研究背景：
在台灣，因健保政策和醫療成本控制等原因，學名藥的使用比例在近年來不斷爬升。在主成分和賦形劑品質符合標準的前提下，各國主管機關大多認可學名藥藉由生體相等性(bioequivalence, BE)試驗來證實其安全性與療效與原廠藥無異，即可上市。然而民眾和一些醫療人員仍對學名藥具有疑慮，或不信任現有之把關措施。目前我國既有之「藥品療效不等通報系統」因案件過少無法達成監測和回答民眾疑慮之效果，對於學名藥與原廠藥的療效相等性若能藉由實證研究予以探討，將有助於釐清前述疑慮。因此，本研究旨在以系統性文獻回顧分析國內外已執行之心血管藥品中學名藥與原廠藥療效相等性的觀察性研究，並參酌其所使用的研究指標和方式，以健保資料庫執行回顧性世代研究，評估我國statin的學名藥和原廠藥是否具有療效相等性。

研究方法：
本研究系統性搜尋Pubmed、Cochrance Library、Embase和華藝線上圖書館，尋找心血管藥品的學名藥與原廠藥療效相等性的觀察性研究，並彙整各研究的特性、研究指標和結果，分析各種研究指標適用之藥物和優缺點。接著，本研究使用2001-2013年全民健保資料庫進行觀察性回溯性世代研究 (retrospective cohort study)。研究對象為2002年至2012年simvastatin或2007年至2012年atorvastatin的新使用者，並排除有精神疾病或癌症共病者後，依藥品廠牌分為學名藥使用者或原廠藥使用者。分析指標為「用藥持續性」(persistence)，即病患從開始服藥直到發生治療改變(停藥、換藥、換廠、加藥)的治療天數；也同時分析兩組發生治療改變的風險比(hazard ratio)，並以最初就醫院所之醫療層級做校正。

研究結果：
系統性文獻回顧共納入34篇文獻，依研究指標分為明確的療效指標12篇、替代性療效指標7篇、安全性1篇、服藥順從性14篇。經分析不同研究指標的特性，挑選服藥順從性中的「用藥持續性」作為同時反應療效與安全性的綜合指標。本研究共納入simvastatin使用者17,724人、atorvastatin使用者19,854人。經性別、年齡、起始劑量、共病症、併用藥物數和指標年份進行傾向分數配對後，simvastatin學名藥與原廠藥使用者各2,054人，兩組平均年齡均為59.5歲，男性皆佔46%；atorvastatin學名藥與原廠藥使用者各4,036人，兩組平均年齡均為58.5歲，男性皆佔47.5%。用藥持續性方面，兩藥皆為原廠藥使用者(simvastatin: 155.3天，SD=126.7；atorvastatin: 179.4天，SD=136)較學名藥使用者(simvastatin：137.2天，SD=117.7；atorvastatin：147.7天，SD=122.4)佳(p<0.001)。相較於原廠藥，學名藥使用者發生治療改變的風險比在以醫療層級校正後，simvastatin無顯著差異(HR 1.03 [0.95-1.11])，atorvastatin則為學名藥使用者風險較原廠藥使用者高8%(HR 1.08 [1.01-1.16])。

研究結論：
本研究結果指出，雖然此二藥品的原廠藥使用者用藥持續性較學名藥使用者佳，且atorvastatin學名藥使用者發生治療改變的風險則稍大於原廠藥使用者，在研究中校正醫療層級和政策性換廠等影響用藥持續性的因子時，發現此二因子對用藥持續性和發生治療改變之風險的影響幅度大於藥品廠牌本身可能造成的影響。因此，本研究所得結論為，不論使用simvastatin和atorvastain的原廠藥或學名藥，藥品本身對療效和安全性本身造成之影響不大，在臨床使用上應不會有顯著之差異。

SUMMARY

The use of generic drugs has become increasingly prevalent in this era. However, the public still have concerns regarding generic drugs, which many of these misconceptions are due to the lower price when compared to brand-name drugs. With the current pharmacovigilance reporting system being inadequate in addressing the concerns from a post-approval perspective, a model to examine therapeutic equivalence of generic and brand-name drugs post-approval is needed. Thus, a systematic review was conducted to review each outcome measure employed in therapeutic equivalence studies on generic and brand-name cardiovascular medicines. Persistence, a global measure of efficacy, safety, and tolerability, was identified as an ideal outcome to be employed in a retrospective claims database study of therapeutic equivalence. Then, we analyzed the Taiwan National Health Insurance Research Database from 2001-2013 and identified new users of simvastatin or atorvastatin. We grouped the patients according to generic or brand-name use, and measured persistence by the days from index date to treatment change or up to one year. After propensity score matching, there were 2,054 and 4,036 user pairs for simvastatin and atorvastatin. For both statins, a better persistence was observed in brand-name drugs (simvastatin: 155.3 vs 137.2 days; atorvastatin: 179.4 vs 147.7 days). There was no significant difference between generic and brand-name users of simvastatin (HR 1.03 [0.95-1.11]), while generic users of atorvastatin had slightly higher risk of treatment change compared to brand-name users (HR 1.08 [1.01-1.16]). During sensitivity analyses, we also identified that hospital level and policy-based brand-switching may play a larger role than the use of generics in treatment change. The findings indicate that there is little significant difference in the effectiveness of generic and brand-name statins. This study provides strong grounds towards building an effective model to evaluate therapeutic equivalency of generic and brand-name cardiovascular medicines in the future.

INTRODUCTION

The use of generic drugs has become increasingly prevalent in Taiwan, while the lower cost and government policy being the main drivers of its growth. Most regulatory authorities agree that after verifying the quality of the ingredients and manufacturing process, a generic drug gains approval by proving therapeutic equivalency through bioequivalence (BE) tests. However, the public still have concerns regarding generic drugs, which many of these misconceptions are due to the lower price when compared to brand-name drugs. While patient education plays a vital role in advertising the efforts of pre-approval examination, the current pharmacovigilance reporting system is insufficient in addressing the concerns from a post-approval perspective. This prompts the TFDA to call for proposal of a model to examine therapeutic equivalence of generic and brand-name drugs post-approval. Thus, the goal of this study is to conduct a systematic review of therapeutic equivalency studies of generic and brand-name cardiovascular medicines; after reviewing different methodologies of each literature, conduct a retrospective cohort study in the Taiwan National Heath Insurance Research Database (NHIRD) accordingly to assess the therapeutic equivalency of generic and brand-name statins.

METHODS

A systematic search is conducted in Pubmed, Cochrance Library, Embase, and Airiti Library for observational therapeutic equivalency studies of generic and brand-name cardiovascular medicines. Studied drugs, cohort selection, study endpoints and results were gathered from each study to analyze the pros and cons of each study endpoint. Then, a retrospective cohort study is conducted using 2001-2013 NHIRD. New users of simvastatin from 2002-2012 and atorvastatin from 2007-2013 were included. After excluding for patients with psychiatry diseases and cancer, patients were grouped according to generic or brand-name use. The study outcome was persistence, which was measured by the days from index date to treatment change (discontinuation, statin-switching, brand-switching, augmentation) or up to one year. Hazard ratio for treatment change were also calculated and adjusted by hospital level.

RESULTS

We included 34 studies in the systematic review. There were 12 studies using hard endpoints and 7 using surrogate endpoints for efficacy, while 14 studies used adherence, and only one utilized safety as their primary study endpoint. After analyzing each study endpoint, persistence (a measure of adherence) was chosen to reflect the efficacy and safety of the drug at the same time. Our cohort study included 17,724 new users of simvastatin, and 19,854 of atorvastatin. After propensity score matching for age, sex, initial dose, comorbidity, number of comedications, and index year, we had 2,054 and 4,036 user pairs for simvastatin and atorvastatin. For both statins, brand-name users (simvastatin: 155.3 days, SD=126.7; atorvastatin: 179.4 days, SD=136) had better persistence than generic users (simvastatin: 137.2 days, SD=117; atorvastatin: 147.7 days, SD=122.4) (p<0.001). Compared to brand-name users, the adjusted hazard ratio for treatment change in generic users was non-significant for simvastatin (HR 1.03 [0.95-1.11]) and was slightly higher for atorvastatin (HR 1.08 [1.01-1.16]).

CONCLUSION

Although persistence was shown to be better in brand-name users for both statins, and generic users of atorvastatin had slightly higher risk of treatment change, the study also identified hospital level and policy-based brand-switching as influential factors of treatment change, which may supersede the influence of generic or brand-name use. The findings indicate that there is little significant difference in the effectiveness of generic and brand-name statins. This study provides strong grounds towards building an effective model to evaluate therapeutic equivalency of generic and brand-name cardiovascular medicines in the future.

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