采访嘉宾：

Scott Marshall PhD VP Clinical Pharmacology Modelling and Simulation: Asia, GSK R&D

As CPMS head for Asia, Scott is in a key role in the rapid expansion of the GSK footprint in North/East Asia, given its ongoing commitment to the discovery and development of new therapies that deliver improved outcomes for patients globally.

In his current role, he is responsible the operation of the CPMS Asian hub which has been established in recognition of the importance of developing unifying strategies that enable simultaneous multi-regional development via early ethnic sensitivity assessment and early deployment of MIDD activities.

He has had a wide range of leadership roles associated with the evolution of Model Informed Drug Development (MIDD) practice, tool, methods and process development over his 25 years in the pharmaceutical industry.

He was lead author on EFPIA MID3 good practice white paper and co-led associated regulatory interactions.  Scott is currently the Rapporteur for the ICH MIDD discussion group which has a one-year remit to align on ICH MIDD guideline development strategy.

采访人：        

        Dr. Kevin Shen (沈凯), currently as Vice President - Head of Clinical Pharmacology, in Clinical Research & Development, Jiangsu Hengrui Medicine Co., Ltd.  Kevin has 19 years’ experience in Clinical Pharmacology area and 12 years in multinational pharmaceutical companies. Before joining Hengrui, Kevin has worked in AstraZeneca R&D China for 4 years as Head of Clinical Pharmacology. Kevin has Doctor degree of Internal medicine from Shanghai Medical College of Fudan University, master degree of Pharmacology from Peking Union Medical College, and bachelor degree of Pharmacology from Peking University Health Science Center.

Dr. Kevin Shen on behalf of the organization committee of ISQP: 

Dear Dr. Scott Marshall, thank you for the acceptance of this interview. As a world class pharmacometrician, could you please share your thoughts on what Model Informed Drug Development (MIDD) is?

Dr. Scott Marshall:

Thank you Dr Shen for this opportunity to discuss this topic with you.
In my view, Model Informed Drug Development (MIDD) is a general philosophy which underpins how drug research and development can be most effectively steered, guided, optimised, made more efficient and accelerated; or to use the all-encompassing adopted term “informed” by the totality of our preclinical and clinical scientific knowledge for the current drug under investigation.  Also, importantly this is in the context of our prior knowledge in terms of relevant prior treatment modalities and knowledge of the physiology, pharmacology and pathology associated with the disease of interest.

If you review current definitions of MIDD from EFPIA, PhRMA, FDA and NMPA it can be generally be broken down to:

•       A Framework in which to operate: plan, implement, report and influence a range of R&D decisions

•       Which utilises Integration of all relevant data (non-clinical, clinical and real-world evidence) from across the causal pathway from drug being administered to effect of interest.

•        In the form of Model(s) providing “fit for purpose” mathematical representation(s) of this knowledge using assumptions based on physiology, pharmacology and pathology associated with the disease of interest.

•       Where subsequent Application via simulations is used to influence decisions: go/no-go, R&D & Regulatory strategy, trial design, dose/ dose individualisation and population choice.

In some ways the framework itself can be seen as a mathematical optimisation problem. However, I see it as larger and more associated with a culture that influences our ways of thinking, planning, describing, reporting, discussing and acting (or Ways of Working). I think the term “Model Informed” is critical in this regard, as it speaks to the need for communication and interaction between analysts, teams and decision makers. This culture should and increasingly does extend beyond any one company to how we collectively engage with global regulators; and as scientific bodies engage with related disciplines such as statistics, epidemiology, health economics etc

I have recently joined GSK and I am really pleased to see how well this culturally aspect is embraced, commonly shared, promoted and valued across the organisation.

Organization Committee of ISQP: 

What do you think MIDD can do in drug development?

Dr. Scott Marshall:

I see that

•       In research MIDD translates to getting the Right pathway, Right target and Right Molecule

•       While in Development MIDD translates to getting the Right treatment at the Right dose to the Right patients.

These ideas were first conceptualised together and latterly made a foundation on which CPT:PSP was established and flourished by esteemed former colleagues in Pfizer at the time.

These concepts were a significant driver of change and adoption of MIDD approaches at the time within the company and beyond.  Unfortunately, the underlying message can get lost in translation.  This is not about what MIDD can, as a separate entity, do in drug development, it is much more what drug development colleagues can do by embracing MIDD concepts across R&D.  It is as I have already said about partnership across lines and functions.  I do also think being right is not good enough anymore.  This does not get at the temporal aspect of what R&D demands today.  We need to be “right” early and “sufficiently right” very early to make the correct decision in order to make R&D more efficient and most importantly get our innovative treatments to patients globally immediately we have them adequately characterised.  Sadly, the pandemic has taught us this important lesson.  The greater emphasis on forward prediction is embodied in GSK in the use of Probability of Pharmacology success to guide go/no go and no regrets dosing paradigms.

In so many disease areas the patient is waiting.  There is only so much you can do with raw data and basic statistics.  We do need to use our scientific knowledge via effective use of modelling and simulation to be truly game changing. Ultimately, this is about of predicting the future for the individual moiety, against a specific target, in a specific disease and all of this is founded in the science that characterises the drug and the system in which it acts. So, key in our R&D problems is the “end to end” effective deployment of MIDD.  In my humble opinion, it is only through the effective integration of this construct into our R&D and Regulatory ecosystem we can truly be ambitious for our patients globally.

I emphasise the last term as this was what attracted me to get involved in how we can align better between industry and regulators and the value of guidelines in this regard.  Going down this path has led to my role as rapporteur on ICH MIDD Discussion Group.  This group has a mission to align on scope of a general principles’ guideline for MIDD and give consideration to provision of other future guidelines in this space including revision of E4.

In my current role as Clinical Pharmacology Modelling and Simulation Asia hub lead at GSK, I really see how embracing MIDD can enable new medicines to be made concurrently available globally.

The question of concordance of the safety and efficacy of drugs across populations is best considered by breaking the observed drug effects down into their component parts, along the causal pathway from PK/PD to outcome, and then building them back up again via MIDD to investigate if  differences in any of the specific components could have an impact on outcome for patients even if one has not been directly observed.

In this way confidence in early de-risking of potential region to region difference should just be an extension of the prediction we do with every new drug we take from smaller to larger populations or to the wider marketplace. Our use of Phase 1 to widen inclusion criteria for patient trials tends to be evidence led.  If an exposure/safety risk in the next study is perceived due to widening of age, WT or organ function range for example, we would normally look at the MIDD informed extrapolation and if the predicted degree of risk was considered acceptable a Phase 1 trial to bridge would be unnecessary.  In past, sometimes risk has been perceived as a general issue and this has led to inefficiencies which have subsequently been reversed e.g. standard need for thorough QT studies giving way to a more evidence-based model informed approach.

I think we are on a similar journey with respect to ethnic sensitivity assessment prior to global trials. Once the basic science, including the potential for ethnopharmacological differences is assessed, then this risk evaluation should really be what is driving the next logical step. Unless the risk is moderate to high and importantly considered dischargeable in a small number of healthy volunteers from the specific ethnic population of interest, a phase 1 study is very unlikely to provide conclusive evidence.  Inclusion in larger global dose ranging trials during initial development would appear a more logical approach to de-risking.  Indeed, if enough evidence has already accumulated in related populations then full extrapolation with effective future monitoring is more likely to identify any unknown risks.  Emerging empirical evidence from various companies and industry bodies tends to support this view. While we are not there yet, greater acceptance of overseas ethnic sensitivity Phase 1 data to enable global studies is definitely a positive step in this direction.

Organization Committee of ISQP: 

What are the opportunities and challenges for MIDD?

Dr. Scott Marshall:

The immediate Opportunities are clear (and I have already covered) in answer to question 1

•       Much needed greater efficiency in R&D

•       Enabling Global drug development

However, there are wider opportunities. All of these relate to what I have said about being more ambitious for the patients globally.

I think from a technical perspective we do need to seek out/ embrace interactions with other quantitative disciplines.  I have been very lucky in my career to have worked with some exceptional statisticians who could really see the synergy in what we can achieve together.  Great to see more and more publications emphasising the value of the collaboration here.

Also I have very much seen that in the wider world of assessing and delivering differentiated patient focused cost-effective treatments we need to link to and integrate with colleagues who look at Quantitative Benefit Risk assessment from patient, prescriber, regulatory and payer perspectives and health economists.  In this and other respects, the interphase between machine learning approaches and scientific or indeed econometric principled model building, evaluation and application is very much our future.  It is not only key in allowing us to “swim” in a sensible direction across the ever-growing “lakes of data”, but ensuring that our “choice of direction” is cognisant of the “currents” that may be hidden in the depths of the data.  Ultimately, our models are going to be more wholistic, defendable and “End to End” in their utility by embracing ventures encompassing both the joining of principles and analytical techniques across disciplines.

Finally, I see a future whereas standard patients will be doing their own therapeutic drug monitoring via apps on their phone.  Of course, the use of apps for monitoring disease this is already happening. However, putting “treatment tailoring”, including dose adjustment, into the hands of physicians and patients based on MIDD principles is in its infancy, even if there are some parallels with the decade’s old clinical management of drugs with a narrow therapeutic index.

In terms of challenges:

Communication & Understanding remains close to the top.  I think this underpins the need for greater acceptance of MIDD within companies and both within & across regulatory agencies. I think it is at the heart of the inconsistency in application of MIDD across the industry and in turn the inconsistency of assessment of MIDD approaches within & across global regulatory agencies.

On a separate topic, I do think we are at the point where demand for appropriately colleagues with MIDD skills is significantly out stripping supply.  We definitely need the companies, MIDD orientated CROs, industry bodies and Scientific societies to give this more focus and look to work with academics to implement a strategy with respect to the training and development of the MIDD practitioners of the future.

I think there are some existing and emerging solutions to these challenges, and I look forward to discussing this in talk and subsequent Q&A.

Organization Committee of ISQP: 

Do you have any advices for the students who are interested in the MIDD?

Dr. Scott Marshall:

In terms of advice, I would suggest you think about further developing your technical skills with a post doc after you PhD. It may seem a long route if your goal is joining the industry, but a wide ranging MIDD skillset which combines both theoretical understanding and applications across R&D with core understanding of clinical pharmacology and statistics is attractive to employers.  If this also includes evidence of linkage to other disciplines such as health economics or indeed use of and preferably integration with machine Learning approaches this would really make you stand out. I think the post doc route also really opens the door to students from other aligned disciplines to come into clinical pharmacology, pharmacometrics and MIDD.

Ultimately, look to where you can best jointly grow your technical, R&D knowledge and influence skills.  You need them all.  A key rationale for the formation of the CPMS Asia hub within GSK, was to create opportunities for learning and development for colleagues across the Asia region both via informal and formal training and via academic collaborations.  One important enabler is that CPMS Asia hub sits within the single global CPMS organisation which opens opportunities for colleagues. This is key as we look to more and more “Asia for Asia “and “Asia first“ drug development.

Overall, in my humble opinion it really is only in the pharmaceutical companies that you get to see how MIDD work impacts and intersects with other aspects of R&D.  This really is critical if you are interested in the application of your work to development of new therapies. In GSK you get to present your work to the decision makers, understand their viewpoints, develop your influencing skills, and learn how to better communicate the value of MIDD to address R&D questions. The ability to do this, have a direct impact on development strategy, study design, decision making and getting breakthrough therapies to patients is what gets me up in the morning.

After 25 years it is still what gets me excited about what I do!

Organization Committee of ISQP: 

Dr. Scott Marshall, thanks again for sharing your insights on MIDD. We think the audiences of ISQP will learn a lot from your sharing. Looking forward to your presentation in the ISQP.

大会报告信息：

大会报告主题：“Zipping” Global Drug Development together with MIDD（MIDD与新药全球研发珠联璧合）

       分会主题1：模型引导的新药开发与应用：挑战与案例分享

报告时间：11月5日上午， 分会场1（新药开发分会场）

会场主席: 赵子微 博士 郭峰 博士

赵子微 博士

现任诺华心血管、肾脏、代谢疾病（CRM）药品中国开发部负责人，执行总监。

赵子微博士毕业于多伦多大学药学院。毕业后于1999至2009年受聘于罗氏制药美国总部，在临床前DMPK部门负责多个项目的药代动力学研究, 并主管药物相互作用及反应性代谢产物实验室。2009年回国，加入强生公司任临床前药代动力学主任，负责亚太区药代动力学研究及事务。2013年加入诺华，曾担任临床药理/药代动力学执行总监及中国/日本负责人，目前任诺华CRM药品中国开发部负责人。她直接参与了三十多个新药的研发，涵盖肿瘤、心血管、病毒、免疫、代谢病等疾病领域，并在Zelboraf和Tabrecta的早期研发做出了重要贡献。作为IFPMA成员参与了ICH M9 (Biopharmaceutics Classification System-based Biowaivers)及ICH M12(Drug Interaction Studies)的制定工作。

郭峰 博士

嘉和生物执行董事兼集团首席执行官、嘉和生物药业董事、玉溪嘉和执行董事

郭峰博士于2020年4月加入嘉和生物，负责集团的整体管理、业务及策略。

郭峰博士在生物制药行业、新药研发及管理领域拥有近20年的工作经验，并在抗肿瘤药物的研发策略制定、临床开发及注册申报等方面积累了丰富经验。

加入嘉和生物前，郭峰博士曾任默克全球研发副总裁兼中国研发中心总经理、辉瑞(武汉)研发中心总经理、轩竹（北京）医药科技有限公司董事长等职位。

期间，他带领团队参与全球的临床试验，开展肿瘤药物、包括免疫肿瘤药物的临床开发及注册。结合中国与全球资源，郭峰博士带领团队针对中国、亚洲乃至全球未被满足的医疗需求积极进行药物研发，加速将创新药物引入中国及欧美市场。

郭峰博士还兼任北京大学客座教授、美国临床药理及治疗学会国际部委员、中国国家食品药品监督管理总局药品审评中心外部专家等职。

        2021年9月30日                优惠注册截止日期
        2021年12月5日-6日         大会正式议程（含现场注册）
        2021年12月7日                东亚论坛（线上会议）
        2021年12月25日-12月4日   会前和会后培训班
大会网站： https://isqp2021.sciconf.cn