参⽐制剂，可以使原研的，也可以的仿制药
今天⽆意中看到RLD（reference listed drug）的翻译，顺便查
了下，RLD和RS的区别，分享给⼤家，欢迎⼀起指正学习哦！
中⽂版区别解析：
017年1⽉，美国FDA发布了题为“Referencing Approved Drug Products in ANDA Submissions”（ANDA申报的参照药品）的新指南草案，在原RLD概念的基础上引⼊了RS概
念，并重新区分了RLD与RS的使⽤。通常情况下，若NDA产品是RLD并且仍在市场销售，那么
问题就很直接。然⽽，若NDA产品可获得性差（⽐如撤市，销售短缺，或可⽤量太少）以⾄于ANDA开发不便，或者ANDA申请者提出其他要求，则情况变得复杂。考虑到这些情形，FDA在
指南草案中对各种ANDA申请情况下如何确定或选择参照药品RLD与RS做了细致的阐述。在本
⽂中，药聚CninMed就该指南草案进⾏简要解析并结合相关案例给予直观说明。
第四部分
对照标准制剂（RS）的确认与选择
RLD为⼀般为原研制剂, RS为RLD的⼀个或多个规格。
a. 通常情况下，RLD的最⼤规格被指定为RS。
通常RLD包含各个剂量规格，其中最⼤规格被指定为RS，其他规格只是RLD不是RS。BE试验
⽤RS进⾏，其他规格可采⽤体外试验证明等效⽽获得BE豁免。
b. 某些情况下，RLD⾼规格不是RS, 中间规格或低规格被指定为RS。
⽰例7 奥氮平因为副作⽤⼤，以及处于安全性的考虑，FDA没有选⼤规格⽽是选5mg作为RS。
如礼来奥氮平⽚(Zyprexa, NDA020592)有2.5、5、7.5、10、15、20 mg共6个规格都为RLD, 其
中中间规格5mg为RS。再如礼来的奥氮平⼝腔崩解⽚(Zyprexa Zydis, NDA201186)有5、10、
15、20 mg共4个规格都为RLD, 其中最低规格5mg为RS。
c. 某些情况下，同⼀个产品有⼀个以上的规格被指定为RS。
某些情况下，同⼀个品种有不只⼀个规格被指定为RLD。
⽰例8 GSK公司拉莫三嗪缓释⽚（Lamictal XR, NDA022115）包括25、50、100、200、250、300mg共6个规格都为RLD, 其中有两个中间规格50及200 mg都被指定为RS。
若RLD及RS因⾮安全及有效性原因撤市，FDA可选择仿制药指定为RS。
通常RS都是RLD。若RLD原研制剂由于⾮安全、有效问题⽽停⽌上市，该原研制剂被移到橙⽪书“已终⽌药品⽬录”中，通常仍为RLD。FDA考虑从与该RLD等效的仿制药中指定RS。⼀般选择销售量最⼤仿制药的为RS，但也遵循考虑其他因素，如该仿制药的剂量规格相对RLD剂量规格应⽐较完整，同
时该仿制药应该包含RS这个规格。⼀旦FDA选定了新的RS，即使原先的RS（如已撤市RLD）恢复上市，新RS通常也会保持不变。
⽰例9 礼来的头孢克洛胶囊 (Cefaclor，NDA050521) 已停⽌上市（⾮安全及有效性原因），其两个规格250，500 mg仍然保留为RLD。 Hikma公司的头孢克洛胶囊仿制药(ANDA065350) 500 mg规格则被指定为RS。
若在上市药品⽬录中不到RS, 申请⼈可要求FDA指定RS。
若橙⽪书“上市药品⽬录”中不到RS, 如FDA没有指定RS，或原RS已撤市但FDA未指定新的RS时, ANDA申请者可以向FDA提交“书⾯咨询”要求指定RS。
即使FDA指定的RS尚未撤市,  ANDA申请者也可申请指定更合适的RS。
尽管FDA已经指定RS，ANDA申请者若认为其他药品⽐指定的RS更适合作为RS，可以向FDA 提出适⽤性请愿。
submitting⽰例10 Clover公司氨基⼰酸⽚(Amicar，NDA015197)包含1000及500 mg两个规格，分别在1982年、2004年获得批准，都被指定为RLD，其中1000 mg规格被指定为RS。1000 mg⽚剂没有仿制药被批准，500 mg⽚剂仅有⼀家仿制药被批准。1000 mg⽚剂虽然还在上市产品⽬录中但实际没有市场供应，
500mg⽚剂是美国市场唯⼀在供货的规格。根据氨基⼄酸⽚BE指导原则，需要使⽤1000 mg 规格进⾏空腹与餐后试验。Menn Law Firm公司计划开发该产品仿制药，显然⽆法获取1000 mg⽚剂进⾏⽣物等效性试验。Menn Law Firm公司认为500 mg规格为更适合作为RS，并于2017年4⽉向FDA提交“公民请愿书”，申请将Amicar⽚500 mg规格指定为RS, 便于进⾏⽣物等效性试验。
若FDA指定的RS尚未撤市，但市场上数量有限或已停产，ANDA申请者可请求更换RS。
有时，尽管橙⽪书显⽰RS还处于上市状态，但市场上可购买产品数量有限，或者⽆法购买到时，或者实际处于停产状态。潜在的ANDA申请者难以获取⾜够数量对照标准制剂⽤于⽣物等效性试验及相关研究时，可向FDA提交“公民请愿书”，请求FDA指定新的RS。FDA基于此类情形，会考虑选择新的对照标准制剂。
⽰例11 阿昔洛韦胶囊200 mg原研产品为Zovirax(NDA018828)，FDA指定其为RLD及RS, FDA ⽹站显⽰仍为上市状态。以岭药业在开发该ANDA产品过程中，该RLD/RS从2016年8⽉起超过半年，出现数量短缺⽽购买不畅。同时以岭药业了解到，⽬前7个仿制⼚家中有3个仿制药⼚家可以供应阿昔洛韦胶囊200mg。为此以岭药业于2017年3⽉向FDA提交“公民请愿书”，请求FDA从这3个仿制药品中重新选择RS，从⽽开展⽣物等效性研究。
⽰例12 GSK公司的盐酸雷尼替丁⽚处⽅药（Zantac, NDA018703）包括150和300 mg两个规格，都指
定为RLD, 其中300 mg为RS，⽬前⽹站显⽰为上市状态。印度VKT Pharma计划开发盐酸雷尼替丁⽚处⽅药ANDA，发现原研产品过去4个⽉⼀直处于短缺状态，并确认其不再⽣产销售。为此VKT Pharma于2017年5⽉向FDA提交“公民请愿书”，请求FDA更换该处⽅药的RLD 与RS。
申请适⽤性请愿ANDA时，引⽤FDA批准回复中RS进⾏申报。
企业在ANDA中引⽤的参照药品必须是这个请愿中的参照药品。RS也为该参⽐制剂。
仿制请愿性ANDA时，RS可以为第⼀个已批准请愿性ANDA。
如果申请⼈想要仿制⼀个已被批准的请愿性ANDA，RLD仍然是第⼀个请愿性ANDA请愿中确认的RLD, 即同⼀个RLD。但第⼀个请愿性ANDA可以作为RS。
英⽂出处
Reference Listed Drug and Reference Standard
A reference listed drug (21 CFR 314.3(b)) means the listed drug identified by FDA as the drug product upon which an applicant relies in seeking approval of its ANDA.  Generally, a reference listed drug is a drug product approved in a new drug application under section 505(c) of the FD&C Act bas
ed on full reports of investigations of safety and effectiveness.  A reference standard is the drug product selected by FDA that an applicant seeking approval of an ANDA must use in conducting an in vivo bioequivalence study required for approval.  FDA generally selects a single reference standard that ANDA applicants must use in in vivo bioequivalence testing.  Ordinarily, FDA will select the reference listed drug as the reference
standard.  However, in some instances (e.g., where the reference listed drug has been withdrawn from sale and an ANDA is selected as the reference standard), the reference listed drug and the reference standard may be different.
FDA has identified reference listed drugs in the Prescription Drug Product and OTC Drug Product Lists.  Forthcoming, FDA will identify reference listed drugs in the Discontinued Drug Product List.  These identified reference listed drugs represent drug products upon which an applicant can rely in seeking approval of an ANDA.  FDA intends to update periodically the reference listed drugs identified in the Prescription Drug Product, OTC Drug Product, and Discontinued Drug Product Lists, as appropriate.
FDA also has identified in the Prescription Drug Product and OTC Drug Product Lists reference stan
dards to which the in vivo bioequivalence is compared.  These identified reference standards represent the FDA’s best judgment at this time as to the appropriate comparator for purposes of in vivo bioequivalence testing.
In some instances when a listed drug is not designated as a reference listed drug, such listed drug may be shielded from generic competition.  If FDA has not designated a reference listed drug for a drug product the applicant intends to duplicate, the potential applicant may ask FDA to designate a reference listed drug for that drug product.  Potential applicants should consult agency guidance related to referencing approved drug products in ANDA submissions for information on submitting such a request.  If the request is granted, the listed drug will be designated as a reference listed drug, in which case an ANDA citing the designated reference listed drug may be submitted.  Section 1.7, Therapeutic Equivalence Evaluations Codes (products meeting necessary bioequivalence requirements) explains the character coding system (e.g., AB, AB1, AB2, ) for multisource drug products listed under the same heading with two reference listed drugs.
A potential applicant should consult agency guidance related to referencing approved drug products in ANDA submissions for information on submitting a request for selection of a reference standard.  FDA may, on its own initiative, select a new reference standard when doing so will help to ensure tha
t potential applicants have adequate information required for in vivo bioequivalence studies, e.g., in the event that the listed drug currently selected as the reference standard has been withdrawn from sale for other than safety and efficacy
reasons.  Historically, there were two situations in which two listed drugs that had been shown to be bioequivalent to each other had both been identified by the symbol “ ” in the Orange Book.  The first situation was when the in vivo determination of bioequivalence is self-evident and a waiver of any in vivo bioequivalence may be granted.  The second situation was when the bioequivalence of two listed products may be determined through in vitro methodology.
If an applicant has a question related to the appropriate reference standard, it is recommended that an applicant planning to conduct an in vivo bioequivalence study submit a controlled correspondence to the Office of Generic Drugs.        WiseMedia

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