今年3月份FDA出臺(tái)了一份《支持加速批準(zhǔn)腫瘤治療藥物的臨床試驗(yàn)考慮因素行業(yè)指南》。考慮到癌癥的嚴(yán)重性、亟需治療的迫切性，加速審批途徑通常用于腫瘤藥物的審批。使用單臂試驗(yàn)來支持加速審批有其局限性，基于單臂試驗(yàn)的加速批準(zhǔn)可能是不合理的。如果設(shè)計(jì)和執(zhí)行得當(dāng)，隨機(jī)對照試驗(yàn)可以解決單臂試驗(yàn)的局限性。
故FDA建議申請人可以考慮進(jìn)行進(jìn)行隨機(jī)對照試驗(yàn)，以支持加速批準(zhǔn)（ A randomized controlled trial(“one-trial” approach) to support accelerated approval）。在適當(dāng)?shù)那闆r下，“單一/一次試驗(yàn)”方法（“one-trial” approach）的長期隨訪可以滿足上市后驗(yàn)證臨床益處的要求。這種“單一/一次試驗(yàn)”方法（“one-trial” approach）保持了藥物開發(fā)的效率，并可以通過加速批準(zhǔn)途徑提供藥物的早期準(zhǔn)入，同時(shí)確保充分積累并順利進(jìn)行上市后試驗(yàn)，以及時(shí)驗(yàn)證長期效益。
1、引言
本指南的目的是向抗癌藥物或生物制品的申請人提供建議，說明設(shè)計(jì)試驗(yàn)以支持加速審批的考慮因素。
一般來說，F(xiàn)DA的指導(dǎo)文件并不具有法律上可執(zhí)行的責(zé)任。相反，指導(dǎo)文件描述了該局目前對某一主題的想法，并應(yīng)僅被視為建議，除非引用了具體的監(jiān)管或法定要求。在機(jī)構(gòu)指導(dǎo)文件中使用 "應(yīng)該 "一詞，意味著建議或推薦某事，但不是必須。
2、背景情況
加速審批途徑通常用于腫瘤藥物的審批，部分原因是由于癌癥的嚴(yán)重性和對生命的威脅性，以及由于現(xiàn)有的替代終點(diǎn)或中間臨床終點(diǎn)被認(rèn)為有可能預(yù)測臨床益處。雖然各種試驗(yàn)設(shè)計(jì)和終點(diǎn)歷來被用來支持加速批準(zhǔn)，但單臂試驗(yàn)設(shè)計(jì)和反應(yīng)終點(diǎn)（反應(yīng)持續(xù)時(shí)間為支持性）在腫瘤學(xué)中最常被使用。反應(yīng)率是藥物活性的一個(gè)標(biāo)志，因?yàn)閻盒阅[瘤通常不會(huì)自行消退，而且這個(gè)終點(diǎn)可以在單臂試驗(yàn)中解釋為單藥治療的腫瘤藥物方案。然而，使用單臂試驗(yàn)來支持加速審批有其局限性，包括但不限于以下幾點(diǎn)：
（1）安全性數(shù)據(jù)庫通常很小，可能無法識(shí)別罕見的、潛在的嚴(yán)重不良事件。對于已確定的嚴(yán)重不良事件，對于已確定的嚴(yán)重不良事件，在缺乏對照組的情況下，將不良事件歸因于所研究藥物可能受到限制。
（2）腫瘤學(xué)中常見的時(shí)間事件終點(diǎn):包括（無進(jìn)展生存期(progression-free survival,PFS)、無病生存期(disease-free surviva)通常是無法解釋的，因?yàn)樵趯⒔Y(jié)果與外部對照比較時(shí)，未能考慮到已知和未知的混雜因素。FDA認(rèn)為這種終點(diǎn)是探索性的，不足以作為旨在支持批準(zhǔn)的單臂試驗(yàn)的療效措施。
（3）一般來說，低幅度的反應(yīng)率可能無法合理地預(yù)測臨床效益（如免疫療法）。
（4）對于聯(lián)合治療方案，個(gè)別成分對所聲稱的效果的貢獻(xiàn)一般來說可能難以確定。
（5）依靠與歷史試驗(yàn)的交叉比較來評(píng)估所觀察到的治療效果是否比現(xiàn)有的治療方法有所改善，是具有挑戰(zhàn)性的。各項(xiàng)試驗(yàn)之間可能存在差異（例如，在設(shè)計(jì)、實(shí)施、反應(yīng)評(píng)估間隔、研究人群等方面），這些差異可能很容易辨別，也可能不容易辨別，這可能導(dǎo)致對調(diào)查組和歷史對照組之間反應(yīng)估計(jì)的觀察差異得出錯(cuò)誤的結(jié)論（例如，錯(cuò)誤地將反應(yīng)率的差異歸因于研究藥物）。
單臂試驗(yàn)的這些和其他局限性會(huì)給藥物的安全性和/或有效性評(píng)估增加不確定性，因此在特定的臨床環(huán)境下，基于單臂試驗(yàn)的加速批準(zhǔn)可能是不合理的。
如果設(shè)計(jì)和執(zhí)行得當(dāng)，隨機(jī)對照試驗(yàn)可以解決單臂試驗(yàn)的局限性，包括但不限于以下幾個(gè)方面：
隨機(jī)對照試驗(yàn)提供了更有力的療效和安全性評(píng)估，并允許與同時(shí)進(jìn)行的對照組進(jìn)行直接比較。
（1）如果歷史上的試驗(yàn)沒有專門評(píng)估生物標(biāo)志物選擇的相關(guān)人群對標(biāo)準(zhǔn)護(hù)理治療的反應(yīng)率（即現(xiàn)有療法被批準(zhǔn)用于所有人群），在同一試驗(yàn)中評(píng)估新藥與現(xiàn)有療法的比較，可以更準(zhǔn)確地反映生物標(biāo)志物定義的患者群中標(biāo)準(zhǔn)護(hù)理的療效和安全性。
（2）在現(xiàn)有療法的試驗(yàn)完成后，治療情況可能發(fā)生了變化，隨機(jī)對照試驗(yàn)可以對可比較的研究人群進(jìn)行研究。
（3）雖然支持加速批準(zhǔn)的試驗(yàn)通常是在難治性疾病患者中進(jìn)行的，但隨機(jī)對照試驗(yàn)可以在較早的治療環(huán)境中對新藥進(jìn)行評(píng)估，從而在更多患者可能受益的病程早期獲得新藥的機(jī)會(huì)。
（4）當(dāng)臨床試驗(yàn)地點(diǎn)跨越幾個(gè)地理區(qū)域時(shí)，如在國際上招募參與者的試驗(yàn)，隨機(jī)對照試驗(yàn)可以評(píng)估可能來自多種因素的潛在區(qū)域差異。
進(jìn)行隨機(jī)對照試驗(yàn)以支持加速批準(zhǔn)的另一個(gè)潛在優(yōu)勢是，在適當(dāng)?shù)那闆r下，同一試驗(yàn)的長期隨訪可以滿足上市后驗(yàn)證臨床益處的要求。這種“單一/一次試驗(yàn)”方法（“one-trial” approach）保持了藥物開發(fā)的效率，并可以通過加速批準(zhǔn)途徑提供藥物的早期準(zhǔn)入，同時(shí)確保充分積累并順利進(jìn)行上市后試驗(yàn)，以及時(shí)驗(yàn)證長期效益。
3、建議
鑒于單臂試驗(yàn)的局限性，隨機(jī)對照試驗(yàn)是支持加速批準(zhǔn)申請的首選方法。申請人可以酌情選擇進(jìn)行單一的隨機(jī)對照試驗(yàn)，以支持加速批準(zhǔn)并驗(yàn)證臨床效益（即采用 "單一試驗(yàn) "的方法），或者，可以進(jìn)行單獨(dú)的試驗(yàn)--一項(xiàng)支持加速批準(zhǔn)，另一項(xiàng)是確證性試驗(yàn)，以驗(yàn)證臨床效益。
雖然隨機(jī)對照試驗(yàn)是首選的方法，但在開發(fā)加速批準(zhǔn)的藥物時(shí)，可能會(huì)出現(xiàn)適合進(jìn)行單臂試驗(yàn)的情況，例如，當(dāng)對隨機(jī)對照試驗(yàn)的可行性存在重大關(guān)切時(shí)。在決定是否進(jìn)行單臂試驗(yàn)時(shí)，應(yīng)仔細(xì)考慮。
雖然隨機(jī)對照試驗(yàn)是首選的方法，但在某些情況下，單臂試驗(yàn)在藥物開發(fā)中是合適的，以加速批準(zhǔn)，例如當(dāng)對隨機(jī)對照試驗(yàn)的可行性存在重大擔(dān)憂時(shí)。在確定單臂試驗(yàn)是否適用于特定的臨床和監(jiān)管環(huán)境時(shí)，應(yīng)仔細(xì)考慮。無論正在考慮的方法是什么，F(xiàn)DA建議在啟動(dòng)試驗(yàn)之前和適當(dāng)?shù)脑囼?yàn)期間與FDA進(jìn)行早期討論。
A、支持加速審批的隨機(jī)對照臨床試驗(yàn)
申請人可以進(jìn)行單獨(dú)的隨機(jī)對照試驗(yàn)--一項(xiàng)試驗(yàn)具有早期終點(diǎn)（如應(yīng)答率），以支持藥物的加速審批，另一項(xiàng)試驗(yàn)以長期臨床終點(diǎn)（如無進(jìn)展生存期（PFS）或總生存期（OS））為動(dòng)力，驗(yàn)證臨床獲益?；蛘?，申請人可以設(shè)計(jì)一個(gè)單一的隨機(jī)對照試驗(yàn)來支持加速批準(zhǔn)，該試驗(yàn)也為長期臨床終點(diǎn)提供動(dòng)力，并在同一試驗(yàn)中隨訪以驗(yàn)證臨床效益（即 "單次試驗(yàn) "方法）。以下是關(guān)于兩個(gè)獨(dú)立的隨機(jī)對照臨床試驗(yàn)的設(shè)計(jì)、實(shí)施和數(shù)據(jù)分析的建議，或者使用 "單次試驗(yàn) "（one-trial）的方法來加速批準(zhǔn)和驗(yàn)證臨床益處。
1.兩項(xiàng)隨機(jī)對照臨床試驗(yàn)的考慮
由于藥物在臨床實(shí)踐中的可用性，在獲得加速批準(zhǔn)之前等待啟動(dòng)隨機(jī)對照驗(yàn)證試驗(yàn)可能會(huì)在招募參與者方面帶來挑戰(zhàn)。因此，為了幫助確保旨在驗(yàn)證臨床益處的試驗(yàn)的可行性和及時(shí)完成，F(xiàn)DA強(qiáng)烈建議在加速批準(zhǔn)之前，如果沒有完全注冊，該試驗(yàn)應(yīng)該順利進(jìn)行。
為了促進(jìn)確證性臨床的完成，在同一癌癥類型但在另一個(gè)治療線中評(píng)估該藥物可能是可以接受的。例如，對于為難治性癌癥的適應(yīng)癥批準(zhǔn)的加速審批，確認(rèn)性試驗(yàn)可以在較早的疾病環(huán)境中進(jìn)行。這種方法有可能為患有早期疾病的患者提供有效的藥物，受益可能更大，并且當(dāng)一種藥物已經(jīng)獲得后期適應(yīng)癥的加速批準(zhǔn)時(shí)，它有助于患者的累積。
鑒于在加速批準(zhǔn)時(shí)，藥物的臨床效益存在固有的和殘留的不確定性，及時(shí)完成旨在驗(yàn)證臨床效益的試驗(yàn)至關(guān)重要。在提交上市申請時(shí)，應(yīng)進(jìn)行確證性臨床。
2. 支持加速審批和驗(yàn)證臨床效益的單一隨機(jī)對照試驗(yàn)的考慮因素
如果計(jì)劃采用 "單次試驗(yàn) "的方法，利用同一試驗(yàn)來支持加速審批，并進(jìn)行長期隨訪以驗(yàn)證臨床效益，那么申請人在啟動(dòng)試驗(yàn)前應(yīng)仔細(xì)評(píng)估現(xiàn)有的初步臨床數(shù)據(jù)。FDA建議為加速批準(zhǔn)選擇一個(gè)適當(dāng)和可行的終點(diǎn)，以便在疾病的早期和進(jìn)行試驗(yàn)的早期進(jìn)行評(píng)估。在選擇加速批準(zhǔn)的終點(diǎn)時(shí)，申請人還應(yīng)該考慮疾病的自然史（例如，惰性癌）、研究性藥物的作用機(jī)制、可靠地描述可測量的疾病以評(píng)估反應(yīng)的能力，以及其他特定情況的因素。
在評(píng)估 "單次試驗(yàn) "方法的可行性和適當(dāng)性時(shí)，維護(hù)試驗(yàn)的完整性至關(guān)重要，因?yàn)閷?shù)據(jù)的評(píng)估和隨后對加速審批申請的監(jiān)管行動(dòng)可能無意中引入偏見。在評(píng)估偏倚的可能性時(shí)，申請人應(yīng)考慮的因素包括：交叉的預(yù)期影響（如允許）；關(guān)于藥物效果的初步數(shù)據(jù)，包括毒性情況、治療情況以及對照組使用的治療方法等。
在啟動(dòng)試驗(yàn)之前，申請人應(yīng)考慮并與FDA討論，根據(jù)現(xiàn)有的初步臨床數(shù)據(jù)，對反應(yīng)率或其他早期終點(diǎn)的預(yù)期影響是否有足夠的規(guī)模，以合理地預(yù)測臨床效益。根據(jù)病程、預(yù)期人群和FDA的指導(dǎo)，也可以用 "單次試驗(yàn) "的方式對反應(yīng)率以外的其他終點(diǎn)的使用進(jìn)行評(píng)估，同時(shí)對臨床獲益終點(diǎn)進(jìn)行后續(xù)評(píng)估。
如果藥物開發(fā)計(jì)劃旨在評(píng)估一個(gè)組合方案，申請人應(yīng)明確說明證明每個(gè)組成部分的貢獻(xiàn)的方法。應(yīng)提供證據(jù)支持各成分對所聲稱的效果的單獨(dú)貢獻(xiàn)，這些證據(jù)通常來自多臂試驗(yàn)，并對無效性進(jìn)行中期分析，或使用其他適應(yīng)性試驗(yàn)設(shè)計(jì)元素。
申請人應(yīng)仔細(xì)考慮試驗(yàn)結(jié)果是否足以支持提交申請。加速審批的一個(gè)要求是，藥物必須證明對替代性終點(diǎn)或中間臨床終點(diǎn)的影響，有理由預(yù)測臨床效益，并提供比現(xiàn)有療法有意義的優(yōu)勢。在評(píng)估是否滿足這些要求時(shí)，F(xiàn)DA考慮的因素包括：在終點(diǎn)上顯示的治療效果的統(tǒng)計(jì)學(xué)意義和臨床意義，其他支持觀察到的效果可能預(yù)測臨床益處的特定背景證據(jù)，以及對照組是否代表適當(dāng)?shù)目捎茂煼ā?/span>
如果自試驗(yàn)開始以來，治療情況發(fā)生了變化（例如，對照組的治療不再反映最佳的可用療法），應(yīng)與FDA討論關(guān)于提交加速批準(zhǔn)申請與推遲提交申請的決定，直到有了支持傳統(tǒng)批準(zhǔn)的結(jié)果。歸根結(jié)底，什么是可用的治療方法是在監(jiān)管做決定的時(shí)候，而不是在開始試驗(yàn)的時(shí)候確定的。
試驗(yàn)的設(shè)計(jì)、執(zhí)行和分析應(yīng)確保對療效終點(diǎn)的有力評(píng)估。試驗(yàn)方案應(yīng)規(guī)定一個(gè)計(jì)劃，以有力地控制支持加速批準(zhǔn)的終點(diǎn)和支持驗(yàn)證臨床效益的終點(diǎn)的總體假陽性率（I型錯(cuò)誤）。
試驗(yàn)樣本量的選擇應(yīng)使其具有足夠的能力來檢測加速批準(zhǔn)的終點(diǎn)（如應(yīng)答率）和臨床獲益驗(yàn)證的終點(diǎn)（如PFS或OS）是否有臨床意義和統(tǒng)計(jì)學(xué)意義上的改善。試驗(yàn)設(shè)計(jì)可以包含適應(yīng)性設(shè)計(jì)元素（例如，樣本量的重新估計(jì)）。對于適應(yīng)性設(shè)計(jì)，申請人應(yīng)根據(jù)臂間（between-arm comparisons）比較的背景考慮I型錯(cuò)誤的控制，解決這種方法可能引起的操作問題，并在設(shè)計(jì)試驗(yàn)時(shí)將及時(shí)完成試驗(yàn)作為首要考慮。欲了解更多信息，請參考《藥物和生物制品臨床試驗(yàn)的行業(yè)適應(yīng)性設(shè)計(jì)指南》（2019年12月）。
對于基于反應(yīng)的終點(diǎn)，支持加速批準(zhǔn)的分析可以基于預(yù)先指定的初始隨機(jī)患者的數(shù)量，而對于時(shí)間到事件的終點(diǎn)，預(yù)先指定事件的數(shù)量是合適的；在每種情況下，申請人應(yīng)確保在較早的分析時(shí)間點(diǎn)上進(jìn)行穩(wěn)健評(píng)估和可靠估計(jì)。支持加速審批的療效分析應(yīng)避免在試驗(yàn)接近或完全注冊之前進(jìn)行，以減輕加速審批時(shí)可能出現(xiàn)的挑戰(zhàn)。確定總反應(yīng)率（ORR）數(shù)據(jù)是否足以支持加速批準(zhǔn)的一般考慮因素在下文B節(jié)中描述。
應(yīng)采取措施，防止出現(xiàn)可能危及試驗(yàn)結(jié)果或試驗(yàn)完整性的情況。例如，對支持驗(yàn)證臨床獲益的終點(diǎn)數(shù)據(jù)應(yīng)保持盲法，直到達(dá)到終點(diǎn)方案規(guī)定的分析時(shí)間點(diǎn)，以確保對該終點(diǎn)的有力評(píng)估。
在審查加速批準(zhǔn)的申請時(shí)，F(xiàn)DA的安全評(píng)估可能包括評(píng)估現(xiàn)有數(shù)據(jù)是否表明研究組治療的潛在危害（例如，對臨床終點(diǎn)(如OS)的有害影響）。FDA可以要求生存數(shù)據(jù)分析的總結(jié)結(jié)果，以支持作為申請?zhí)峤坏囊徊糠值脑u(píng)估，并可以在申請審查過程中要求更新的生存結(jié)果。申請人應(yīng)指定一個(gè)計(jì)劃，說明為這種分析保持研究盲法的措施。
B、支持加速審批的單臂試驗(yàn)
如上所述，在特定的臨床和監(jiān)管背景下，單臂試驗(yàn)是否適合支持加速批準(zhǔn)，應(yīng)與FDA討論。本節(jié)概述了設(shè)計(jì)、進(jìn)行和分析旨在支持加速審批的單臂試驗(yàn)數(shù)據(jù)的考慮因素，以及確定數(shù)據(jù)是否足以實(shí)現(xiàn)這一目的的考慮因素。
1. 研究功效的考慮
終點(diǎn)：在腫瘤學(xué)中，當(dāng)批準(zhǔn)是基于單臂試驗(yàn)的數(shù)據(jù)時(shí)，反應(yīng)率是支持加速批準(zhǔn)最經(jīng)常使用的終點(diǎn)。應(yīng)使用適當(dāng)?shù)姆磻?yīng)率評(píng)估標(biāo)準(zhǔn)（例如，基于實(shí)體瘤反應(yīng)評(píng)估標(biāo)準(zhǔn)[RECIST]的ORR）。在某些疾病的情況下，除ORR外的其他反應(yīng)措施可能更適合于描述療效（如完全緩解率、主要分子反應(yīng)等）。使用新的反應(yīng)評(píng)估標(biāo)準(zhǔn)或修改已有的標(biāo)準(zhǔn)應(yīng)該有強(qiáng)有力的基本理由支持，并應(yīng)在試驗(yàn)設(shè)計(jì)階段與FDA討論。在可能的情況下，試驗(yàn)中使用的反應(yīng)評(píng)估方法應(yīng)與產(chǎn)品標(biāo)簽使用的方法相同。
現(xiàn)有療法：加速批準(zhǔn)是為那些有望提供比現(xiàn)有療法更有意義的優(yōu)勢（包括療效優(yōu)勢）的藥物設(shè)置的。為了便于證明其優(yōu)于現(xiàn)有療法，申請人應(yīng)預(yù)先指定作為比較基礎(chǔ)的歷史試驗(yàn)，以及選擇試驗(yàn)的理由。試驗(yàn)的時(shí)間框架、試驗(yàn)規(guī)模、試驗(yàn)人群的臨床和人口統(tǒng)計(jì)學(xué)特征，以及評(píng)估反應(yīng)的任何潛在偏見，是評(píng)估歷史試驗(yàn)的適用性時(shí)需要考慮的一些因素。FDA認(rèn)識(shí)到，確定歷史試驗(yàn)可能具有挑戰(zhàn)性，特別是對于在分子定義的患者群體中開發(fā)的藥物;在這種情況下，提供數(shù)據(jù)來證明分子定義亞組的治療效果的量級(jí)優(yōu)于歷史試驗(yàn)可能是合適的。
樣本量：單臂試驗(yàn)的規(guī)模應(yīng)允許在點(diǎn)估計(jì)周圍有足夠的精度，提供反應(yīng)持續(xù)時(shí)間的可靠性，并充分描述藥物的不良事件概況。
2. 試驗(yàn)分析的考慮
當(dāng)療效終點(diǎn)為反應(yīng)率時(shí)，支持加速批準(zhǔn)的結(jié)果的充分性應(yīng)基于緩解的程度和持續(xù)時(shí)間。申請人應(yīng)考慮必要的隨訪時(shí)間，以充分表征特定疾病環(huán)境下的反應(yīng)率和反應(yīng)的持久性（例如，快速進(jìn)展的疾病vs.惰性疾?。?。在單臂試驗(yàn)中，沒有必要用統(tǒng)計(jì)推斷程序來評(píng)估這些端點(diǎn)。在大多數(shù)情況下，需要對大多數(shù)應(yīng)答者在應(yīng)答后至少隨訪6個(gè)月，以確定應(yīng)答的持久性特征。然而，在某些情況下，可能需要在應(yīng)答后進(jìn)行更長時(shí)間的最低隨訪，以充分說明臨床效益的特點(diǎn)。在某些情況下，F(xiàn)DA在審查申請時(shí)可能會(huì)要求提供有關(guān)反應(yīng)持久性的額外數(shù)據(jù)。
應(yīng)預(yù)先規(guī)定反應(yīng)的試驗(yàn)樣本量和分析人群。鑒于大多數(shù)單臂試驗(yàn)的規(guī)模較小，分析人群一般預(yù)計(jì)為整個(gè)試驗(yàn)人群。然后，已經(jīng)接受了至少一劑研究藥物的患者將被納入分析人群，無論他們是否因隨訪時(shí)間短而有機(jī)會(huì)回應(yīng)。在沒有預(yù)先規(guī)定的計(jì)劃的情況下，多次增加研究樣本量，反復(fù)查看數(shù)據(jù)，可能會(huì)在療效評(píng)估中引入偏差，應(yīng)避免。
為了減少引入偏見的可能性，并減少評(píng)估反應(yīng)的差異，應(yīng)該對反應(yīng)評(píng)估進(jìn)行盲法獨(dú)立中央審查（BICR）。
包括裁決程序的BICR章程應(yīng)作為上市申請的一部分提供給FDA。
一般來說，在適當(dāng)?shù)呐R床背景下，F(xiàn)DA將反應(yīng)率定義為部分反應(yīng)和完全反應(yīng)之和。當(dāng)以這種方式定義時(shí)，反應(yīng)是對藥物抗腫瘤活性的直接衡量，可以在單臂研究中進(jìn)行評(píng)估。穩(wěn)定的疾病不應(yīng)該是反應(yīng)率的一個(gè)組成部分。同樣，也不應(yīng)該使用臨床獲益率（例如，反應(yīng)率+穩(wěn)定的疾病>6個(gè)月）等措施。這種措施在很大程度上可以反映疾病的自然史，而腫瘤的縮小則代表了直接的治療效果。
C、加速批準(zhǔn)后的確證性臨床
對于獲得加速批準(zhǔn)的腫瘤學(xué)藥物，上市后的確證性臨床試驗(yàn)被要求驗(yàn)證和描述預(yù)期的臨床效益。這種試驗(yàn)有助于解決替代或中間終點(diǎn)與最終臨床效益之間關(guān)系的剩余不確定性。為了盡量減少這種不確定性的持續(xù)時(shí)間，F(xiàn)DA可能會(huì)酌情要求在批準(zhǔn)適用產(chǎn)品之前，或在批準(zhǔn)日期之后的特定時(shí)間段內(nèi)，進(jìn)行旨在驗(yàn)證臨床益處的研究。上市后試驗(yàn)必須盡職盡責(zé)地進(jìn)行，并符合FDA規(guī)定的上市后試驗(yàn)條件，其中可能包括招募目標(biāo)、研究方案和里程碑，包括研究完成的目標(biāo)日期。“單一試驗(yàn) "（“one-trial” ）方法的優(yōu)點(diǎn)是可能不需要單獨(dú)的確認(rèn)性試驗(yàn)。然而，當(dāng)單臂試驗(yàn)支持加速批準(zhǔn)時(shí)，F(xiàn)DA要求進(jìn)行上市后試驗(yàn)以評(píng)估PFS或OS，可能需要進(jìn)行單獨(dú)的隨機(jī)對照試驗(yàn)。建議盡早與FDA討論旨在支持加速批準(zhǔn)的試驗(yàn)和上市后試驗(yàn)的設(shè)計(jì)和啟動(dòng)，以便迅速提供臨床效益的證據(jù)。
英文原文：
Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics Guidance for Industry
I. INTRODUCTION
The purpose of this guidance is to provide recommendations to sponsors of anti-cancer drugs or biological products on considerations for designing trials intended to support accelerated approval.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
II. BACKGROUND
The accelerated approval pathway is commonly used for approval of oncology drugs in part due to the serious and life-threatening nature of cancer and because of available surrogate or intermediate clinical endpoints considered reasonably likely to predict clinical benefit. While a variety of trial designs and endpoints have historically been used to support accelerated approval, single-arm trial designs and response endpoints (with duration of response as supportive) have most commonly been used in oncology. Response rate is a marker of drug activity because malignant tumors do not typically regress on their own, and because this endpoint can be interpreted in single-arm trials for monotherapy oncology drug regimens. However, there are limitations to the use of single-arm trials in support of accelerated approval, including but not limited to the following:
• Safety databases are typically small and may not allow for the identification of rare, potentially serious adverse events. For identified serious adverse events, attribution of adverse events to the drug under study can be limited in the absence of a comparator arm.
• Common time-to-event efficacy endpoints in oncology (e.g., tumor progression, survival) are generally uninterpretable due to failure to account for known and unknown confounding factors when comparing the results to an external control. FDA considers such endpoints exploratory and not adequate to be used as measures of efficacy in single arm trials intended to support approval.
• Low magnitude response rates generally may not be reasonably likely to predict clinical benefit (e.g., immunotherapy).
• For combination regimens, the contribution of the individual components to the claimed effect(s) generally may be challenging to establish.
• Reliance on cross-trial comparisons to historical trials to assess whether the observed treatment effect represents an improvement over available therapy is challenging. There can be differences across trials (e.g., in design, conduct, response assessment intervals, study population, etc.) which may or may not be easily discernible and which could lead to erroneous conclusions regarding observed differences in the response estimate between the investigational arm and a historical control (e.g., erroneously attributing differences in response rate to the investigational drug).
These and other limitations of single-arm trials can add uncertainty to the assessment of the safety and/or effectiveness of a drug such that accelerated approval based on a single-arm trial may not be justified in a given clinical setting.
When properly designed and executed, a randomized controlled trial can address the limitations of single-arm trials, including but not limited to, the following ways:
A randomized controlled trial provides a more robust efficacy and safety assessment and allows for direct comparison to a concurrent control arm.
?In cases wherein historical trials did not specifically evaluate the response rate for the standard of care treatment in a biomarker-selected population of interest (i.e., available therapy is approved for an all-comer population), assessing the new drug compared to the available therapy in the same trial provides a more accurate representation of the efficacy and safety of standard of care in the biomarker-defined cohort of patients.
?In settings wherein the treatment landscape may have changed since completion of the trial(s) for available therapy, a randomized controlled trial enables comparable study populations to be studied.
?While trials that support accelerated approval have typically been conducted in patients with refractory disease, a randomized controlled trial may allow for the evaluation of a new drug in an earlier treatment setting, thereby enabling access to a new drug earlier in the course of the disease when more patients are likely to benefit.
?When clinical trial sites span several geographic regions as would be the case for trials that enroll participants internationally, a randomized controlled trial allows for an assessment of potential regional differences that may stem from multiple factors.
Another potential advantage to conducting a randomized controlled trial to support accelerated approval is that, in appropriate cases, longer term follow-up in the same trial could fulfill a postmarketing requirement to verify clinical benefit. This “one-trial” approach maintains efficiency in drug development and can provide early access to a drug using the accelerated approval pathway, while ensuring that a postmarketing trial is fully accrued and well underway to verify longer term benefit in a timely fashion.
III. RECOMMENDATIONS
Given the limitations of single-arm trials, a randomized controlled trial is the preferred approach to support an application for accelerated approval. Sponsors can, as appropriate, elect to conduct a single randomized controlled trial to support an accelerated approval and to verify clinical benefit (i.e., follow a “one-trial” approach) or, they can conduct separate trials – one to support the accelerated approval and another, a confirmatory trial, to verify clinical benefit.
Although a randomized controlled trial is the preferred approach, there can be circumstances wherein a single-arm trial is appropriate in the development of a drug for accelerated approval, for example when there are significant concerns about the feasibility of a randomized controlled trial. Careful consideration should be taken in determining whether a single-arm trial is appropriate in a particular clinical and regulatory context. Regardless of the approach under consideration, FDA recommends early discussion with the Agency before initiating and, as appropriate, during the conduct of, a trial(s).
A. Randomized Controlled Clinical Trials to Support Accelerated Approval
Sponsors can conduct separate randomized controlled trials – one trial with an early endpoint (e.g., response rate) to support the accelerated approval of the drug and a second trial powered for a longer-term clinical endpoint (e.g., progression-free survival (PFS) or overall survival (OS)) to verify clinical benefit. Alternatively, sponsors could design a single randomized controlled trial to support accelerated approval, that is also powered for the longer-term clinical endpoint with follow-up in the same trial to verify clinical benefit (i.e., “one-trial” approach). Below are recommendations for addressing the design, conduct, and analyses of data for either two separate randomized controlled clinical trials or for using the “one-trial” approach for accelerated approval and to verify clinical benefit.
1.Considerations for Two Randomized Controlled Clinical Trials
• Waiting to initiate a randomized controlled confirmatory trial until after an accelerated approval has been granted can create challenges in enrolling participants due to the availability of the drug in clinical practice. Therefore, to help ensure the feasibility and timely completion of the trial intended to verify clinical benefit, FDA strongly recommends that this trial be well underway, if not fully enrolled, by the time of the accelerated approval action.
• To facilitate completion of the confirmatory trial, it may be acceptable to evaluate the drug in the same cancer type but in another line of therapy. For instance, for an accelerated approval granted for an indication in a refractory cancer setting, the confirmatory trial could be conducted in an earlier disease setting. This approach has the potential to provide access to effective drugs to patients with earlier-stage disease in which benefit may be greater, and it facilitates patient accrual when a drug has already received accelerated approval for a later-stage indication.
• Given the inherent and residual uncertainties regarding the clinical benefit of the drug at the time of accelerated approval, timely completion of the trial(s) intended to verify clinical benefit is critical. Confirmatory trials should be underway when the marketing application is submitted.
1. Considerations for a Single Randomized Controlled Trial to Support Accelerated Approval and to Verify Clinical Benefit
• If planning a “one-trial” approach that uses the same trial to potentially support 156 accelerated approval with longer term follow-up to verify clinical benefit, sponsors should carefully assess the available preliminary clinical data prior to initiating the trial. FDA recommends selection of an endpoint for accelerated approval that is appropriate and feasible to evaluate earlier in the disease and earlier during the conduct of the trial. Sponsors should also consider the natural history of the disease (e.g., indolent cancers), the mechanism of action of the investigational drug, the ability to reliably characterize measurable disease to assess response, and other context-specific factors in selecting the accelerated approval endpoint.
• Preserving the integrity of the trial is critical in assessing the feasibility and appropriateness of the “one-trial” approach because the evaluation of the data and subsequent regulatory action on an accelerated approval application may inadvertently introduce bias. In assessing the potential for bias, sponsors should consider factors such as the anticipated impact of crossover (if permitted); the preliminary data on the drug’s effects, including the toxicity profile, the treatment landscape, and the treatment used in the control arm, among other factors.
• Before initiating the trial, sponsors should consider and discuss with FDA whether based on the available preliminary clinical data, the expected effect on response rate or other early endpoint is of a sufficient magnitude to be reasonably likely to predict clinical benefit. Depending on the disease course, the intended population, and guidance from FDA, use of endpoints other than response rate could also be evaluated in a “one-trial” approach together with subsequent evaluation of clinical benefit endpoints.
• If the drug development program is intended to evaluate a combination regimen, sponsors should specify the approach for demonstrating the contribution of each component. Evidence should be provided to support the individual contribution of components to the claimed effect(s), which would generally come from multi-arm trials with interim analyses for futility or from the use of other adaptive trial design elements.
• Sponsors should carefully consider whether the results of the trial are adequate to support submission of an application. A requirement of accelerated approval is that the drug must demonstrate an effect on a surrogate endpoint or intermediate clinical endpoint that is reasonably likely to predict clinical benefit, and provide meaningful advantage over available therapy. Among the factors FDA considers in evaluating whether these requirements have been met are the statistical significance and clinical meaningfulness of the treatment effect demonstrated on the endpoint, other context-specific evidence supporting why the observed effect is likely to predict clinical benefit, and whether the control arm represents the appropriate available therapy.
• If the treatment landscape has evolved since initiation of the trial (e.g., the treatment on the control arm no longer reflects best available therapy), the decision regarding submission of an application for accelerated approval versus deferring submission of an application until the results to support traditional approval are available should be discussed with FDA. Ultimately, the determination of what constitutes available therapy is made at the time the regulatory decision is made rather than at the time the trial was initiated.
• The trial should be designed, executed, and analyzed in such a way as to ensure a robust assessment of the efficacy endpoints. The protocol should specify a plan to strongly control the overall false positive rate (type-I error) for the endpoint supporting accelerated approval and the endpoint supporting verification of clinical benefit.
• The trial sample size should be chosen so that it has adequate power to detect a clinically meaningful and statistically significant improvement in both the endpoints for accelerated approval (e.g., response rate) and verification of clinical benefit (e.g., PFS or OS). The trial design can incorporate adaptive design elements (e.g., sample size re-estimation). With an adaptive design, sponsors should consider the type I error control based on the context of the between-arm comparisons, address the operational issues that this approach may raise, and design the trial with timely completion of the trial as a paramount consideration. For additional information, refer to the guidance for industry Adaptive Designs for Clinical Trials of Drugs and Biologics (December 2019).
• For a response-based endpoint, the analysis to support accelerated approval could be based on a pre-specified number of initially randomized patients, while for a time-to-event endpoint, pre-specifying the number of events is appropriate; in each case, the sponsor should ensure a robust assessment and reliable estimation at the earlier analysis time point. Analyses of efficacy to support accelerated approval should be avoided until the trial is close to or fully enrolled to mitigate potential challenges in accrual if an accelerated approval is granted. General considerations for determining the adequacy of the overall response rate (ORR) data to support accelerated approval are described in Section B below.
• Measures should be in place to prevent circumstances that may jeopardize the trial results or trial integrity. For example, blinding of data for the endpoint supporting verification of clinical benefit should be maintained until the endpoint’s protocol-specified analysis time point is reached to ensure a robust assessment of this endpoint.
• In reviewing an application for accelerated approval, FDA’s safety assessment may include evaluating whether the available data suggest a potential for harm from treatment on the investigational arm (e.g., detrimental effects on clinical endpoints such as OS). FDA may request summary results of the analysis on survival data to support such an assessment as part of an application submission and may request updated survival results during the course of the review of the application. Sponsors should specify a plan that describes measures to maintain study blind for such an analysis.
B. Single-Arm Trials to Support Accelerated Approval
As described above, whether a single-arm trial is appropriate to support accelerated approval in a particular clinical and regulatory context should be discussed with FDA. This section outlines considerations for designing, conducting, and analyzing data from a single-arm trial intended to support accelerated approval when appropriate, and considerations for determining whether the data may be adequate for this purpose.
1. Study Efficacy Considerations
• Endpoints: In oncology, response rate is the most frequently used endpoint to support accelerated approval when the approval is based on data from single-arm trials. Appropriate criteria for assessing the response rate (e.g., ORR based on Response Evaluation Criteria in Solid Tumors [RECIST]19) should be used. In certain disease settings, measures of response other than ORR may be more appropriate to characterize efficacy (e.g., complete remission rate, major molecular response, etc.). Use of new response assessment criteria or modifications of established criteria should be supported by a strong underlying rationale and should be discussed with FDA at the trial design stage. Whenever possible, the method of assessing response used in the trial should be the same one used for product labeling.
• Available therapy: Accelerated approval is reserved for drugs that are expected to provide a meaningful advantage (including an efficacy advantage) over available treatment.To facilitate the demonstration of advantage over available therapies, sponsors should pre-specify the historical trial(s) that will serve as the basis for the comparison, and the rationale for the selected trial(s). The time frame for the trial(s), trial size, clinical and demographic characteristics of the trial population, and any potential bias in the assessment of response, are some of the factors to consider in evaluating the applicability of a historical trial. FDA recognizes that it may be challenging, particularly for drugs being developed in molecularly defined patient populations, to identify a historical trial; in such cases, it may be appropriate to provide data to demonstrate that the magnitude of the treatment effect in the molecularly defined subgroup is better than in the historical trial.
• Sample Size: A single-arm trial should be sized to permit adequate precision around the point estimate, provide robust estimation of the duration of response, and sufficiently describe the adverse event profile of the drug.
2. Trial Analysis Considerations
• When the efficacy endpoint is response rate, the adequacy of the result to support accelerated approval should be based on the magnitude and duration of response. Sponsors should consider the follow-up time necessary to adequately characterize the response rate and the durability of response in a particular disease setting (e.g., a rapidly progressing disease vs. an indolent disease). Statistical inferential procedures are not necessary to evaluate these endpoints in single-arm trials. In most cases, a minimum follow-up of six months after the response is needed for most of the responders to characterize durability of response. However, there may be instances where a longer minimum follow-up after response is necessary to adequately characterize clinical benefit. In some cases, FDA may request additional data on the durability of response during the review of an application.
• The trial sample size and analysis population for response should be pre-specified. Given the small size of most single-arm trials, the analysis population is generally expected to be the entire trial population. Patients who have received at least one dose of the study drug would then be included in the analysis population regardless of whether they have had the opportunity to respond due to short follow-up time. Multiple increases to the study sample size with repeated looks at the data in the absence of a pre-specified plan may introduce bias in the assessment of efficacy and should be avoided.
• To reduce the potential to introduce bias and to mitigate variance in the assessment of response, blinded independent central review (BICR) of the response assessment should be performed.
A BICR charter that includes procedures for adjudication should be made available to FDA as part of a marketing application.
• Generally, and in the appropriate clinical context, FDA has defined response rate as the sum of partial responses plus complete responses. When defined in this manner, response is a direct measure of a drug’s antitumor activity which can be evaluated in a single-arm study. Stable disease should not be a component of response rate. Likewise, measures such as clinical benefit rate (e.g., response rate + stable disease > 6 months) should not be used. Such measures can largely reflect the natural history of disease, whereas reduction in tumor size represents a direct therapeutic effect.
C. Confirmatory Trial Following Accelerated Approval
For drugs granted accelerated approval in oncology, postmarketing confirmatory trials have been required to verify and describe the anticipated clinical benefit. Such trials help address residual uncertainties regarding the relationship between the surrogate or intermediate endpoint to the ultimate clinical benefit. In order to minimize the duration of this uncertainty, FDA may require, as appropriate, that studies intended to verify clinical benefit be underway prior to approval, or within a specified time period after the date of approval, of the applicable product. Postmarketing trials must be carried out with due diligence, and in accordance with the postmarketing trial conditions specified by FDA, which may include enrollment targets, the study protocol, and milestones, including the target date of study completion. An advantage of the “one-trial” approach is that a separate confirmatory trial may not be necessary. However, when a single-arm trial supports the accelerated approval, and FDA requires a postmarketing trial to evaluate PFS or OS, a separate randomized controlled trial may be needed. Early discussions with FDA regarding the design and initiation of both the trial intended to support accelerated approval and the postmarketing trial are recommended to provide evidence of clinical benefit in an expeditious manner.
京公網(wǎng)安備11010802046783號(hào)
