在最近一次稽查中，有一個(gè)關(guān)于文盲受試者知情同意的討論，挺有意思的，和大家分享一下。

受試者為文盲，不會(huì)寫字，所以由其監(jiān)護(hù)人簽署了知情同意書，理由是根據(jù)中國(guó)GCP第二十三條（七）受試者或者其監(jiān)護(hù)人，以及執(zhí)行知情同意的研究者應(yīng)當(dāng)在知情同意書上分別簽名并注明日期，如非受試者本人簽署，應(yīng)當(dāng)注明關(guān)系。因?yàn)檫@里用的是“或者”，所以被稽查方認(rèn)為如果受試者本人不能簽署ICF，則由其監(jiān)護(hù)人簽署就可以了，注明關(guān)系即可，這符合中國(guó)GCP的要求。

聽上去似乎很有道理，但其實(shí)是不正確的。中國(guó)是ICH成員，中國(guó)GCP大部分脫胎于ICH GCP，但是中國(guó)GCP在借鑒ICH GCP時(shí)有些信息遺漏，導(dǎo)致了理解的偏差。

ICH GCP關(guān)于受試者知情同意的要求是在4.8 Informed Consent of Trial Subjects中闡述的，其中4.8.1-4.8.4只提到了研究者或者受試者，均未涉及到監(jiān)護(hù)人，承上啟下的是4.8.5 The investigator, or a person designated by the investigator, should fully inform the subject or, if the subject is unable to provide informed consent, the subject's legally acceptable representative, of all pertinent aspects of the trial including the written information given approval/ favourable opinion by the IRB/IEC。在這里首次出現(xiàn)了“subject's legally acceptable representative”，直譯是“法定代理人”，為了方便和中國(guó)GCP比較，下文中均用“監(jiān)護(hù)人”指代。根據(jù)這一條款，只有在受試者沒有能力完成知情同意時(shí)，監(jiān)護(hù)人才適用。所謂“沒有能力完成知情同意”是指沒有能力在完全理解知情的內(nèi)容后表達(dá)主觀同意的受試者，如未成年人和嚴(yán)重癡呆的病人。而監(jiān)護(hù)人是不適用于文盲受試者的知情同意的，因?yàn)槲拿な怯心芰斫夂捅磉_(dá)同意的，只是無法閱讀，不能由監(jiān)護(hù)人代替文盲受試者完成知情同意過程。

同樣，因?yàn)橛辛?.8.5的約定，ICH GCP條款4.8.6-4.8.15中涉及的“the subject's legally acceptable representative”均和4.8.5一樣，僅適用于“沒有能力完成知情同意的受試者”。如4.8.8 Prior to a subject’s participation in the trial, the written informed consent form should be signed and personally dated by the subject or by the subject's legally acceptable representative, and by the person who conducted the informed consent discussion。如果孤立地看這個(gè)條款，好像受試者或者監(jiān)護(hù)人其中一人簽署知情同意書就可以了，但聯(lián)系上下文，我們就可以知道只有當(dāng)受試者本人沒有能力完成知情同意時(shí)（如未成年人），才可以由其監(jiān)護(hù)人簽署知情同意書。所以，監(jiān)護(hù)人是不能代替文盲受試者簽署知情同意書的，如果受試者是文盲，則需由見證人參與知情同意過程并簽署知情同意書（具體規(guī)定參見ICH GCP4.8.9和中國(guó)GCP第二十三條（八））。

至于文首提到的中國(guó)GCP第二十三條（七）和ICH GCP4.8.8所要表達(dá)的是一個(gè)意思。所以，基于以上的分析，不能夠依據(jù)中國(guó)GCP第二十三條（七），而讓監(jiān)護(hù)人代替文盲受試者來簽署知情同意書。這不符合ICH GCP，也不符合中國(guó)GCP的主旨。

大家之所以對(duì)第二十三條（七）這一條款產(chǎn)生誤解，主要是中國(guó)GCP在借鑒ICH GCP4.8.5時(shí)遺漏了監(jiān)護(hù)人的適用場(chǎng)景。在中國(guó)GCP中，和ICH GCP4.8.5相對(duì)應(yīng)的條款是第二十三條（四）“研究者或者指定研究人員應(yīng)當(dāng)充分告知受試者有關(guān)臨床試驗(yàn)的所有相關(guān)事宜，包括書面信息和倫理委員會(huì)的同意意見”。與ICH GCP4.8.5相比，這里未提及監(jiān)護(hù)人，也就未說明監(jiān)護(hù)人的適用場(chǎng)景 “The investigator should fully inform the subject or, if the subject is unable to provide informed consent, the subject's legally acceptable representative”，以至于大家在理解后續(xù)條款（第二十三條（五）-（九））中的“監(jiān)護(hù)人”會(huì)有誤解或者困惑。直到第二十三條（十）才補(bǔ)充了監(jiān)護(hù)人的適用場(chǎng)景：“受試者為無民事行為能力的，應(yīng)當(dāng)取得其監(jiān)護(hù)人的書面知情同意；受試者為限制民事行為能力的人的，應(yīng)當(dāng)取得本人及其監(jiān)護(hù)人的書面知情同意?！保?yàn)轫樞虻怪?，?dǎo)致大家在理解之前條款中的“監(jiān)護(hù)人”時(shí)，未能考慮到其也只適用于無民事行為能力或者限制民事行為能力的受試者。

希望大家能夠記住監(jiān)護(hù)人在知情同意過程中的適用場(chǎng)景，也建議大家靜下心來，好好讀一下GCP。下一期和大家分享知情同意過程中見證人的使用，一個(gè)非常灰色的角色。

附：GCP中關(guān)于知情同意的條款。

中國(guó)GCP：第二十三條  研究者實(shí)施知情同意，應(yīng)當(dāng)遵守赫爾辛基宣言的倫理原則，并符合以下要求：

（一）研究者應(yīng)當(dāng)使用經(jīng)倫理委員會(huì)同意的最新版的知情同意書和其他提供給受試者的信息。如有必要，臨床試驗(yàn)過程中的受試者應(yīng)當(dāng)再次簽署知情同意書。

（二）研究者獲得可能影響受試者繼續(xù)參加試驗(yàn)的新信息時(shí)，應(yīng)當(dāng)及時(shí)告知受試者或者其監(jiān)護(hù)人，并作相應(yīng)記錄。

（三）研究人員不得采用強(qiáng)迫、利誘等不正當(dāng)?shù)姆绞接绊懯茉囌邊⒓踊蛘呃^續(xù)臨床試驗(yàn)。

（四）研究者或者指定研究人員應(yīng)當(dāng)充分告知受試者有關(guān)臨床試驗(yàn)的所有相關(guān)事宜，包括書面信息和倫理委員會(huì)的同意意見。

（五）知情同意書等提供給受試者的口頭和書面資料均應(yīng)當(dāng)采用通俗易懂的語(yǔ)言和表達(dá)方式，使受試者或者其監(jiān)護(hù)人、見證人易于理解。

（六）簽署知情同意書之前，研究者或者指定研究人員應(yīng)當(dāng)給予受試者或者其監(jiān)護(hù)人充分的時(shí)間和機(jī)會(huì)了解臨床試驗(yàn)的詳細(xì)情況，并詳盡回答受試者或者其監(jiān)護(hù)人提出的與臨床試驗(yàn)相關(guān)的問題。

（七）受試者或者其監(jiān)護(hù)人，以及執(zhí)行知情同意的研究者應(yīng)當(dāng)在知情同意書上分別簽名并注明日期，如非受試者本人簽署，應(yīng)當(dāng)注明關(guān)系。

（八）若受試者或者其監(jiān)護(hù)人缺乏閱讀能力，應(yīng)當(dāng)有一位公正的見證人見證整個(gè)知情同意過程。研究者應(yīng)當(dāng)向受試者或者其監(jiān)護(hù)人、見證人詳細(xì)說明知情同意書和其他文字資料的內(nèi)容。如受試者或者其監(jiān)護(hù)人口頭同意參加試驗(yàn)，在有能力情況下應(yīng)當(dāng)盡量簽署知情同意書，見證人還應(yīng)當(dāng)在知情同意書上簽字并注明日期，以證明受試者或者其監(jiān)護(hù)人就知情同意書和其他文字資料得到了研究者準(zhǔn)確地解釋，并理解了相關(guān)內(nèi)容，同意參加臨床試驗(yàn)。

（九）受試者或者其監(jiān)護(hù)人應(yīng)當(dāng)?shù)玫揭押炇鹦彰腿掌诘闹橥鈺蛘吒北竞推渌峁┙o受試者的書面資料，包括更新版知情同意書原件或者副本，和其他提供給受試者的書面資料的修訂文本。

（十）受試者為無民事行為能力的，應(yīng)當(dāng)取得其監(jiān)護(hù)人的書面知情同意；受試者為限制民事行為能力的人的，應(yīng)當(dāng)取得本人及其監(jiān)護(hù)人的書面知情同意。當(dāng)監(jiān)護(hù)人代表受試者知情同意時(shí)，應(yīng)當(dāng)在受試者可理解的范圍內(nèi)告知受試者臨床試驗(yàn)的相關(guān)信息，并盡量讓受試者親自簽署知情同意書和注明日期。

（十一）緊急情況下，參加臨床試驗(yàn)前不能獲得受試者的知情同意時(shí)，其監(jiān)護(hù)人可以代表受試者知情同意，若其監(jiān)護(hù)人也不在場(chǎng)時(shí)，受試者的入選方式應(yīng)當(dāng)在試驗(yàn)方案以及其他文件中清楚表述，并獲得倫理委員會(huì)的書面同意；同時(shí)應(yīng)當(dāng)盡快得到受試者或者其監(jiān)護(hù)人可以繼續(xù)參加臨床試驗(yàn)的知情同意。

（十二）當(dāng)受試者參加非治療性臨床試驗(yàn)，應(yīng)當(dāng)由受試者本人在知情同意書上簽字同意和注明日期。

只有符合下列條件，非治療臨床試驗(yàn)可由監(jiān)護(hù)人代表受試者知情同意：臨床試驗(yàn)只能在無知情同意能力的受試者中實(shí)施；受試者的預(yù)期風(fēng)險(xiǎn)低；受試者健康的負(fù)面影響已減至最低，且法律法規(guī)不禁止該類臨床試驗(yàn)的實(shí)施；該類受試者的入選已經(jīng)得到倫理委員會(huì)審查同意。該類臨床試驗(yàn)原則上只能在患有試驗(yàn)藥物適用的疾病或者狀況的患者中實(shí)施。在臨床試驗(yàn)中應(yīng)當(dāng)嚴(yán)密觀察受試者，若受試者出現(xiàn)過度痛苦或者不適的表現(xiàn)，應(yīng)當(dāng)讓其退出試驗(yàn)，還應(yīng)當(dāng)給以必要的處置以保證受試者的安全。

（十三）病史記錄中應(yīng)當(dāng)記錄受試者知情同意的具體時(shí)間和人員。

（十四）兒童作為受試者，應(yīng)當(dāng)征得其監(jiān)護(hù)人的知情同意并簽署知情同意書。當(dāng)兒童有能力做出同意參加臨床試驗(yàn)的決定時(shí)，還應(yīng)當(dāng)征得其本人同意，如果兒童受試者本人不同意參加臨床試驗(yàn)或者中途決定退出臨床試驗(yàn)時(shí)，即使監(jiān)護(hù)人已經(jīng)同意參加或者愿意繼續(xù)參加，也應(yīng)當(dāng)以兒童受試者本人的決定為準(zhǔn)，除非在嚴(yán)重或者危及生命疾病的治療性臨床試驗(yàn)中，研究者、其監(jiān)護(hù)人認(rèn)為兒童受試者若不參加研究其生命會(huì)受到危害，這時(shí)其監(jiān)護(hù)人的同意即可使患者繼續(xù)參與研究。在臨床試驗(yàn)過程中，兒童受試者達(dá)到了簽署知情同意的條件，則需要由本人簽署知情同意之后方可繼續(xù)實(shí)施。

ICH GCP: 4.8 Informed Consent of Trial Subjects

4.8.1 In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement(s), and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. Prior to the beginning of the trial, the investigator should have the IRB/IEC's written approval/favourable opinion of the written informed consent form and any other written information to be provided to subjects.

4.8.2 The written informed consent form and any other written information to be provided to subjects should be revised whenever important new information becomes available that may be relevant to the subject’s consent. Any revised written informed consent form, and written information should receive the IRB/IEC's approval/favourable opinion in advance of use. The subject or the subject’s legally acceptable representative should be informed in a timely manner if new information becomes available that may be relevant to the subject’s willingness to continue participation in the trial. The communication of this information should be documented.

4.8.3 Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or to continue to participate in a trial.

4.8.4 None of the oral and written information concerning the trial, including the written informed consent form, should contain any language that causes the subject or the subject's legally acceptable representative to waive or to appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor, or their agents from liability for negligence.

4.8.5 The investigator, or a person designated by the investigator, should fully inform the subject or, if the subject is unable to provide informed consent, the subject's legally acceptable representative, of all pertinent aspects of the trial including the written information given approval/ favourable opinion by the IRB/IEC.

4.8.6 The language used in the oral and written information about the trial, including the written informed consent form, should be as non-technical as practical and should be understandable to the subject or the subject's legally acceptable representative and the impartial witness, where applicable.

4.8.7 Before informed consent may be obtained, the investigator, or a person designated by the investigator, should provide the subject or the subject's legally acceptable representative ample time and opportunity to inquire about details of the trial and to decide whether or not to participate in the trial. All questions about the trial should be answered to the satisfaction of the subject or the subject's legally acceptable representative.

4.8.8 Prior to a subject’s participation in the trial, the written informed consent form should be signed and personally dated by the subject or by the subject's legally acceptable representative, and by the person who conducted the informed consent discussion.

4.8.9 If a subject is unable to read or if a legally acceptable representative is unable to read, an impartial witness should be present during the entire informed consent discussion. After the written informed consent form and any other written information to be provided to subjects, is read and explained to the subject or the subject’s legally acceptable representative, and after the subject or the subject’s legally acceptable representative has orally consented to the subject’s participation in the trial and, if capable of doing so, has signed and personally dated the informed consent form, the witness should sign and personally date the consent form. By signing the consent form, the witness attests that the information in the consent form and any other written information was accurately explained to, and apparently understood by, the subject or the subject's legally acceptable representative, and that informed consent was freely given by the subject or the subject’s legally acceptable representative.

4.8.10 Both the informed consent discussion and the written informed consent form and any other written information to be provided to subjects should include explanations of the following:

4.8.11 Prior to participation in the trial, the subject or the subject's legally acceptable representative should receive a copy of the signed and dated written informed consent form and any other written information provided to the subjects. During a subject’s participation in the trial, the subject or the subject’s legally acceptable representative should receive a copy of the signed and dated consent form updates and a copy of any amendments to the written information provided to subjects.

4.8.12 When a clinical trial (therapeutic or non-therapeutic) includes subjects who can only be enrolled in the trial with the consent of the subject’s legally acceptable representative (e.g., minors, or patients with severe dementia), the subject should be informed about the trial to the extent compatible with the subject’s understanding and, if capable, the subject should sign and personally date the written informed consent.

4.8.13 Except as described in 4.8.14, a non-therapeutic trial (i.e. a trial in which there is no anticipated direct clinical benefit to the subject), should be conducted in subjects who personally give consent and who sign and date the written informed consent form.

4.8.14 Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled:

(a) The objectives of the trial can not be met by means of a trial in subjects who can give informed consent personally.

(b) The foreseeable risks to the subjects are low.

(c) The negative impact on the subject’s well-being is minimized and low.

(d) The trial is not prohibited by law.

(e) The approval/favourable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects, and the written approval/ favourable opinion covers this aspect.

Such trials, unless an exception is justified, should be conducted in patients having a disease or condition for which the investigational product is intended. Subjects in these trials should be particularly closely monitored and should be withdrawn if they appear to be unduly distressed.

4.8.15 In emergency situations, when prior consent of the subject is not possible, the consent of the subject's legally acceptable representative, if present, should be requested. When prior consent of the subject is not possible, and the subject’s legally acceptable representative is not available, enrolment of the subject should require measures described in the protocol and/or elsewhere, with documented approval/favourable opinion by the IRB/IEC, to protect the rights, safety and well-being of the subject and to ensure compliance with applicable regulatory requirements. The subject or the subject's legally acceptable representative should be informed about the trial as soon as possible and consent to continue and other consent as appropriate (see 4.8.10) should be requested.