Guillaume Desachy, Alessandra Serra, Sandrine Guilleminot, Nicole Krämer, Karl Köchert, Nils Ternès.

PSI Webinar of the European Biomarkers European Special Interest Group: A promising adaptive biomarker-based design strategy for early phase and machine learning as an enabler of precision medicine!

Presentation 1: A promising adaptive biomarker-based design strategy for early phase clinical trials
Identifying predictive biomarkers is crucial in patient-centric clinical development. Enrichment strategies in late stages of drug development have been widely studied in the literature. However, implementing these strategies in early stages presents significant challenges due to the small sample size and numerous uncertainties that arise at this point in the development process. These uncertainties encompass biomarker (BMK) predictive value, cutoff value of the biomarker used to identify patients in the BMK-positive subgroup, the proportion of patients in the BMK-positive subgroup and the magnitude of the treatment effect in patients BMK-positive and BMK-negative. Early phase adaptive designs can improve trial efficiency by allowing for adaptions during the course of the trial. In this work, we are interested in adaptations based on interim analysis permitting a refinement of the existing study population according to their predictive biomarkers. Simulations show that the proposed design leads to better decision-making compared to a classical design that does not consider an enrichment expansion. Specifically, in the considered settings, gains up to 30% in the overall probability to hit the study success criteria at the end of the trial were achieved in comparison to a conventional design. 

Presentation 2: Machine Learning as an enabler of precision medicine
Since the re-creation of the Biomarkers ESIG in 2022, people from different horizons and job titles have expressed some interest in machine learning (ML) and artificial intelligence (AI) methods applied to drug development, from research to clinical. With this fact and the increasing interest in ML/AI from the scientific community and beyond, a group of a dozen people was set-up in the past months with the ambition to create a cross-company best practices guidance on the use of AI/ML in drug development. The group started with some proactive joint discussions to better understand each other’s interest in this area and has already contributed to the review and feedback to FDA’s recent discussion paper on usage of AI/ML in drug development. Now, the group is in a highly dynamic ideation phase to identify and choose topics which have the potential to impact drug development, e.g., virtual twin (VT) technology, GxP compliant AI/ML, use of image-based or digital biomarkers.

Kristian Brock (AstraZeneca) and Pater Thall (MD Anderson) present their recent work on Bayesian designs in efficacy and safety with discussions led by Sebastian Weber.

Presenters & Papers: 
1. Kristian Brock, Chen Chen, Shuyen Ho, Greg Fuller, Jared Woolfolk, Cindy McShea, Nils Penard: 'A Bayesian method for safety signal detection in ongoing blinded randomised controlled trials' 
https://onlinelibrary.wiley.com/doi/10.1002/pst.2278

2. Yun Qing, Peter F. Thall, Ying Yuan: 'A Bayesian piecewise exponential phase II design for monitoring a time-to-event endpoint' 
https://onlinelibrary.wiley.com/doi/10.1002/pst.2256

Steve Mallet is presenting ways to visualise a complex testing strategy. In the example of nine hypotheses in three families interactive plots help to make educated design decisions. Visualisations are available on the Wonderful Wednesday blog. 

The display of multiple dependencies can be handled with trellis plots. Three dimensional plots are supported by plotly. All options can be explored in an interactive facet plot embedded in a shiny app. The next challenge is on displaying outliers in demographic data. See the Wonderful Wednesday homepage for more detail.

Wonderful Wednesdays are brought to you by the Visualisation SIG. The Wonderful Wednesday team includes: Bodo Kirsch, Alexander Schacht, Mark Baillie, Zachary Skrivanek, Lorenz Uhlmann, Rachel Phillips, David Carr, Steve Mallett, Rhys Warham, Lovemore Gakava, Zara Sari, Paolo Eusebi, Martin Brown, Martin Karpefors, Benjamin Lang.

Yunda Huang, Dean Follmann and Fabian Tibaldi 

Dr Huang shares her experience in extending/innovating methodology and concepts developed in vaccine statistics to the analyses of pre-efficacy and efficacy trials of monoclonal antibodies.

Dr. Byron Jones, Dr. Brett Hauber, Dr. Bennett Levitan, Dr. Christine Sturchler, Dr. Hannah Penton, Dr. Marco Boeri, Teodora Trasieva.

Day 2 of the patient-focused drug development meeting presented 3 industry case studies and finished with a panel discussion:
“The importance of different symptoms to people living with Chronic Obstructive Pulmonary Disease (COPD): results of a multi-country patient preference study. Industry case (Novartis)”, presented by Dr. Byron Jones, Biostatistician Specialising in Patient Preference Studies in the Patient Engagement Science group at Novartis

“Using Patient Preferences to Inform Dose Selection”, presented by Dr. Brett Hauber, Senior Director, Patient Preferences in Worldwide Medical and Safety of Pfizer

“The relevance of fatigue to relapse rate in multiple sclerosis: Applying patient preference data to the OPTIMUM trial”, presented by Dr. Bennett Levitan, Senior Director, Benefit-risk Assessment, Department of Epidemiology at Johnson & Johnson

Panel discussion, including Dr. Byron Jones, Dr. Brett Hauber, Dr. Bennett Levitan, Dr. Christine Sturchler, Dr. Hannah Penton, Dr. Marco Boeri.

Dr. Christine Sturchler, Prof. Peter Mol, Caroline Vass, Dr. Hannah Penton, Dr. Marco Boeri, Teodora Trasieva.

The following topics were presented during day 1 of the patient-focused drug development meeting:
“The perspective of Patients as Research Partners in Patient Preference Studies”, presented by Dr. Christine Sturchler, Director of Patient Engagement Scientific Excellence at Novartis

“The perspective of an EU regulator”, presented by prof. Petr Mol, CHMP member for the Dutch Medicines Evaluation Board and professor of drug regulatory science at the University Medical Center Groningen

“Incorporating Patient outcomes, Preferences, and Perspectives into HTA”, presented by Caroline Vass, Senior Economist in the Health Preference Assessment team at RTI Health Solutions; Dr. Hannah Penton, a Senior Scientist in the Patient-Centered Outcomes team at OPEN health; and Dr. Marco Boeri, Director of Preference Research at OPEN Health and honorary professor in practice in Health Economics at Queen’s University Belfast

How can effective visualisations help to spot implausible data? In the example of Likert scale data there was an entry error at one site. Zak Skrivanek presents visuals that nicely show the outlier. Visualisations are available on the Wonderful Wednesday blog. 

To spot irregularities in the data relatively simple graphs like density plots can be use. Stacked bar charts made it obvious what happened in this data example. The demonstrated R notebook gives a lot of different views on the data. Finally the pros and cons of alluvial plot are discussed. The next challenge is on power and multiplicity. See the Wonderful Wednesday homepage for more detail.

Wonderful Wednesdays are brought to you by the Visualisation SIG. The Wonderful Wednesday team includes: Bodo Kirsch, Alexander Schacht, Mark Baillie, Zachary Skrivanek, Lorenz Uhlmann, Rachel Phillips, David Carr, Steve Mallett, Rhys Warham, Lovemore Gakava, Zara Sari, Paolo Eusebi, Martin Brown, Martin Karpefors, Benjamin Lang.

Yulia Dyachkova, Nathalie Barbier, Cornelia Dunger-Baldauf on behalf of the Launch & Lifecycle eSIG.

Do you really want to stay single? Single arm trials (SAT) are not preferred but remain in use throughout the drug development cycle.  They may be accepted by regulators in oncology and in rare disease when potential effects of new treatments are very large and placebo treatment is unethical. However, in the post-regulatory space, SAT are common, and perhaps even more poorly suited to address the questions of interest. We review regulator and HTA positions on SATs, further challenges posed by SATs even in the context of evolving methods, case studies, and communication tips to influence decision making and optimize design to answer questions.

To find out a little more about our Speakers, please visit the event page for full details. And if you'd like to learn more about the Launch & Lifecycle SIG, whether to share your feedback, get involved or simply stay up to date, please visit our SIG page.

Satrajit Roychoudhury, Kenneth Koury, Sebastian Weber, Emma Clark.

The use of Bayesian methods within clinical development has greatly increased in recent years. This is particularly true for earlier stage trials but they are also being used in later stage work. In this webinar, three different examples of where Bayesian methodology has been used within confirmatory settings will be provided.

The examples describe: A Bayesian framework used to incorporate several interim analyses to monitor the trial for efficacy and futility, while controlling the overall type 1 error. Use of the meta-analytic-predictive prior methodology, interpreting study data in the context of trial external data while accounting for between-trial heterogeneity. Incorporating a hybrid external control arm using Bayesian dynamic borrowing with propensity score matching. 

Medication planning is an important issue for multimorbid patient. It can be measured by the Medication Appropriate Index (MAI). But how can it be visualised? Martin Brown presents the proposed visualisations in contrast to the regular tabulation of the results. Visualisations are available on the Wonderful Wednesday blog. 

An advantage of the visual display is the possibility to include individual patient data. This can be done in combination with a box-and-whisker plot. The dumbbell plot is showing individual changes and is giving a good impression on the distribution, especially with the right sorting applied. Depending on  the message to be transported also scatter plots or a simple histogram can be useful. The next challenge is on exploring dirty data. See the Wonderful Wednesday homepage for more detail.

Wonderful Wednesdays are brought to you by the Visualisation SIG. The Wonderful Wednesday team includes: Bodo Kirsch, Alexander Schacht, Mark Baillie, Zachary Skrivanek, Lorenz Uhlmann, Rachel Phillips, David Carr, Steve Mallett, Rhys Warham, Lovemore Gakava, Zara Sari, Paolo Eusebi, Martin Brown, Greg Ball, Martin Karpefors, Benjamin Lang

Hosted by Claire Britain and Chetan Mistry, for this session we're joined by: Kleio Kipourou, Andy Nicholls, and Tom Fisher.

In this session we discuss the advances of AI and its applications within the pharmaceutical industry. We focus on opportunities, challenges and changes that lie ahead for the roles of programmers and statisticians. Join in to hear more on what ChatGPT is and whether the robots are really going to take over our roles!

There are no expectations or requirements on the previous experience on using ChatGPT or AI for this session. This session is aimed at anyone who is interested in learning more about these topics. 

Claire Brittain, Steve Mallet, Nicola Voyle, Doug Thompson, Emma Crawford.

Do you remember your career talks at school? What opportunities were promoted for maths and science? When did you   first discover the pharmaceutical industry as a career choice?  Raise awareness of our rewarding careers in schools For me, I only discovered the pharmaceutical industry when searching for industrial placements as part of my undergraduate degree. My decision to continue studying maths was fairly generic in that I was good at it at school and thought it was general enough to give me a few different career opportunities - although I was adamant I didn’t want to end up in teaching or finance. Any awareness of drug development I had would have come from science lessons, and never once had it crossed my mind that it was a field where maths skills were widely used and sought after - alongside several other data centric industries.  School outreach plays a vital role However not all students are encouraged to share the same passion and interest for maths that I did. This is where school outreach activities can play an important role in helping to raise awareness of the many exciting opportunities for working with data and inspiring the next generation to continue their studies in relevant subjects to allow them to do so.  Learn about the benefits of schools outreach volunteering Join us in this webinar to kick off the 2023/24 academic year, and find out how PSI can support you in engaging in school outreach activities and how you can take part in our new award scheme, “Outreach Champions Challenge Cup” which will recognise members who make exceptional contributions to outreach throughout the year. Listen to reflections from our panelists of their real-life experiences of participating in schools outreach activities and the benefits they have found from doing so.  If as a PSI community, every member engaged in at least one school's outreach activity per academic year, we could reach an impressive number of students and help to shape the future workforce of pharmaceutical statisticians.