科普:clinicaltrial.gov上对于双盲实验的解释

醉卧花底间
楼主 (文学城)

关于对这个trial是如何操作的,下面是summary的第一句

This study is an adaptive, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19.

什么是double-blind 

In many trials, no one—not even the research team—knows who gets the treatment, the placebo, or another intervention. When participants, family members, and staff all are “blind” to the treatment while the study is underway, the study is called a “double-blind, placebo-controlled” clinical trial.

醉卧花底间
科普:双盲实验如何发药。

有专门的CRO,他们拿到药,根据protocol,会randomize药瓶,然后在上面贴好标签,按需要发到每个做临床的医院,医生   来源: mickey222 于 2020-05-22 06:48:00  [档案] [博客] [旧帖] [给我悄悄话] 本文已被阅读: 次 (897 bytes)  字体:调大/重置/调小 | 加入书签 | 打印 | 所有跟帖 | 加跟贴 |  当前最热讨论主题 本文内容已被 [ mickey222 ] 在 2020-05-22 07:00:28 编辑过。如有问题,请报告版主或论坛管理删除.  回答: 问个问题。双盲实验医生也不知道,那药是怎么发的。 由 borisg 于 2020-05-22 06:20:37

收到药,只看见一个编号,不知道里面是什么,病人更加不会知道了。physician's brochure里面有很详细的指导如何给药的。而那个CRO保存database,里面哪个标号对应的是药还是placebo,他们知道,但是CRO不到最后揭盲,是不会告诉任何公司,医生,病人的。否则就是违反 GCP了。

临床试验也不是一次性收100个病人大家同时做,病人都是一个个收的,因为有很多手续的,也需要符合很多条件的病人才可以收的,所以某个试验中心或者医院收了病人,医生会通知公司,公司会通知那个CRO,他们就会寄送药品去哪个试验中心或者医院。

大部分生药公司都在临床试验中大量使用CRO,因为这样可以build很多barrier,避免很多信息泄露,同时也是术业有专攻。

C
Cecilia123
支持扫盲!学习了,公众平台的信息,应该客观、真实,而不是误导,或似是而非
吃与活
说得很对。只补充一点

随机双盲当然最好,但由于具体条件的不同,很多试验并不随机,也不双盲,甚至并不单盲。尽管如此,它们也是临床试验,也有价值。

a
awr
谢谢科普
要管3721
没有被FDA批准的药没有你这种情况。
吃与活
不明白你的意思。
要管3721
最后解释一次,在美国,没有被FDA认证的药没有你说的这种情况发生。

“,很多试验并不随机,也不双盲,甚至并不单盲”你的这种临床试验,新药在FDA过不了,

吃与活
可以读读这篇文章

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059315/

没时间就读2.1即可。

如果这也太多,就读下面一段。

"Despite the limitations, single-arm trials may be the only (or one of few) options for trials evaluating therapies for which placebos are not ethical and options for controlled trials are limited. Single-arm trials have been commonly implemented in oncology."

0
0862
这个解释简明扼要,排除各种可以影响药物疗效的因素,才能得出可信的结论。
甜酒甜
吃教授的耐心真好........

吃与活
我差点就没耐心了

这不想着得给人家做个示范么

甜酒甜
哈哈哈哈

一个大牛,不经常发言,每个月要审核很多临床用药的,看了中坛的跟帖,没说话.......

吃与活
给我一个link,看看大牛怎么说

人家没说话,你怎么知道人家去看了

甜酒甜
其他方式

说呀

说了,大牛不经常发言的

吃与活
(⊙o⊙)哇

能跟牛人说上话,你也是大牛啊

甜酒甜
哈哈哈哈,

我就一家庭妇女

吃与活
同意杨安泽的观点

管孩子,管家,都是工作。有人觉得容易,其实是非常的不容易。非常重要的工作。

甜酒甜
谢谢教授的肯定

m
mickey222
就是一个FDA的reviewer吧?呵呵

很多工业界混不好华人的去FDA做reviewer。FDA里面reviewer的structure比较flat,也没啥可以竞争的了,不是reviewer就是senior reviewer。不少是华人,因为需要的语言功能比较少,很多reviewer就懂她自己那一块。没有全局观。没有华人做到Janet Woodcock那位子的,所以不知道是什么大牛。呵呵。Janet还是很牛的。是个大牛。

m
mickey222
那你太牛了,认识Janet这样level的人

我只有一次跟她一个桌子吃饭的机会。没能真正的认识这样的牛人。唯一可以跟她提的跟她差不多的一个FDA华人,我知道,可是不是做新药的。有个发明是行业标准。是个男的。

m
mickey222
哦,你咋到处删帖呢,我话头都掉了
要管3721
才知道你是教授,原来抄帖子也能成为教授。

phase 3 也是这要求?

不需要对照组?

要管3721
第一次知道你如此谦虚好学呀?中坛没见过你了,原来如此。
吃与活
一般用historical control
n
nowayitsover
Being so rude.....看来你还很年轻,去twitter上吵架泄恨吧,这里是健康养生版。
欲千北
+。应该尊重人,反对吵架。
虎嗅蔷薇
我想请教你,为什么Gilead自己做的两个试验都没有双盲。

中国内的试验没做成,在美国疫情爆发期有许多病人。这家公司对这个药的研发已经投入很多,难道药厂以后还会计划做双盲的?不做blinding可能出于什么考虑?想听听你的看法。

欲千北
对照组不是自动 = placebos,可以有不同情况下的对照。安慰剂对照只是其中一种。有些情况不适合双盲。
醉卧花底间
我也只是搬过来,好好学习天天向上,长一点常识很必要。

醉卧花底间
还请米总多来科普。
n
nowayitsover
非专业人士,记得见过报道印象中说是FDA特许,有效就会批药。

这次gilead那么多临床试验,不是gilead做三期的本意,是特殊时期为了救人。

阿明.
中坛有个专业人员的解释:

我在制药公司工作了很多年,管过很多clinical trials. Phase 3 study can be randomize   尤其是急性严重疾病,从ethical 方面考虑试验可能设计成open label. 另外病人不管分到哪个组只要病情严重恶化就可以用其它药了。美国的临床实验非常讲究ethical, 不可能分到placebo 就宁愿病人面临生命危险而不给其他药。placebo 通常是指standard care, 在楼主这种情况下能够拿到血清的话是会给用的 https://bbs.wenxuecity.com/rdzn/4408692.html
吃与活
我粗看了中坛个别人的观点,基本上是把人当老鼠对待了

其实不懂是没问题的,问题是只懂一点就觉得自己都懂了。对网友报告治病经历打压就更缺乏同情心了。这些人在伦理方面需要补课。

米奇的厨房
这次有双盲的啊, 虽然sponsor不是Gilead,但是其实他们也必须同意这个试验才得以进行的啊。

我不做infectious disease的。我觉得 Gilead本身是比较谨慎的一个公司,所以他自己设计的临床对风险的考虑比较多。何况这个病毒本身比较tricky,也不知道它是怎么来的,变化很快,我都不知道这个病的standard of care是什么,看起来好像每个州,国家都有自己的一套,很乱,重症病人的死亡率高。Remdisevir本来只是用于Ebola的,没有做冠状病毒的1期,2期,现在这个病高度政治化,所以Gilead比较严谨,怕落下口实。open label有利于降低风险。

如果其他sponsor做,他家也乐见其成,如果他们效果好,Gilead再上也不迟,就这个病毒这么强的感染能力,我觉得这个病的传播还会延续一段时间,到时候需要病人应该不是大问题。

 

 

 

 

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

 

Study Details Tabular View No Results Posted Disclaimer How to Read a Study Record Study Description   Go to   Brief Summary: This study is an adaptive, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19. The study is a multicenter trial that will be conducted in up to approximately 100 sites globally. The study will compare different investigational therapeutic agents to a control arm. There will be interim monitoring to introduce new arms and allow early stopping for futility, efficacy, or safety. If one therapy proves to be efficacious, then this treatment may become the control arm for comparison(s) with new experimental treatment(s). Any such change would be accompanied by an updated sample size. Because background standards of supportive care may evolve/improve over time as more is learned about successful management of COVID-19, comparisons of safety and efficacy will be based on data from concurrently randomized subjects. An independent Data and Safety Monitoring Board (DSMB) will actively monitor interim data to make recommendations about early study closure or changes to study arms. To evaluate the clinical efficacy, as assessed by time to recovery, of different investigational therapeutics as compared to the control arm.   Condition or disease  Intervention/treatment  Phase 
COVID-19 Other: PlaceboDrug: Remdesivir Phase 3
  Detailed Description:

This study is an adaptive, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19. The study is a multicenter trial that will be conducted in up to approximately 100 sites globally. The study will compare different investigational therapeutic agents to a control arm. There will be interim monitoring to introduce new arms and allow early stopping for futility, efficacy, or safety. If one therapy proves to be efficacious, then this treatment may become the control arm for comparison(s) with new experimental treatment(s). Any such change would be accompanied by an updated sample size. Because background standards of supportive care may evolve/improve over time as more is learned about successful management of COVID-19, comparisons of safety and efficacy will be based on data from concurrently randomized subjects. An independent Data and Safety Monitoring Board (DSMB) will actively monitor interim data to make recommendations about early study closure or changes to study arms.

The initial sample size is projected to be 572 subjects to achieve 400 subjects with a "recovered" status (per the primary objective). The primary analysis will be based on those subjects enrolled in order to 400 recoveries. An additional analysis of the moderate severity subgroup (those with baseline status of "Hospitalized, requiring supplemental oxygen" or "Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care") is also of public health importance. Hence, enrollment will be permitted until the date of April 20, 2020 to ensure 400 recoveries and provide additional data about this important subgroup. With recent enrollment rates, the total sample size may be 600 to over 800.

Subjects will be assessed daily while hospitalized. If the subjects are discharged from the hospital, they will have a study visit at Days 15, 22, and 29 as an outpatient. For discharged subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety laboratory tests and OP swab and blood (serum only) samples for secondary research as well as clinical outcome data. However, infection control or other restrictions may limit the ability of the subject to return to the clinic. In this case, Day 15 and 29 visits may be conducted by phone, and only clinical data will be obtained. The Day 22 visit does not have laboratory tests or collection of samples and may also be conducted by phone.

All subjects will undergo a series of efficacy, safety, and laboratory assessments. Safety laboratory tests and blood (serum and plasma) research samples and oropharyngeal (OP) swabs will be obtained on Days 1 (prior to infusion) and Days 3, 5, 8, and 11 (while hospitalized). OP swabs and blood (serum only) plus safety laboratory tests will be collected on Day 15 and 29 (if the subject attends an in-person visit or are still hospitalized).

The primary outcome is time to recovery by Day 29. A key secondary outcome evaluates treatment-related improvements in the 8-point ordinal scale at Day 15. As little is known about the clinical course of COVID-19, a pilot study will be used for a blinded sample size reassessment.

Study Design   Go to  

 

Study Type  : Interventional  (Clinical Trial)
Estimated Enrollment  : 800 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults
Actual Study Start Date  : February 21, 2020
Estimated Primary Completion Date  : April 1, 2023
Estimated Study Completion Date  : April 1, 2023
Arms and Interventions   Go to  

 

Arm  Intervention/treatment 
Placebo Comparator: Placebo 200 mg of Remdesivir placebo administered intravenously on Day 1, followed by a 100 mg once-daily maintenance dose of Remdesivir placebo while hospitalized for up to a 10 days total course. n=286. Other: Placebo The supplied placebo lyophilized formulation is identical in physical appearance to the active lyophilized formulation and contains the same inactive ingredients. Alternatively, a placebo of normal saline of equal volume may be given if there are limitations on matching placebo supplies.
Experimental: Remdesivir 200 mg of Remdesivir administered intravenously on Day 1, followed by a 100 mg once-daily maintenance dose of Remdesivir while hospitalized for up to a 10 days total course. n=286. Drug: Remdesivir Drug Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular delivery of a modified adenine nucleoside analog GS-441524. In addition to the active ingredient, the lyophilized formulation of Remdesivir contains the following inactive ingredients: water for injection, sulfobutylether beta-cyclodextrin sodium (SBECD), and hydrochloric acid and/or sodium hydroxide.  

 

 

米奇的厨房
你说的情况自然是有的,但是那位楼主写的清清楚楚:进了安慰组。 没写:进了对照组。
米奇的厨房
他说的不对,open label是有的,紧急情况是病人退出试验,然后给其他的药,不会同时给placebo加抗血清。

placebo不是standard of care. placebo是专门生产的,外观和药品完全一致的(几乎完全,特殊情况有的时候会有微小差别)药品,里面除了没有API,其他的excepients 和药品应该是一样的。用placebo的目的就是用来blind的。让病人和医生无法从外观上猜测出哪个是药品,哪个是placebo。Remdisivir是冻干剂,placebo也是设计成一样的包装了,administration方法也是一致的。在那个临床试验的网站上可以看到一点的。

standard of care 是当时业界通过的医疗此病的标准,不是什么placebo。我不知道这位是管clinical trial的哪一块的,这样的说法明显不对。

虎嗅蔷薇
双盲的ACTT-I trial,福奇的 NIH NIAID做的,

它的早期数据已被FDA用作授予Remdesivir EUA 的依据。

论文也刚新鲜出炉,在这里:
Remdesivir for the Treatment of Covid-19 — Preliminary Report

第一阶段已经结束了,安慰剂组的病人也给予用药
Inside the NIH’s controversial decision to stop its big remdesivir study

不过它还有第二阶段的新trial。

Gilead被中国抢注专利之后的回应,迅速放弃孤儿药认证,给两个open label trials增加同情用药渠道等做法,都给人不错的印象。

Standard of Care确实很杂乱,有个一线医生说,we throw everything at it except the kitchen sink.

临床试验也是一大堆蜂拥而上。

虎嗅蔷薇
又是一例把control和placebo名称混用的。有行业背景的人都这么做。没医学背景的病人家属很容易搞混。
欲千北
虎网友已经解释了,说的在理,在点子上。病人家属把 “常规治疗组” 或 “对照组” 误写成了 “安慰剂组”。

整个事情的关键词是病人家属说的“安慰剂组”。 换成“常规治疗组”或“对照组”,就不奇怪了。   来源: 虎嗅蔷薇 于 2020-05-22

在健坛会时常看到患者和家属来问问题或者写长篇分享诊疗过程,里面有各种医学名词概念混乱, 叙述过程颠三倒四, 或重要事实语焉不详或者对不上需要澄清, 占不小比例。

我的判断是她母亲参加的是Gilead的open label trial。被分到常规治疗组。被她理解为安慰剂组。

米奇的厨房
我不知道这位是怎么回事,她这样的语言写在工作的Email上,被FDA看见就是麻烦。你说的当然有道理,不过那位有争议的人写的

言之凿凿:医生打电话告诉她,妈妈被分在安慰剂组了。

我相信她的每个字写的,所以才有疑问啊,因为她写的情况不可能存在。

米奇的厨房
紧急情况下,能有一个药算是有clinical benefits,算是不错了。混乱是没办法了。我对Gilead 的印象还是很不错的

很内敛,很hold的住。坚持自己的信念。不为外部所动。

米奇的厨房
不是她理解,那位自己解释:医生打电话给她,说她母亲被分在安慰剂组,是医生说的,不是她说的
米奇的厨房
乱用中药,才是把人当老鼠对待;而中药注射剂,完全的谋财害命
虎嗅蔷薇
同意
虎嗅蔷薇
我的解释是我的个人判断。我还是这么判断。但那位网友不但言之凿凿而且坚持说是安慰剂组。她自己不想搞清楚吗?有许多简单办法的。
虎嗅蔷薇
前不久有位网友说自己高烧到110度。被质疑。她意识到打错了数字,澄清一下就行。 中坦人多,质疑的也有不同程度的。有的是过火了。
n
nowayitsover
吃教授说的太对了。
欲千北
+。十有八九是她记错了,或误解了。一件小事,但她没有出来公开澄清。
米奇的厨房
有可能,但是她写一长篇来反驳,就是不澄清也很奇怪,不是吗?一般人不是专业的,澄清一下就好了。
米奇的厨房
同意,她要是在她那篇长篇反驳文里面澄清一下,疑问立马解决了
欲千北
+100
p
pickshell
+1 有疑问可平心静气质疑,在怎么样也不能成为那帮劈头盖脸谩骂的理由。