佰家言 | Amin Rostami：引领全球药品开发，深耕中国市场

人物介绍

PART 1 —— Certara in China

要讨论关于Certara在中国的定位，先要明确我们的目的。事实上，Certara在中国建立了专门的办事处，拥有专门的科学家团队。Certara通过办事处来主持即将在中国进行的沟通交流和所有药物开发相关的事宜。我们非常赞赏中国在药物开发领域作为全球参与者的方式。我们已经看到了中国在技术进步方面的所有成就，特别是在发现新疗法方面所作出的努力。我们希望帮助他们在某个阶段不仅满足中国自身的药物开发要求，还能实现 全球申报 。

With respect to Certara's position in China, our intention I think must be clear by the fact that now we have got a dedicated office in China and a dedicated group of scientists that they are leading the communications that we are going to have all the business related to drug development in China via this office. Therefore we appreciate the way that the China is inserting itself as a global player in the drug development scene. We have seen all the things that they are happening with regard to the technological advancement and particularly the push that they are putting into discovery of the new modalities and so on. And we would like to help them to achieve the global, I would say submissions at some stage beyond just China's own requirements for the drug development.

对于不太熟悉Certara的人来说，了解Certara至关重要。Certara是应用建模和模拟技术并将其融入整个药物开发过程方面经验最丰富的公司。实际上，许多公司内部设有自己的建模和模拟团队，这些团队也在进行相关工作。即便如此，Certara仍然为这些公司提供所需的工具。Certara的运营可以分为两大核心部分。一方面，我们为药物开发过程中的内部建模师提供工具，支持他们做出决策并推进药物开发。另一方面，我们拥有一支经验丰富的专家团队，专门为那些内部不具备建模和模拟能力或在特定时期内能力不足的公司提供实际建模和模拟服务。此外，我们还提供其他服务，包括加速高质量申报的相关内容和法规撰写等，这是我们的主要服务之。然而，这本身是另一个需要详细解释的领域，特别是 结合AI的应用 ，我稍后会详细介绍。

It is very important for those people who may not be familiar with Certara to know that Certara is the biggest firm with experience in applications of modeling and simulation and incorporation of that into whole process of drug development. It is true that many companies they have got their own internal modeling and simulation group, but even with those companies, we provide in many cases the tools for those companies that they are doing the modeling and simulation themselves. So the operations within Certara, they can be divided into two major parts when it comes to the drug development itself, is the provision of the tools by which the internal modelers they actually helped with the drug development, with their decisions, but the second part is actually I would say team of experts with lots of experience who can help actually doing and conducting the modeling and simulation, exercise for the companies who do not have their internal capacity or in some circumstances, their capacity is not fulfilling the needs at that particular certain time. Of course, we do have other elements related to accelerated quality submissions with regard to the regulatory writing that comes at the top of what we're offering, but that is in itself is another, I would say requires another time to explain, particularly with you know the incorporation of AI that I will come back to later on.

当然大部分学术中心以及在中国所有机构都拥有带头进行这些活动的科学技术，不过大家可能不知道最后该如何将这些科学研究转化成满足监管机构筛选符合上市要求的药物。这与你们所知的科学观点略有不同，申报对于质量要求大有不同。所以尽管PBPK和QSP在中国科学界广为人知，但将研究成果转化为药物开发的实际申报是完全不同的事情。我们在过去25年中积累的PBPK经验，以及过去10到15年中的QSP经验，向我们展示了 PBPK和QSP联系密切 ，需要相互协作。因此，这不仅仅是科学研究的问题，还需要符合监管要求的质量保证。使得监管机构接受这些研究结果，以替代某些临床研究。

For sure that I would say scientific know-how exist in many of the academic centers and all the institutions that they are leading these activities in the Chinese environment. The things that you know they are perhaps not known is that how these scientific endeavors can turn into at the end, an application that satisfies the regulatory, perspective on what drug can go into the market or not. That is slightly different than you know the scientific view. The quality that is required in the submissions is very different and therefore I would say while the PBPK and QSP they are both known well in China in the scientific community but transferring that exercise into a practical submission for drug development is a completely different matter. Our experience with both PBPK and QSP over the last 25 years for PBPK and over the last 10 to 15 years for the QSP demonstrated to us that these two hand in hand, you know, need to work with each other. So, it's not just a scientific exercise, but it requires you know building some quality around the models in a way that the regulators take comfort in accepting these in lieu of some of the clinical studies.

我近期参加了康龙化成的内部研讨会，会上重点讨论了DMPK（药物代谢和药代动力学）领域的一些问题。有一点非常清楚，不仅仅是康龙化成，很多其他为药物发现和开发提供服务的公司也是如此。研讨会清晰地展示了其研究的实际规模和发展速度，他们不仅在许多领域取得了技术进步，还在操作层面上取得了成功，并且能够大规模地将这些服务提供给各种中国生物技术公司，这些公司往往因规模较小而难以独立开展研发活动。在我看来，这正是许多生物技术公司目前的真实写照——它们需要进行药物发现阶段常见的各类研究，但在将研究成果转化为实际行动指南时，建模与模拟技术（如基于生理的药动学模型PBPK或定量系统药理学模型QSP）就显得至关重要。无论是PBPK还是QSP，这些科学知识都已经存在，但如何将其转化为符合最佳决策和最终满足监管要求的质量，是Certara可以大力帮助的领域。

With what I have seen, as you know, I am just coming back from the internal symposium within Pharmaron which was in the DMPK, arena and one of the things that was very clear. This is not just Pharmaron, but no many other you know providers of the services for the drug discovery and development. One of the things that is very clear is the sheer size of the exercise. How fast they can go take not just the technological advances that they have got in many areas, but also the operational successes that they are having and in mass quantity that they provide all of these to variety of the Chinese biotech groups that they are too small to get into the development themselves. So what is actually happening in my perspective is that all these biotech companies, they require all those typical studies that there are common in the discovery stage, but when it comes to translation of those into what decision they should be making and how they will get into the drug development and next the stages is where the modeling and simulation can actually help. Whether it is PBPK, whether it is QSP and this is the part that as I said, the scientific know-how exist, but how to turn that into a quality that satisfies you know the best decisions internally, but ultimately go into the regulatory acceptance. That is something that definitely Certara can help a lot.

PART 2 —— PBPK

关于PBPK（基于生理的药动学模型），Certara不仅专注于开发模型、工具及平台，更重要的是它为那些提供科学信息和数据的核心机构提供了持续的支持。这些信息和数据被输入到模型中，为整个行业带来了广泛的利益。我们的目标不仅仅是提供一个平台，尽管我们发表了大量文章，这些文章也为竞争对手提供了有用的信息。但我们认识到，信息本身并不是关键，更重要的是整个领域能够选择并开始使用这些信息，并在一定程度上达成共识。在这方面，我认为Certara做得非常成功，这也使其成为了该领域的领导者。Certara在实际应用、注册申请以及用于内部决策等方面取得了显著成就，特别是在处理那些以往难以解决的说明书语言问题上。为了构建全球范围内的共识，Certara在科学研讨会上投入了大量资源。例如，在中国、日本乃至韩国等亚太地区举办的众多研讨会，都极大地促进了共识的形成，从而填补了模型中的信息缺口。此外，通过我们的Simcyp GPS（赠款与合作伙伴计划）奖项，我们为实验室建设和研究项目提供了资金支持。这一计划非常有名且备受赞誉，它正引领我们继续填补这些空白领域，并因此命名为Simcyp GPS。Certara已经完成了许多这样的工作，使其在PBPK领域达到了今天的领导地位，并且我们期待未来能够开发出更多新的应用。

One of the big things that Certara has done with regard to the PBPK has been that rather than just focusing on developing the models and tools and platforms, it had a continuous support for all the centers that they are providing the scientific I would say information and data that feeds into these models. This is for the general benefit of the whole community. It's not just informing the platforms that set our goals because we do lots of lots of publications and of course, our competitors are also using you know such information, but the early on decided that no some of this information are the things that whole community need to settle on and start using. In a way, that there is a consensus with regard to those. So I would say that the biggest success that Certara has had and as a result has become the leader in this area, with so many actually applications, regulatory applications, forget about the internal decisions that they have been successful to cover many areas of the particularly label language that previously we were not addressing relates to this fact that Certara has made huge investment with regard to building consensus, building educational workshops and so on worldwide. We had several workshops in China as many people will know as well as in, of course, in Japan and also sometimes in Korea in this part in the Asia Pacific , but all of these they have helped you know to build consensus provide information for the gaps that we have got in the models by investment in the lab side of the things providing grants. We have got famous and very prestigious you know award of Simcyp actually GPS grant and partnership scheme which obviously is guiding us towards where we should be going in filling these gaps and hence the name Simcyp GPS. So many of these activities they have helped to put Certara in the forefront of taking PBPK to where it is today and hopefully you know for going to future further applications that they are going to happen.

我猜您提到的EPA是美国环保署（Environmental Protection Agency），而FDA则是熟知的美国食品药品监督管理局（Food and Drug Administration）。您提到的是最近由中国团队使用AI对PBPK（生理药代动力学）领域进行的调查。在这项调查中，EPA和FDA被认为是过去25年对PBPK发展做出重要贡献的主要机构。根据这项调查的图表，EPA看起来与Certara及其Simcyp部门所提供的服务差异较大，似乎像是一个完全不同的领域，而 FDA则更接近Certara及Simcyp 部门的贡献 。如果将这些信息结合起来Simcyp部门与Certara UK则是该领域的另一重要参与者。从这些机构的工作来看，EPA专注于开放源码的PBPK建模，而FDA则更侧重于确保提交材料的质量、版本控制及模型的可靠性，并为此提出了“Glassbox”概念。与“Blackbox”不同，“Blackbox”是指使用者不知道平台内部发生了什么，而“Glassbox”则在提供一定的透明度的同时保护平台，防止用户在不被注意的情况下更改内容，或者故意更改而不告知他人。这也是为什么在过去20年中，FDA在PBPK应用的速度和信任度方面明显超越了EPA的原因。我个人的观点是，虽然开放源码对于学习有益，但在实际应用中可能会导致复杂性增加，因为模型评估变得更加困难。这些模型通常由数百行代码构成，若全部开放给用户，任何未经记录的改动都将带来理解上的难题，特别是考虑到许多部分与系统相关，而不是与药物相关，所以在不同药物的分析中应保持不变。综上所述，尽管EPA在90年代中期在PBPK领域占据领先地位，但如今FDA已成为该领域的领跑者。

And I'm guessing when by referring to EPA, this is environmental protection agency in U.S. that FDA is known for many other people, food and drug administration in U.S.. You are referring to the recent survey that was done by actually Chinese group using AI for the landscape of the PBPK. In this particular survey, EPA and FDA came as the top organizations that they have fed into the PBPK development over the last 25 years. EPA was a completely you know even you look at the graphics that you know this group when in 2024 in pharmaceutical research they have provided, you will say EPA isn't a completely different block like a different planet. While FDA is very close to what actually Certara and a Simcyp branch of Certara Simcyp Limited, Certara UK has been providing. So if you put all of these together and particularly in that analysis, Simcyp Limited with Certara UK together, these are the three major players. However, with the proximity when you look at these graphics, you will notice that while EPA has been focusing on what they call open-source code, PBPK modeling. FDA has taken a different route. They have basically focused on the quality submissions and the version control and so on and the trust in the model and they have come up with you know something that we coined as glassbox while nobody likes black box when you don't know what is happening within the platform that you are actually using. Glassbox is a halfway house that gives that transparency of what is happening, but at the same time, protects the platform from sometime you know sort of inadvertently you know the user changing something without anyone else, not noticing, oh god, forbid you know intentionally changing something and not telling others and this is the reason that over the last 20 years when you talk about EPA versus FDA, the applications of the PBPK in the FDA arena has gone up much faster with numbers and you know sort of the trust that is put on them as opposed to the EPA. So that is my personal view. We have talked about it. You know I have even talks in EPA conferences itself that you know how come that in mid 90s EPA had the lead in the PBPK while now 20 years later on. You know it is on the FDA and with the help of center for and alike you know that they are taking this. So my view is that there is a misconception with regard to the open source code. Open-source code is good for learning the students and so on but when it comes to the application side of the things, it is actually asking for trouble because assessment becomes a nightmare. These models are made of several you know hundreds of the lines that of the coding and if all of the elements are open to the user, then it is very hard to actually to understand if any part they have changed or not but many part they are related to system not the drug. They should be kept actually the same when you are looking at different drugs.

很多人回顾PBPK（生理药代动力学）在监管接受度上取得进展时，会发现其起点与药物间相互作用的应用有关。尽管在监管领域中PBPK的应用早期就已存在，但其广泛应用的推动主要是在药物间相互作用领域，PBPK模型的主要作用在于解决那些无法进行临床研究的情况。在FDA的框架内，通常会进行少量的关键性研究来提供必要的信息并校准模型。然而，对于那些无法开展或计划之外的条件下，PBPK模型则提供了巨大的帮助。在过去二十年里，PBPK的应用已从最初的药物间相互作用扩展到更多的应用领域，特别是针对那些在药物上市初期未能得到充分研究的患者群体, 例如，严重肾功能不全或肝功能不全的患者，或者一些我们知道在早期阶段无法得到充分关注的患者群体等。我们正利用这些建模方法来探索和解决这些问题。令人欣喜的是，最新的申报资料和建模应用表明，无论是在公开发表的研究数量，还是在提交给多个监管机构的应用数量上，PBPK模型都得到了明显的提升。尤其是在 儿科 和特定人群方面的应用增加尤为明显。可以说，我们帮助填补了信息空白，扩展了PBPK模型的应用范围，特别是在研究困难的罕见疾病和复杂病情上。此外，我们还在处理多种因素的组合效应，如药物相互作用在 儿童群体 中的表现，或是肥胖患者中的肾功能不全等复杂情况等。最终，患者将是这些进步的最大受益者。因为医生可以根据充分验证的PBPK结果来做出决策，而不是仅凭个人经验。

The starting point many people when you look back you know to the PBPK taking off with the regulatory acceptance, even there have been odd occasions of use of PBPK in regulatory space a long time before goes back to the applications in the area of the drug-drug interactions And many aspects of this is basically addressing the ultimately the conditions in which you cannot do their clinical studies. So in the terms of FDA, you may run few index studies that they inform you and also they inform your models, but then for all the other conditions that you are not going to run or you were not going to be able to run their studies, then you take the benefit of the modeling that you have seen that it has worked in those index studies. The advantages that we have actually brought up is that we have over the years, that's you know over the last 20 years, slowly but firmly, we have been taking this from purely the drug-drug interaction, side of the things, into applications that they are related to the patient groups that they are not served well at the time of at least entry of the drug to the market For instance, severe renal impairment or severe hepatic impairment or group of patients that we know that they are not going to be addressed at the early stage and so on and we are looking into many of these using these modeling approaches. And I'm glad to say that when we look at the latest submissions and applications of the modeling, both in the size, you know based on publication but also the applications that they are going through many of the regulatory agencies be noticed very clear that increase in the quality and the number of the applications, they are going for pediatrics, they are going for these special populations and so on. So I would say that we have helped with gathering the information as I previously said for filling the gaps and expanding the breadth of what PBPK is now addressing. Particularly in the orphan disease groups, that they are not easy to study and combination of conditions, then you have got not just, for instance, drug-drug interaction but you are talking about drug-drug interaction pediatrics or you are not talking about just renal impairment but you are talking about renal impairment in very obese patient. So the combination of these parameters are now we are addressing and patients are the ultimate beneficiary of this because the prescriber has got that possibility of understanding and then acting on many of the things that they are related to these groups, on the basis of well informed PBPK model, rather than just leaving them with I would say void that everybody decides for their own, you know sort of based on their own experience and so on.

PART 3 —— QSP

对于那些不熟悉