely high amounts for treatment sometimes as high as $700,000 a year, as in the case of Spinraza (Biogen), FDA approved in December 2016 for spinal muscular atrophy,[73] placing a large amount of stress on insurance companies and patients. An analysis of 12 orphan drugs that were approved in the US between 1990 and 2000 estimated a price reduction of on average 50% upon loss of marketing exclusivity, with a range of price reductions from 14% to 95%.[74]

Governments have implemented steps to reduce high research and development cost with subsidies and other forms of financial assistance. The largest assistance are tax breaks which can be as high as 50% of research and development costs.[75] Orphan drug manufacturers are also able to take advantage of the small customer base to cut cost on clinical trials due to the small number of cases to have smaller trials which reduces cost. These smaller clinical trials also allow orphan drugs to move to market faster as the average time to receive FDA approval for an orphan drug is 10 months compared to 13 months for non-orphan drugs. This is especially true in the market for cancer drugs, as a 2011 study found that between 2004 and 2010 orphan drug trials were more likely to be smaller and less randomized than their non-orphan counterparts, but still had a higher FDA approval rate, with 15 orphan cancer drugs being approved, while only 12 non-orphan drugs were approved.[76] This allows manufactures to get cost to the point that it is economically feasible to produce these treatments.[75] The subsidies can total up to 30 million dollars per fiscal year in the United States alone [来源请求].

By 2015, industry analysts and academic researchers agreed, that the sky-high price of orphan drugs, such as eculizumab, was not related to research, development and manufacturing costs. Their price is arbitrary and they have become more profitable than traditional medicines.[77]

"Public resources went into understanding the molecular basis of the disease, public resources went into the technology to make antibodies and finally, Alexion, to their credit, kind of picked up the pieces."

——Sachdev Sidhu 2015

Public-funding[编辑]

Evaluation criteria[编辑]

By 2007 the use of economic evaluation methods regarding public-funding of orphan drugs, using estimates of the incremental cost-effectiveness, for example, became more established internationally.[78] The QALY has often been used in cost-utility analysis to calculate the ratio of cost to QALYs saved for a particular health care intervention.[79][80] By 2008 the National Institute for Health and Care Excellence (NICE) in England and Wales, for example, operated with a threshold range of £20,000–£30,000 per Quality-adjusted life year (QALY).[81] By 2005 doubts were raised about the use of economic evaluations in orphan drugs.[78] By 2008 most of the orphan drugs appraised had cost-effectiveness thresholds "well in excess of the ‘accepted’ level and would not be reimbursed according to conventional criteria."[81] As early as 2005 McCabe et al argued[82][83] that rarity should not have a premium and orphan drugs should be treated like other pharmaceuticals in general.[82][83] Drummond et al[83] argued that the social value of health technologies should also be included in the assessment along than the estimation of the incremental cost-effectiveness ratio.

Abuse potential[编辑]

Rosuvastatin (brand name Crestor) is an example of a drug that received Orphan Drug funding but was later marketed to a large consumer base.

The very large incentives given to pharmaceutical companies to produce orphan drugs have led to the impression that the financial support afforded to make these drugs possible is akin to abuse.[84] Because drugs can be used to treat multiple conditions, companies can take drugs that were filed with their government agency as orphan drugs to receive financial assistance, and then market it to a wide population to increase their profit margin. For example AstraZeneca's cholesterol drug Crestor was filed as a treatment for the rare disease pediatric familial hypercholesterolemia. After the drug was approved for orphan drug designation, and AstraZeneca had received tax breaks and other advantages, AstraZeneca later applied and received FDA approval for the drug to be used to treat cholesterol in all diabetics.[71]

NICE[编辑]

By 2008 if an orphan drug cost more than £30,000[需要解释] the NICE required other arguments for funding.[81]

In 2015, NICE held consultations with "patient groups, the Department of Health, companies, learned societies, charities and researchers" regarding the appraisal of medicines and other technologies. There was a call for more research into new processes including the [85]

"model of pharmaceutical research and development, the expectations that companies and patient groups have about how risk and reward is shared between the industry and a publicly funded NHS, and in the arrangements for commissioning expensive new treatments."

——NICE 2014

备注[编辑]

  1. ^ 潜在新药从发现到上市至少需要十年，其中临床试验平均会花费六到七年。
  2. ^ 在美国成功上市的新药的平均开发花费是二十六亿美元。
  3. ^ 美国2006－2015年间，所有进入第一期临床试验只有9.6 %取得上市许可（英语：marketing authorization）。
  4. ^ 美国在1973－1983年间只有10种孤儿药上市，但在1983年法案生效后的三十年期间有超过3,900种药物登记为孤儿药，当中有590种成功上市。
  5. ^ 孤儿药条例（英语：Orphan drugs Exemption to the Medicines Act）是医疗法（英语：Medicines Act）第一七六章第九节，其于1991年生效。
  6. ^ 孤儿药管理条款：编号1998-23（英语：Regulation on Orphan Drug Designation. Notification No.1998-23）
  7. ^ 澳大利亚的孤儿药政策始于1997年在医疗用品规范（英语：Therapeutic Goods Regulations）中的特别规定。2017年经过重新修订，主要的更动是放宽盛行率标准，但收紧病情严重度标准，并增列可视为孤儿药的特例。
  8. ^ 8.0 8.1 2018年中国政府基于中共中央办公厅、国务院办公厅提出的《关于深化审评审批制度改革鼓励药品医疗器械创新的意见》，国家卫生健康委员会、科学技术部、工业和信息化部、国家药品监督管理局以及国家医药管理局联合制定了《第一批罕见病目录》。
  9. ^ 视为孤儿药的条件包括罕见疾病用药、针对原本没有治疗方法的疾病的药物、年度进口额低于五百万美元的药物、或是生产额低于十五亿韩元的国产药物。
  10. ^ 台湾财团法人罕见疾病基金会订有补助办法可补贴试验经费不足部分。
  11. ^ 依新药查验登记加速核准机制规定，如具医疗迫切需求且在美、日、加拿大、澳洲、英国及德、法、瑞典、瑞士、比利时中任一国被认定为孤儿药，则适用加速核准流程。
  12. ^ 新药开发可享有研发投资抵减税率50%、研发费用抵减率35%-50%、人才培训支出35%抵减营利事业所得税、高阶专业人员认股权得延缓至转让时以转让价格扣除成本课个人所得税、以及技术投资人技术作价得延缓至转让时以转让价格扣除成本课个人所得税等；投资新药开发商得申请最高20%购买新药研发公司股价的所得税抵减。
  13. ^ 本草案于1999年通过并生效。
  14. ^ 例外：孤儿药法案中规定即使药物适应症的的患者人数超过20,000人，只要能举证该药物在上市七年内无法获利就能登记为孤儿药，但由于举证困难，少有厂商透过此规定登记孤儿药。

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