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使用者:Hiko.C/孤兒藥

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孤兒藥（英語：Orphan drug，亦稱為罕用藥）指的是專門用於治療罕見疾病的藥物。[1]因為其孤苦無依且乏人重視的印象，這些罕見疾病有時也被稱為孤兒病。[2]由於孤兒藥的市場需求太小，正常情況下藥物開發上難以收回成本，因此許多國家將罕見疾病的定義以及孤兒藥的開發列為重要的政策，透過給予補貼、延長廠商對孤兒藥的專賣權（英語：Exclusive right）等優惠以鼓勵開發商投入資源開發此類藥物。[3][4][5][6]此外，孤兒藥在許多國家比起一般藥物更容易取得上市許可（英語：marketing authorisation）。[3][4][5][6]各國對於認定罕見疾病的標準並不一致，因此甲地的孤兒藥在乙地有可能被視為一般藥物，各國的孤兒藥種類多寡也可能有數倍的差距。[7]

定義

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更多資訊：罕見疾病

藥物開發（英語：Drug development）的過程費時[註 1][8]、昂貴[註 2][8]、而且困難[註 3][9]，因此開發治療罕見疾病的藥物對藥廠而言難以回收成本。雖然詳細的規定在各國有所不同，但一般而言孤兒藥指的就是這類公共衛生上有需求，但因為市場規模問題，藥商不願投入開發或生產的藥物[10]。雖然多數孤兒藥用於治療罕見疾病，但這個問題並不僅限於罕見疾病用藥，有時候即使是治療常見疾病的藥物也有可能「孤兒化」。舉例來說，苄青黴素是唯一可以預防及治療梅毒垂直傳染的藥物，但由於其價格低廉，對藥商而言生產販售苄青黴素沒有獲利空間，因此苄青黴素短缺的問題長期無法解決[11]。

政策

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規範概論

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從公共衛生的角度而言，罕見疾病以及孤兒藥問題的處理帶來許多挑戰。美國為了解決這些問題在1983年通過孤兒藥法案（英語：Orphan Drug Act of 1983）[12]，孤兒藥法案所採取的策略包括直接補貼孤兒藥的研究開發與臨床試驗、優先上市審查、延長藥物專賣權、以及租稅優惠等等。由於這些優惠有效的促進了孤兒藥的開發[註 4][13]，稍後各國陸續採取的政策也常使用相似的策略[14][15]。下表中之相關規範與政策，罕見疾病及孤兒藥當地法規規定需登記者，在表格中會列出已登記罕見疾病及孤兒藥之數量，如果未特別規範則標為不表列。

臺灣 新加坡 中國 日本 大韓民國 澳大利亞 歐盟 美國
相關規範 罕見疾病防治
及藥物法[16]		 孤兒藥條例[註 5][17] 無[18] 藥事法（：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）
第七十七條
第二款[18][19][20]		 孤兒藥管理
條款[註 6][21]		 孤兒藥
計畫[22][註 7]		 歐洲孤兒藥
規範[23]		 孤兒藥法案（英語：Orphan Drug Act of 1983）
主管機關 衛生福利部 衛生科學局（英語：Health Sciences Authority） 衛生部 厚生勞動省 食藥安全部（英語：Ministry of Food and Drug Safety）[21] 藥物管理局（英語：Therapeutic Goods Administration）[24] 歐洲藥品
管理局[25]		 食品藥物管理局
罕見疾病定義 發生率少於
1/10,000[26]		 患病者少於
20,000人[27]		 政府核定[註 8][5] 患病者少於
50,000人[28]		 患病者少於
20,000人[21]		 發生率少於
1/2,000[29]		 發生率少於
1/2,000[15]		 發生率少於
3/4,000[15]
罕見疾病種類 220[30] 不表列[27] 121[註 8][31] 331[32] 不表列 不表列[24] 不表列 不表列
孤兒藥種類 235[33] 不表列[27] 不表列[34] 417[35] 158[36][註 9] 287[37] 1627[38] 4846[39]
研究或臨床試驗補助 無[註 10][40] 無[17] 無 補助研發費用[28] 申請費減免
50 %[21]		 免申請費[24] 各國自主[18] 補助研究費用
免申請費[18]
優先審查 加速核准[註 11][41] 若經處方進口
不須審查[27][18]		 小型或豁免
臨床試驗[18][34]		 獨立審查窗口[28] 不需複審[21] 無[24] 有[15] 優先審查（英語：priority review）
速審（英語：fast track）
突破性新療法（英語：breakthrough therapy）
專賣權 10年[18] 10年[18] 無 10年[28] 無[21] 無[18] 10年[18] 7年[15]
稅務優惠 同一般新藥[註 12][42] 無[17] 無 稅務減免[28] 無[21] 無[18] 各國自主[18] 稅務減免[18]


規範個論與歷史

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臺灣

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行政院在1997年提案的罕見疾病防治及藥物法[16][註 13]是世界上第五部專門用來管理罕見疾病及藥品的法律[43]。依照該法規定，衛生福利部應該設立由政府代表、醫療人員、以及社會公正人士組成的罕見疾病及藥物審議委員會。這個委員會主要負責審批孤兒藥與提供罕見疾病防治與治療相關政策的建議[16]。以盛行率萬分之一以標準，治療照護困難又不受全民健康保險給付的疾病可以登記為罕見疾病[26]，罕見疾病患者的診斷、治療與照護均可以申請補助[44]。

有研究支持可用於預防、診斷或治療罕見疾病的藥物，在申請登記為孤兒藥時需要再提供。安全性試驗報告及臨床試驗報告[45]。成功登記孤兒藥的藥商在登記的有效期間可以享有最長十年的專賣期[16]。衛生福利部如果有計畫鼓勵藥商投入進口、生產、或是開發孤兒藥，罕見疾病及藥物審議委員會也要負責評估藥商是否符合獎勵標準[46]。

新加坡

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新加坡在1991年通過孤兒藥條例，該法定義孤兒藥用於治療有生命危險且對日常生活有極大影響的疾病[17]。符合該條件的藥物如果在他國已取得許可，但在新加坡尚未核准，則可以提出專案申請進口該項藥物。新加坡不補助孤兒藥的開發，但孤兒藥核准後享有十年專賣權[17][18]。

中國

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中國雖然沒有針對孤兒藥與罕見疾病的特別法規。[47]，但於2015年國務院曾指示應加速審查孤兒藥[48]。2017年時國家食品藥品監督管理總局提出了相應的意見稿，其中指出孤兒藥應該優先審批[49]。2018年8月，國家衛生健康委員會與其他機關發布《第一批罕見病目錄》，其收錄121種疾病，但尚未將治療這些疾病的藥物列入中華人民共和國醫療保險範圍當中[47]。

日本

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歐盟

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歐洲共同體在2000年[23]通過鼓勵孤兒藥開發的相關法規。該法案的立法宗旨與美國孤兒藥法案相似，但孤兒藥的定義較廣，除罕見疾病外，治療被忽視的熱帶病也被歸為孤兒藥[50]。廠商在藥物研發過程中可以向歐洲藥物管理局所屬的孤兒藥物醫材委員會（Committee on Orphan Medicinal Products）申請登記為孤兒藥，成功登記為孤兒藥的藥物在開發過程中會得到技術支援，上市審查的過程則可以透過歐洲藥物管理局的單一窗口負責辦理。核准上市之後，開發商享有自核准日起十年的專賣權，另外還有行政規費的減免與研發經費的支援等[51]。2007年下半年，美國食品藥物管理局與歐洲藥物管理局為方便廠商提出申請，決定將孤兒藥申請流程一致化[52]。雖然歐美的孤兒藥登記流程是相同的，但審核仍然獨立進行[52]。

美國

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在美國罕見疾病組織為首的罕見疾病支持團體的推動下，孤兒藥法案（英語：Orphan Drug Act of 1983）於1983年通過[53]。訂定孤兒藥法案的目的是鼓勵藥商開發市場較小的藥物[54]。根據孤兒藥法案的規定，如果藥品、疫苗及檢驗器材的適應症在美國境內的病人數少於20萬或或者新藥的預期收入不足以收回研發成本均可登記為孤兒藥[55]。為了刺激孤兒藥的研究，孤兒藥的研發廠商將獲得7年的專賣權、最高50 %研發費用可抵免稅金、研究經費補助、美國食品藥物管理局行政規費減免、以及申請流程諮詢與協助等[55]。孤兒藥的開發商可以在提出上市許可前向孤兒藥開發辦公室申請，將開發中的藥品登記為孤兒藥[56]。申請時開發商需要說明該藥物預計治療的疾病的盛行率以及支持該藥物治療目標疾病的科學證據[13][57][註 14]。2002年罕見疾病法案（英語：Rare Diseases Act of 2002）通過，該法案的內容包括設立罕見疾病辦公室（英語：Office of Rare Diseases Research）以及進一步增加投入孤兒藥開發的預算。[58]

除了政府機關的投入，學術機構也對孤兒藥的開發扮演重要角色。舉例來說，明尼蘇達大學藥學院設立於2005年的馬奎爾轉譯醫學中心在2007年更名為孤兒藥研究中心（英語：Center for Orphan Drug Research），致力於協助專業知識與資源較少的小公司進行藥物合成、調配（formulation）、定量藥理分析（英語：Pharmacometrics）、以及生物處理（英語：Bioprocess）[59]。凱克應用生命科學研究所的罕見疾病療法中心則以協助分析潛在藥物的調配與生物處理特性來讓更多潛在的孤兒藥能夠成功上市。[59]

在關注罕見疾病權益的倡議組織方面，除了推動孤兒藥法案的美國罕見疾病組織外，還有全球基因（英語：Global Genes）[60]、弗里德希氏共濟失調研究連線（英語：Friedreich's Ataxia Research Alliance）[61]等團體以促進罕見疾病患者權益為宗旨。

成效

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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]

例如治療龐貝氏症的藥物Myozyme便是一例，發展出該藥的中央研究院生物醫學科學研究所所長陳垣崇便是投入研究數十年，也放棄了許多收入更高的工作機會。

現況與展望

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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

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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.[來源請求]

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

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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

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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 [來源請求].

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

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Evaluation criteria

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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

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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

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By 2008 if an orphan drug cost more than £30,000[需要解釋] 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

備註

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  1. ^ 潛在新藥從發現到上市至少需要十年，其中臨床試驗平均會花費六到七年。
  2. ^ 在美國成功上市的新藥的平均開發花費是二十六億美元。
  3. ^ 美國2006－2015年間，所有進入第一期臨床試驗只有9.6 %取得上市許可（英語：marketing authorization）。
  4. ^ 美國在1973－1983年間只有10種孤兒藥上市，但在1983年法案生效後的三十年期間有超過3,900種藥物登記為孤兒藥，當中有590種成功上市。
  5. ^ 孤兒藥條例（英語：Orphan drugs Exemption to the Medicines Act）是醫療法（英語：Medicines Act）第一七六章第九節，其於1991年生效。
  6. ^ 孤兒藥管理條款：編號1998-23（英語：Regulation on Orphan Drug Designation. Notification No.1998-23）
  7. ^ 澳大利亞的孤兒藥政策始於1997年在醫療用品規範（英語：Therapeutic Goods Regulations）中的特別規定。2017年經過重新修訂，主要的更動是放寬盛行率標準，但收緊病情嚴重度標準，並增列可視為孤兒藥的特例。
  8. ^ 8.0 8.1 2018年中國政府基於中共中央辦公廳、國務院辦公廳提出的《關於深化審評審批制度改革鼓勵藥品醫療器械創新的意見》，國家衛生健康委員會、科學技術部、工業和信息化部、國家藥品監督管理局以及國家醫藥管理局聯合制定了《第一批罕見病目錄》。
  9. ^ 視為孤兒藥的條件包括罕見疾病用藥、針對原本沒有治療方法的疾病的藥物、年度進口額低於五百萬美元的藥物、或是生產額低於十五億韓元的國產藥物。
  10. ^ 臺灣財團法人罕見疾病基金會訂有補助辦法可補貼試驗經費不足部分。
  11. ^ 依新藥查驗登記加速核准機制規定，如具醫療迫切需求且在美、日、加拿大、澳洲、英國及德、法、瑞典、瑞士、比利時中任一國被認定為孤兒藥，則適用加速核准流程。
  12. ^ 新藥開發可享有研發投資抵減稅率50%、研發費用抵減率35%-50%、人才培訓支出35%抵減營利事業所得稅、高階專業人員認股權得延緩至轉讓時以轉讓價格扣除成本課個人所得稅、以及技術投資人技術作價得延緩至轉讓時以轉讓價格扣除成本課個人所得稅等；投資新藥開發商得申請最高20%購買新藥研發公司股價的所得稅抵減。
  13. ^ 本草案於1999年通過並生效。
  14. ^ 例外：孤兒藥法案中規定即使藥物適應症的的患者人數超過20,000人，只要能舉證該藥物在上市七年內無法獲利就能登記為孤兒藥，但由於舉證困難，少有廠商透過此規定登記孤兒藥。

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[編輯]
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