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天士力孙鹤与他的“三跑理论”

玉见 玉见 来源:医药魔方
2019-03-15
天士力 孙鹤
原文

孙鹤博士是天士力副总裁、“复方丹参滴丸”的国际化负责人。他也是当时中国大陆医药界留美学生中进入FDA工作的第一人,并在FDA做到了临床计量药理学最高级别的首席科学家和主审官。近日,孙鹤来到苏州生物医药产业园(BioBAY),给园内几十家做新药研发的企业分享了他近30年的行业思考。医药魔方记者在会后与孙鹤进行了一番交流。


“我没做PPT,因为按照以往的经验来看,对着PPT讲到最后多少都会变成读PPT了,所以我就跟大家干讲吧,中间有什么问题欢迎随时打断我。”孙鹤的开场似乎有些另类。简明扼要地介绍后,孙鹤就开讲了。他主要分享了三个方面的内容:一是企业究竟应该怎么去做新药;其次是做好了如何走向美国,走向全球;最后是产品如何在欧美市场上进行销售。


天士力副总裁孙鹤

1

树立先写“产品说明书”的研发理念

 

 「在整个医药创新布局上,中药(植物药)一直在全世界是领跑者,海外还没有咱们中国做得这么好;在化学药上,中国相对要比较落后,咱们只能是一个跟跑者,人家上百年前启动了,我们最近一二十年才刚开始,这远远落后,人员的经验程度都不一样;生物药相对来说中国与国外基本上是同步的,差的不太多。孙鹤说,中国的新药研发可以用他的“三跑理论”来描述,即“化学药是在跟着别人跑,生物药是在并排跑,植物药是在领跑”。


“药品上市后归根到底还是一种商品,如果是盖大楼,也得先有个建造图纸。然而很多医药创业型企业,几乎都是走一步看一步。”孙鹤指出,“目前很少有企业事先将商品说明书写好,然后按照说明书的要求,把该解决的问题一个个解决掉。”


孙鹤认为,商品说明书不仅包括产品的品规、给药途径、适应症设计、最高耐受剂量等研发内容,甚至还与后续的产品生命周期管理、药品经济学分析,流行病学数据以及在不同国家/地区的销售途径等商业化内容相关。


在开发阶段,孙鹤比较倾向于“先有司机,再买车和地图”的理念。在对美国大药厂发展规律总结后,他发现很少有企业是先花大价钱“买好车”,再琢磨找谁来开;多数是找到了好的司机,再去买地图和车,在好司机的带领下,几乎不会走弯路就能到达目的地。在孙鹤看来,即便是非常有前景的项目,如果没有好的项目管理者,也也很难顺利推动。

 

2

立项人员要擅于“算账”


孙鹤还指出,平时大家普遍会被一个现象所“迷惑”。就是经常有咨询公司会发布一些数据说“上市一个新药平均需要XX年,耗费XX资金,投资回报率只有XX%……”按照他过往的经验发现,不同的药物开发成本与时间,差异非常大。


在他看来,尽管临床试验失败不可避免,但是一些研发费用还是可以提前预测的。对于一个临床试验设计者而言,试验方案的设计不仅会影响试验的成败,还影响研究经费。孙鹤说,在药企临床项目的人一定得会“算账”。


他以化学药为例,目前业内公认的是大概从1万个候选分子中最终能够获得1~2个产品,II期失败率30%,III期临床失败50%,30%的研发费用在临床前,70%研发费用在临床试验。如果是研发抗菌素,一般临床试验不会超过5到7天,研发成本就会低很多,而如果是那种临床使用频次较多的,不仅临床花费很高,按照FDA规定新药一年内使用频次超过28天,需要做全套长毒,又是一笔费用。

 

具体到临床试验的收费,在美国,临床费用包括用药随访次数计算。每一次涉及基础检查费用,医生访谈费用,心电图费用。从目前普遍情况,抗癌药一个试验周期的研发费用大约是30万美金/人;高血压,心血管等慢性疾病3~4万美金/人;感冒大概是2~3万美金/人。企业在开展临床试验前,应该有所准备,合理规划,合理融资。


3

要具备全球化视野

 

“新药研发的一个最大特点,就是受政府的高度监管,其他任何行业受到政府的监管都没有像医药行业如此之严。”孙鹤坦言,“做新药开发,一定要具备前瞻性的视野以及全球化的格局。”


孙鹤谈到,任何药企在开发产品,不仅要想明白究竟是为谁开发的,还要搞清楚谁是潜在竞争对手。在他看来,一般做创新药不外乎两种商业模式,要么把项目做到一定阶段转让出去获得服务费以及后期的分成;要么就是奔着产品上市。他进一步解释道。


他甚至举例,假如目标药品的研发真的需要耗费12年,那么该企业建立的标准至少得是保证12年后不会被淘汰的,同时应该对12年后的疾病状态、全球疾病谱有个合理的估计预测。在此期间通过政府监管将是企业能否活下去的生死线。在孙鹤看来,企业从第一天开始搞新药研发,就应该瞄准全球市场,用最高标准要求自己是毋庸置疑的。 


此外,孙鹤还谈到了一些商业化成功的秘诀,比如建议先申报FDA,学习FDA关于试验方案设计及试验数据等诸多方面的具体要求,再回过头来报国家药品管理局,从“知其所以然”到“知其然”,会轻松很多。同时,他还建议企业要提前熟悉美国商业保险报销制度和销售体系,也是有助于产品开发的。


在孙鹤看来,国内创新药在海外做产品销售的话,是选择海外分公司自己建立销售团队,还是与当地大的医药企业合作?这些都是要提前考虑的。此外针对不同的产品,销售模式会存在较大差异,所需要的团队人数,人员结构也是显著不同的。他认为这些问题,药企都要想明白,搞清楚。

 

医药魔方:孙教授您好!如果重新选择,第一份工作还会选择去FDA吗?为什么?


孙鹤:时隔20多年,我常在感叹。其实我们当年留学生的选择不外乎三条路径。要么去产业界(大型药企或生物科技公司),要么回到校园在大学教书,要么就是去政府部门,像FDA这种。


在当时,其实如果直接进入产业界,在企业的收入是要比政府高很多很多的。但当时个人感觉是在美国那些大药厂基本上就是一条线,管生产的管生产,管研发的管研发,管注册的注册;去大学的话,就是天天写课题,申报课题,做课题,似乎也可以预测到。


而到政府里工作,就大不一样了。几乎每天都可以看到全世界最大的企业以及最小的企业在做的事情,视角顿时就不太一样了。重新选择的话,我可能还是会去。一开始,工资少点就少点吧,毕竟能塑造一个人的格局。不过话说回来,医药是一个日异月新的行业。无论在哪里,都需要不断学习。即使我已经有了20多年的积累,到今天依旧是边学习边发展。


医药魔方:您在FDA呆了那么久,感受到哪些理念是值得我们分享和学习的?


孙鹤:至少我在FDA工作的时候,FDA的理念不是监管,而是怎么帮新药尽快地上市。所以你在这里(FDA)工作,拿着纳税人的钱,每天是要想着怎么为纳税人服务,尽快将一些“好药”推向市场。


其次,FDA制定的很多标准,其背后很多也是站在企业角度考虑的,是有科学依据的。举个例子,FDA在设立一些临床试验数据结果的有效性时,是已经考虑到了临床实验上的患者“脱落”,而有时候药企为了避免药效表现不好,去选择一个范围比较窄的群体,得到数据反而还不符合既定的标准。


医药魔方:您觉得当前国内创新药企在开发中普遍存在的问题是?


孙鹤:我的感觉是这样,现在做新药研发,都是做完临床前研究,然后I期临床做完了,开始II期,再临床III期,一边干着,一边规划着。很多企业可能并不是很清楚下一步到底该往哪个具体方向发展。基本上,很少有企业像咱们建大楼一样,先有一个非常详细的设计图,然后在这个设计图上“添砖加瓦”。


简而言之,可能很少有一家企业先把药品“产品说明书”写好,然后说明书把该解决的问题一个个解决掉。大多数可能都是一边走,一边弄,到了最后再一起去吸收。


而从监管角度,最后的产品并不是你那个物质,那个物质在申请临床试验前就已经有了。最后的产品,应该是你的那个产品说明书。产品说明书写得好,能够解决患者的某个问题(或者是某些患者的问题),就能卖得掉,医生就会使用。我觉得事先没有把产品说明书写好,就是“蒙着干”。中国药企可能还没有这个习惯,我想应该重视起来。  

 

医药魔方:能否详细地阐述您的“三跑理论”以及您所看到的现实?


孙鹤:化学药开发在美国至少有将近上百年的历史,咱们真正正规的做化学药的新药研发,也就是最近十到二十年开始的。所以我认为化学药的研发,中国仍然需要不断学习欧美经验,短期内赶超的可能性不大。


以化学合成为例,如今去美国的大药厂参观,他们的合成只需要在 “小型收音机”大小的容器中进行,容器里面密密麻麻布置了细小管子。研究人员只需要按照不同的次序操作(在显示屏上点击不同数字),把母体化合物导入,就可以收获不同的化合物。他们目前每天大概能合成700个先导化合物,据我所知中国目前还没有企业可以做到这个地步。


一方面是高通量筛选技术方面的不足,另一方面是开发经验有限。有些有经验的工程师,从电脑上你和的二维/三维空间,一眼就能看出来这个药的成药概率,但是要他说具体原因他可能也说不完整,这好比是长期积累的经验。因此目前国内化学药要追赶上美国的话,还是需要努力。

 

生物药相对来说好一点,原因是十几年前生物药开始出现时,中国就已经开始起步了。大概是2003年到2006年期间,FDA没有批准一个抗体药物。我是2006年回来的,当时很多人问我应该做什么?我就跟他们说,要不你试试生物药。所以现在国内生物药这么热,也是有一定原因的。


其次生物药从0到1的工作还是比较容易的,在体内刺激产生抗体,然后想办法做培养,扩大后通过比对做成毒副反应比较小,靶点比较明确的候选分子。所以一旦成了以后,临床试验中间由于毒副作用失败的概率就小多了。但是中国,真正影响产品研发的不是前期工作,而是生产能力。生物仿制药的发展,从2006年到如今十多年来,国家给了很多创新专项资金支持,最近才刚刚批了一个生物仿制药。


为什么一直没做出来?原因之一就是成本太高。为什么成本太高?要么是因为一点污染都得作废,要么是生产原料能力不足造成的,特别是培养液以及佐剂都需要靠进口。比如说南韩,他们的生物仿制药的发酵罐都是成吨发酵的,而国内真正能做到成吨发酵的只有广东那边一家做胰岛素的企业。

 

因此在生物药领域,从0到1的活能干好,从1到10的活,还有很大进步空间。原来我们在做国家新药重大专项答辩时,很多企业回答从0到1的工作,都做得很好,但是到了从1到10,问他怎么降低成本,就有些卡壳了。因此分享下我的建议,做生物药,不要因为从0到1的工作做好了就盲目乐观,真正的瓶颈在从1到10。

 

最后植物药这块,我们国家一直叫中药。很多人会说中药肯定是全世界第一,因为中药只有你中国能干这个,别的国家不能干是吧?事实上,并不是这样,现在就说植物药这一块,别忘了日本韩国是以东南亚国家,它们已经是有大量的在植物药上面的科研投入,不得不企业角度。

 

我们前一段时间统计,报FDA的临床试验申请的植物药资料是134个,中国只有12家企业的14个产品在申报。所以从FDA角度,我们的植物药至少是没有德国日本韩国这么大力推进。


医药魔方:为什么您建议,做新药一定要奔着到美国上市呢?


孙鹤教授:美国是全世界唯一一个不对新药定价的国家,他们完全靠企业和保险公司讨价还价。由于产品价格可以自己定,这导致全球90%的创新药都会考虑到美国上市。欧洲大部分国家都是政府定价,日本也是政府定价的。所以说,真正的first in class 产品,去美国上市回报率相对也比较高。 


医药魔方:美国这种企业和保险可以谈判的体系,对药品开发商有何启示?


孙鹤:我以“孤儿药”开发来举例吧。假设一个孤儿药,保险公司是答应每年可以报销100万美金。美国有600个这样的患者,仅凭一个药物就可能获得6亿美元的市场,只要建立这样的患者社区,组织一批患者参与临床试验,试验成功了,患者口口相传,连销售人员都免了。所以孤儿药在美国只要能开发出具有疗效的产品,一定有市场。


所以我建议如果要走中美双报,希望就在美国开拓市场的企业,最好提前熟悉美国商业保险体系,也方便日后与保险部门进行谈判。


医药魔方:除了报销,其药品销售是不是与国内也有很大差异?


孙鹤:的确,美国的药品销售体系与中国很大不同。对于仿制药(包括生物仿制药),主要是跟当地的三大药品供应商签订协议。除了通过FDA要求的各种审查外,对供应商而言,选择与谁合作最重要的是看对方能否保证产量(供应量),不要在关键时候“掉链子”。 


对于创新药,美国也有规定,每一个产品的销售大概不超过100人的队伍,按照GSP规定,好像是每天见面时间不能超过15min,超过约束时间就算犯规。所以新药在美国销售,并不像中国这样,需要几千人的队伍。


我还有个建议,就是国内在开发药品时,一定要考虑病人的发病分布状态,全球的疾病市场是不是一致的?不要等到好不容易熬过了12年,活干完了,这个药已经没市场了。


医药魔方:为什么美国政府不愿意对新药进行定价?


孙鹤:美国当时也曾经有人提出来过要搞国家定价,就像英国、欧洲那样来搞医药定价,也是说这个药物价值太高。可是这个方案一提出来以后糟糕了三大团体的反对,反对的最厉害的是保险公司,第二个反对的是FDA,第三个反对的就是医药企业。


保险公司的理论是,他们总结了一下过去历史的经验,发现花1美元在创新药上,能够解决临床未满足的需求,后能够为保险公司节约8美元的费用,所以他们坚决反对搞医药定价。如果医保医药定价就损失了创新力,保险公司的精算师算下来以后,他们的花费一定是提高的,而不是减少的。


从FDA的角度来说,他们认为整个国际上的新药创新其实95%都在美国产生,如果一旦造成创新能力核心意愿下降,整个美国医药创新趋势也就下降了。三大团体一起反对的结果是至今为止美国是全世界新药产品不由国家定价的区域。这就造成了整个美国的创新趋势和创新意愿一直保持一个高涨的状态,这一点也是中美之间一个重要的不同点。新药回报率比较高,全球95%的新药到美国报批。


医药魔方:您也说了,新药过了专利期,很容易被仿制。有哪些措施可以延长产品生命周期呢?


孙鹤:对于化学药而言,为了避免被仿制,是可以做些特定标记,现在去美国药房里买药,也是很容易看到在胶囊或者片剂上打上标记的产品。最早的时候,是辉瑞把伟哥做成了“蓝色菱形小药片”,给人的识别感很强。


因为一般化合物的专利是21年,可能研发就花去了十几年,剩下的生命周期并不长。像伟哥,它可能是等到快上市时才去申请“外观设计”的专利,在外观专利期内,别的产品就不能仿制其外观,也是一种延长生命周期的方式。所以我建议,对于中国原研的药品出口,在做产品设计的时候,也应该想到这点。

 

医药魔方:接下来您还有哪些计划或者愿望?


孙鹤:目前国内翻译FDA的文件都比较偏向字面翻译,FDA规定是什么数字就是什么数字,比如生物等效性(BE)试验结果的有效性要求是Cmax在80~125%之间。很少有人解释出为什么是这个规定,翻译文件也没有具体说明。甚至很多人并不是很理解FDA为什么要求PK(药代动力学)研究?以及什么时候可做(可不做)?做到什么程度?


如果有机会和资金,我很想组织一批人,对FDA研发指南文件做些综合梳理或者说是另类翻译(而不是简单地字面翻译),希望通过这项工作能更好地帮助中国企业理解为什么要这么规定,如何灵活应用这些规定。


医药魔方:天士力“复方丹参滴丸”从上世纪末年开始申报FDA在美国做临床试验,网络上有一些评论说试验失败了。能否分享最近的进展?


孙鹤:我们正在准备NDA,等有新的结果一定会告知你,谢谢。


机器翻译

Dr. Sun He is Vice President of Tasly."Compound Danshen Dripping Pills," the international head. He was also the first person to enter the FDA in the Chinese medical profession in mainland China, and he achieved clinical measurement pharmacology in the FDA. The highest level of chief scientist and chief judge. Recently, Sun He came to Suzhou Biological Medicine Industrial Park (BioBAY), to the park dozens of companies doing new drug research and development shared his industry thinking for nearly 30 years. Pharmcube had a Meeting with Sun He after the meeting.

I didn’t do PPT, because according to past experience, how much will last in the PPT I became a PPT, so I will talk to you. If there is any problem in the middle, please feel free to interrupt me. "Sun He's opening seems to be somewhat different. After a brief introduction, Sun He began to speak. The first is how enterprises should do new drugs. Secondly, how to go to the United States and go global. Finally, how products are sold in the European and American markets.

Sun He, Vice President of Shili

1

Provides the R&D concept of “Product Manual”

In the whole medical innovation layout, Chinese medicine (botanical medicine) It has always been a leader in the world, and China has not done so well in China. In terms of chemical drugs, China is relatively backward. We can only be a follower. People started up a hundred years ago. At the beginning of the year, this is far behind, and the level of experience of personnel is different. Biopharmaceuticals are basically synchronized with China and abroad, and there are not too many differences. Sun He said that China’s new drug research and development can use his “ "Three-run theory" to describe, that is, "chemical drugs are running with others, biological drugs are running side by side, botanical drugs are leading the way."

After the drug is listed, it is still a commodity, if it is Building a building, you must first have a construction drawing. However, many pharmaceutical entrepreneurial enterprises are almost one step by step. "Sun He pointed out that "there are very few companies that have written the product specifications in advance, and then follow the instructions. Solve the problem solved one by one."

Sun He believes that the product specification not only includes the product specifications. Route of administration. Indication design. The highest tolerated dose and other research and development content, and even with the subsequent product life cycle management. Physiology data and commercialization content such as sales channels in different countries.

In the development stage, Sun He prefers the concept of “first driver, then car and map”. After summing up the development rules of the US major pharmaceutical companies, he found that few companies first spent a lot of money to “buy a good car” and then wondered who to open. Most of them found a good driver, then went to buy maps and cars, good drivers. Under the leadership, almost no detours can reach the destination. In Sun He's view, even a very promising project, if there is no good project manager, it is difficult to promote smoothly.

2

The project personnel should be good at "counting"

Sun He also pointed out that usually everyone will be "confusing" by a phenomenon. It is often that a consulting company will release some data. Said that "a new drug for listing will take XX years on average, costing XX funds, investing The rate of report is only XX%..." According to his past experience, the cost and time of different drug developments are very different.

In his view, although clinical trial failures are inevitable, some research and development costs It can still be predicted in advance. For a clinical trial designer, the design of the trial program will not only affect the success or failure of the trial, but also affect the research funding. Sun He said that people in the clinical project of pharmaceutical companies must be "counted". /p>

He takes chemical medicine as an example. Currently, it is recognized that about 10,000 products can be obtained from 10,000 candidate molecules. The failure rate of phase II is 30%, and the clinical failure of phase III is 50%. % of research and development costs are in pre-clinical, 70% of research and development costs are in clinical trials. If it is to develop antibiotics, the general clinical trial will not exceed 5 to 7 days, the research and development costs will be much lower, and if it is the kind of clinical use frequency is more Not only is the clinical cost high, according to the FDA, the new drug is used more than 28 days in a year, and it needs to be a full set of long-term poison, which is also a fee.

Specific to clinical trial fees, in the United States, clinical expenses Including medication follow-up Calculation. Every time involved in basic examination costs, doctor interview fees, ECG costs. From the current general situation, the development cost of an anticancer drug in a test cycle is about 300,000 US dollars / person. High blood pressure, cardiovascular and other chronic diseases 30,000 to 40,000 US dollars / person. The cold is about 20,000 to 30,000 US dollars / person. Enterprises should be prepared, reasonable planning, and reasonable financing before conducting clinical trials.

3

To have Global Vision

One of the biggest features of new drug research and development is that it is highly regulated by the government. Any other industry is not regulated by the government as much as the pharmaceutical industry.” Sun He said frankly, “Doing new drug development, Be sure to have a forward-looking vision and a globalized landscape."

Sun He said that any pharmaceutical company is developing products, not only to understand who developed it, but also to figure out who is Potential competitors. In his view, generally do innovative drugs are nothing more than two business models, or transfer the project to a certain stage to obtain service fees and later share. Or just go to the market, he further explained.

He even gives examples If the development of the target drug really takes 12 years, then the standard established by the company should at least be guaranteed not to be eliminated after 12 years, and should have a reasonable estimation of the disease state after 12 years. In the meantime, government regulation will be a lifeline for companies to survive. In Sun He's view, companies should start from the first day of research and development of new drugs, they should aim at the global market, and it is undoubted to ask for the highest standards.

In addition, Sun He also talked about some of the secrets of commercial success. For example, it is recommended to declare the FDA first, learn the FDA's specific requirements on the design of the test plan and test data, and then return to the national drug. The Authority, from "knowing it" to "knowing it", will be much easier. At the same time, he also suggested that companies should be familiar with the US commercial insurance reimbursement system and sales system in advance, which is also conducive to product development.

In Sun He’s view, if domestic innovative drugs are sold overseas, is it to choose an overseas branch to establish a sales team or cooperate with a local pharmaceutical company? These are all considered in advance. In addition, for different products, the sales model will be quite different, the number of teams required, and the structure of the staff are also significantly different. He believes that these problems, pharmaceutical companies must understand and figure out.

Pharmcube: Hello Professor Sun! If you choose again, will the first job choose to go to the FDA? why?

Sun He: After a lapse of more than 20 years, I often sigh. In fact, our choice of international students is nothing more than three paths. Either go to the industry (large pharmaceutical companies or biotechnology companies), or go back to campus. Teaching at a university is either going to a government department like the FDA.

At the time, if you went directly into the industry, the income of the company was much higher than the government. But at the time, the personal feeling was In the United States, those large pharmaceutical companies are basically a line, the production of tubes for tube production, the research and development of tube research and development, and the registration of tube registration. If you go to university, it is to write a topic every day, to declare a topic, to do a project, it seems that you can also predict.

It’s a big deal to work in the government. Almost every day, you can see what the world’s largest companies and the smallest companies are doing. The angle of view is not the same. Re-choice I may still go. In the beginning, if you pay less, you will be less. After all, you can shape a person. But then, medicine is a new industry with different days and months. No matter where you are, you need to keep learning. Even I have With 20 years of accumulation, to this day still while studying development

Pharmcube:. You spent so long at the FDA, which feel is worth sharing ideas and learning?

Sun He: At least when I was working at the FDA, the FDA's philosophy was not to regulate, but how to help new drugs get listed as soon as possible. So you work here (FDA), holding taxpayers' money every day. It is to think about how to serve taxpayers and bring some "good medicines" to the market as soon as possible.

Secondly, many of the standards set by the FDA are also considered from a business perspective. For example, the FDA has taken into account the clinical trials of patients when they set the validity of some clinical trial data, and sometimes the drug companies choose a range in order to avoid poor drug performance. For a narrower group, the data does not meet the established standards.

Pharmcube: What do you think is the current problem in the development of innovative pharmaceutical companies in China?

Sun He: My feeling is this. Now I am doing a new drug research and development, and I have completed the preclinical study. Then I finished the clinical phase I, started the second phase, and then the clinical phase III, while doing the dry side. Planning. Many companies may not be very clear about which direction to go in the next step. Basically, few companies like us to build a building, first have a very detailed design, and then add bricks and tiles on this design. ”

In short, there may be very few companies that write the “product specification” of the drug first, and then the manual solves the problem solved one by one. Most of them may be walking on the side. While getting it, at the end, go together and absorb it.

And from a regulatory point of view, the final product is not your substance, the substance is already there before applying for clinical trials. The last product should be you. The product manual. The product manual is well written, can solve a patient's problem (or some patient's problem), can be sold off, the doctor will use it. I feel that the product manual has not been written beforehand. It’s “dull to dry.” Chinese pharmaceutical companies may not have this habit yet, I think we should pay attention to it.

Pharmcube: Can you elaborate on your “three-run theory” and the reality you see? ?

Sun He: The development of chemical drugs in the United States has been at least a hundred years old. We are really developing new drugs for chemical drugs, which started in the last ten to twenty years. So I think chemical drugs R & D, China still needs to continue to learn European and American experience, the possibility of catching up in the short term is not big.

In the case of chemical synthesis, nowadays to visit the big pharmaceutical companies in the United States, their synthesis only needs to be Small radios are sized in containers that are densely packed with small tubes. Researchers only need to operate in different orders (click on different numbers on the display) and introduce the parent compound to harvest different compounds. They are currently About 700 lead compounds can be synthesized every day. As far as I know, there is no enterprise in China that can do this.

On the one hand, there are shortcomings in high-throughput screening technology, and on the other hand, limited development experience. Some experienced engineers can see the probability of the drug from the 2D/3D space on the computer, but he may say that he may Incomplete, this is like a long-term accumulation of experience. Therefore, if domestic chemical drugs are catching up with the United States, it still needs to work hard.

Biopharmaceuticals are relatively better because of biopharmaceuticals more than a decade ago. When China began to appear, China began to take off. Probably from 2003 to 2006, the FDA did not approve an antibody drug. I came back in 2006, when many people asked me what should I do? I told them, if you try biopharmaceuticals. So now the domestic biopharmaceuticals are so hot, there are also some reasons.

Second biomedical work from 0 to 1 is still relatively easy, The body stimulates the production of antibodies, and then tries to do the culture. After the expansion, the candidate is made to have a relatively small toxic side reaction and a clear target. Therefore, once it becomes later, the probability of failure due to toxic side effects is much less in the clinical trial. However, China, the real impact on product development is not the preliminary work, but the production capacity. The development of biosimilars, from 2006 to now more than 10 years, the state has given a lot of special funds for innovation, recently just approved a Biosimilars.

Why haven’t they been made? One of the reasons is that the cost is too high. Why is the cost too high? Either because a little pollution has to be abolished, or because of insufficient raw material production capacity, especially the culture solution and the adjuvant need to be imported. For example, South Korea, their biosimilar fermenters are fermented in tons, and Only one company in Guangdong that can do tons of fermentation in China is an insulin-producing company.

So in the field of bio-pharmaceuticals, from 0 to 1, the work is good, from 1 to 10, and A lot of room for improvement. Originally, when we were making a major national drug special defense reply, many companies answered the work from 0 to 1 and did a good job, but when it came from 1 to 10, how to reduce the cost, some stuck. So share my suggestion, do biopharmaceuticals, don't be blindly optimistic because the work from 0 to 1 is done, the real bottleneck is from 1 to 10.

The last botanical drug, our country It has always been called Chinese medicine. Many people will say that Chinese medicine is definitely the first in the world, because Chinese medicine is only available to you in China. Can other countries not do it? In fact, this is not the case. Let's talk about botanical medicine now. Don't forget that Japan and South Korea are Southeast Asian countries. They already have a large amount of research investment in botanicals, and they have to have a business perspective.

We have statistics for a while ago, and there are 134 botanical drug materials reported to the FDA for clinical trials. There are only 14 products from 12 companies in China. So from the FDA's point of view, our botanicals are at least not German, Japanese, Korean. So aggressively.

Pharmcube: Why do you suggest that new drugs must go public in the US?

Professor Sun He: The United States is the only country in the world that does not price new drugs. They rely solely on companies and insurance companies to bargain. Since product prices can be set by themselves, 90% of the world's innovative drugs will be considered. US listing. Most European countries are government-priced, and Japan is also priced by the government. So, the real first in class products, the return to the US market is relatively high.

Pharmcube: What is the system that companies and insurance can negotiate, and what are the implications for drug developers?

Sun He: Let me take the example of “orphan drug” development. Assume an orphan drug, the insurance company promises to reimburse 1 million US dollars a year. There are 600 such patients in the United States, only one drug It is possible to get a market of 600 million US dollars. As long as such a patient community is established, a group of patients will be organized to participate in clinical trials. The trial is successful, and the patients are passed on and the sales staff are free. So orphan drugs can be developed in the United States. The product must have a market.

So I suggest that if you want to go to the China-US double-report, it is best to familiarize yourself with the US commercial insurance system in advance, and also facilitate the future with the insurance department. Negotiation.

Pharmcube: In addition to reimbursement, is the sales of drugs different from domestic ones?

Sun He: Indeed, the US drug sales system is very different from China. For generic drugs (including biosimilars), it is mainly to sign agreements with the local three major drug suppliers. In addition to the FDA requirements In addition to the various reviews, for suppliers, the most important thing to choose to work with is to see if the other party can guarantee the output (supply), and not to “drop the chain” at a critical time.

For innovative drugs In the United States, there is also a rule that the sales of each product is probably no more than 100 people. According to the GSP regulations, it seems that the meeting time cannot exceed 15 minutes per day. If the time exceeds the constraint time, it will be a foul. Therefore, the new drug is sold in the United States, not like China. A team of thousands of people.

I also have a suggestion that when developing drugs in China, we must consider the distribution of the patient's disease. Is the global disease market consistent? Don't wait until it's been 12 years. After the work is done, the drug is no longer available.

Pharmcube: Why is the US government not willing to price new drugs?

Sun He: At that time, there were people in the United States who had proposed to do state pricing. Just like the UK and Europe, the price of medicine was too high. But this plan was bad after it was put forward. The opposition of the three major groups, the most powerful opposition is the insurance company, the second is against the FDA, the third is against pharmaceutical companies.

The theory of insurance companies is that they summed up The experience of past history found that spending $1 on innovative drugs can solve the unmet needs of the clinic, and then can save the insurance company $8, so they resolutely oppose the pricing of medicine. If the price of medical insurance is lost, the innovation will be lost. After the insurance company's actuaries have calculated, their expenses must be increased, not reduced.

From the perspective of the FDA, they believe that 95% of the new international drug innovations are actually In the United States, if the core willingness to innovate is reduced, the trend of global pharmaceutical innovation will decline. The result of the opposition of the three major groups is that the United States is the world’s new drug product to date. The region priced by the state. This has caused the entire US innovation trend and the willingness to innovate to maintain a high state. This is also an important difference between China and the United States. The return rate of new drugs is relatively high, 95% of the world's new drugs are US Approved.

Pharmcube: You also said that the new drug has been patented and can be easily copied. What measures can extend the product life cycle?

Sun He: For chemical drugs, in order to avoid being copied, it is possible to make certain marks. Now, when you go to the US pharmacy to buy medicine, it is easy to see the mark on the capsule or tablet. At the earliest time, Pfizer made Viagra a "blue diamond-shaped small pill", which gives a strong sense of recognition.

Because the patent for general compounds is 21 years, it is possible to develop it. For more than ten years, the remaining life cycle is not long. Like Viagra, it may wait until the time of listing to apply for the “design” patent. During the appearance patent period, other products cannot imitate its appearance. A way to extend the life cycle. So I suggest that for the export of Chinese original medicines, you should also think of this when designing products.

Pharmcube: What plans or wishes do you have next? ?

Sun He: At present, the domestic translation of the FDA documents are more literal translation, what is the number of the FDA regulations, such as the validity of the bioequivalence (BE) test results is Cmax at 80~ Between 125%. Few people explain why this is the case, and the translation documents are not specified. Even many people do not understand why the FDA requires PK (pharmacokinetics) research? And when can I do it (or not)? To what extent?

If there is opportunity and funding, I would like to organize a group of people to do a comprehensive combo or alternative translation of the FDA research and development guide documents (rather than simply literal translation), I hope that through this work Better help Chinese companies understand why this is the case and how to apply these regulations flexibly.

Pharmcube: Tasly "Composite Danshen Dropping Pills" has been filed for clinical trials in the United States since the end of the last century. Some commentators say the trial failed. Can you share recent progress?

Sun He: We are preparing NDA, we will tell you when there are new results, thank you.

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