John Michael Sauer, PhD Executive Director, Predictive ... Michael Sauer, PhD Executive Director, Predictive Safety Testing Consortium (PSTC) John Michael Sauer, PhD\爀䔀砀攀挀甀琀椀瘀攀
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John Michael Sauer, PhD Executive Director, Predictive Safety Testing Consortium (PSTC)
John Michael Sauer, PhD Executive Director, Predictive Safety Testing Consortium (PSTC)
Presenter
Presentation Notes
John Michael Sauer, PhD Executive Director, Predictive Safety Testing Consortium (PSTC) Dr. John Michael Sauer is a toxicologist by training with over 15 years of experience in drug discovery and development. He has been responsible for leading multiple functional areas across several pharmaceutical companies. He is dedicated to bringing quantitative translational science approaches to safety assessment, as well as transforming the way we use nonclinical safety data to drive clinical study design and data interpretation. John Michael has over 100 scientific publications in the areas of toxicology, drug metabolism, clinical pharmacology, pharmacokinetics, and pharmacology. Prior to joining C-Path in 2013, John Michael had the opportunity to play an individual contributor role at Eli Lilly where he participated in the development, registration, and commercialization of Strattera for the treatment of ADHD in children and adults, as well as supported many other discovery and development teams. He also played a pivotal leadership role in the transformation of Elan Pharmaceutical’s discovery and development strategies including the incorporation of several quantitative translational science approaches. John Michael also gained operational and management experience in the Contract Research Organization (CRO) environment as the Site Scientific Head for the Covance Chandler site in Arizona. John Michael received his undergraduate and Master’s degree in Biomedical Sciences at Western Michigan University and his Doctorate degree in Pharmacology and Toxicology from The University of Arizona.
Critical Path Institute - 10 years of progress: A brief history of the biomarker qualification efforts in the Predictive Safety Testing Consortium
March 19, 2014 DILI Conference XIV
John-Michael Sauer, Ph.D. Executive Director of Predictive Safety Testing Consortium
Critical Path Institute
Presenter
Presentation Notes
Great. Thank you for the introduction. Today what I would like to do is just go through and tell you a little bit about Critical Path Institute. I am sure that many of you are aware of it. Critical Path Institute is now 10 years old. It was founded in 2004. What I would also like to do is dive a little bit into the Predictive Safety Testing Consortia and talk a little bit about what we're thinking about in the future, as well as what we have done in the past.
Accelerating Pathways to a Healthier World
Founded in 2004 Located in Tucson, Arizona, USA The Critical Path Institute (C-Path) is an independent, non-profit public-private partnership with the Food and Drug Administration (FDA) created under the auspices of the FDA’s Critical Path Initiative program. The Critical Path Institute is a catalyst in the development of new approaches that advance medical innovation and regulatory science. We achieve this by leading teams that share data, knowledge, and expertise resulting in sound, consensus based science.
Presenter
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So, Critical C‑Path is located in Tucson, Arizona. As I said, it was founded in 2004. Really, we live in that drug development tool space. We are a nonprofit organization. We are a public/private partnership with the FDA. And I'll tell you, that's a real thing for C‑Path. I mean, my career has primarily been in industry, and it's amazing the collaboration that C‑Path has with the FDA around developing biomarkers and other drug development tools. Again, as I said, we're all about developing these tools as well as data sharing.
A Timeline of C-Path
C-Path creates unprecedented collaboration between pharmaceutical companies and the FDA to form the Predictive Safety Testing Consortium (PSTC).
2006 – MAR 16
Presenter
Presentation Notes
Here is a brief timeline of C‑Path over the last 10 years, and I don't expect you to even see this. But what is important for PSTC is we were founded in 2006 in this timeline. And we were the first consortia that was actually founded under C‑Path. As C‑Path has evolved, there has been many consortia that have been formed. And it is just not about Predictive Safety. Instead, it is also about understanding and developing tools for efficacy. So, diagnostic ‑‑ or excuse me ‑- biomarker tools for diseases such as Parkinson's disease, Alzheimer's disease, tuberculosis, MS, polycystic kidney disease, as well as understanding drug effects through patient-reported outcomes. Interestingly, and to note, one of the first clinical biomarkers that we will probably go ahead and qualify as C‑Path will be within the polycystic kidney disease area.
C-Path: What We’ve Built
Seven global consortia collaborating with 1,000+ scientists and 41 companies
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Biomarkers – something that can be measured or observed to determine the progression of a disease. e.g. looking for new biomarkers for Alz. Can you do an imaging test of an individual to determine if they have Alz and what their level of progression is. Goal – looking to establish blood based biomarker for Alz or CSF – cerebral spinal fluid. Determine level of cognitive impairment Disease Progression Models – take multiple data sets and aggregate through CDISC TA data standard and create large pooled dataset. I give a specific example for Alz. Patient Recorded Outcomes – if you’re trying to determine if a person is depressed, you have to actually go through an assessment of how they’re feeling. Lab won’t work
Translational Safety Strategies that Accelerate Drug Development
Predictive Safety Testing Consortium (PSTC) PSTC was formed and officially announced on March 16, 2006.
PSTC brings together pharmaceutical companies to share and validate innovative safety testing methods under advisement of the FDA, EMA, and PMDA. PSTC’s nineteen corporate members have the same goal: to find improved safety testing approaches and methods.
Presenter
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So, let me talk to you a little bit about Predictive Safety Testing Consortia. Again, what we do is we go ahead and we pull together industry members and we pull together regulators to go ahead and work on biomarkers primarily for safety.. Key message: C-Path has a consortium model with many collaborators and has been proven through multiple consortia and can be applied in different ways (e.g. CAMD, CPTR) Re Data Standards, C-Path does not develop data standards, but data standards are very important to their work in aggregating large data sets, and therefore have partnered with CDISC.
PSTC Collaborators Consortia Members (19)
Partners (8)
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We have 19 corporate members. We also have academic members. And we are just not FDA-centric. We also pull in members from EMA and PMDA. Here are our members that we're primarily involved with. As you can see, it's the cast of characters from industry as well as many other major players, such as SAFE‑T, FNIH, just to name a few. We also have really good interactions with The Hamner Institute as well as S.T. Hessan.
May 2008: PSTC facilitated joint qualification process between FDA and EMA
June 2008: FDA and EMA qualifies 7 rodent kidney safety biomarkers
December 2009: PSTC initiates drug induced liver and skeletal muscle injury qualification process with FDA
June 2010: PMDA qualifies 7 rodent kidney safety biomarkers
October 2010: Initiation of FNIH KSP
October 2011: PSTC and The Hamner Institute sign a Memorandum of Understanding
January 2013: Formal initiation of SAFE-T collaboration
Presenter
Presentation Notes
So, let me talk about some of the milestones that we have accomplished over the last several years of PSTC. I mean, we worked really, really diligently early on to go ahead and define what this qualification process was really going to look like, right? Because this hasn't been around very long. If we think about this, we have been doing this for six or seven years. Our first qualification came in June of 2008, and that was around seven kidney safety biomarkers. That was both with FDA as well as with EMA that was accomplished. We also initiated several activities around skeletal muscle as well as looking at biomarkers for liver injury. Later, in 2010, we actually were able to accomplish a qualification with the Japanese, which was pretty important because now we basically had a worldwide qualification for the utilization of these non-clinical kidney safety biomarkers. It seems that really the bar has been raised for what's required for qualification of biomarkers, and we have seen this over the past several years. So, what we have seen is kind of a lull and really a resetting of how we need to go ahead and go through biomarker qualification. That is what we are currently working on, is how to go ahead and basically reset the table, if you will, to go ahead and move through qualifying those additional biomarkers. �What we have really concentrated on is around partnerships, so partnering with other consortia. There's no doubt that everyone in the room has heard of this idea of consortia fatigue. There's a number of consortia out there.
Vascular (VIWG)
Skeletal Muscle (SKM)
Testicular (TWG)
Liver (HWG)
Cardiac (CHWG)
Kidney (NWG)
PSTC Planned Milestones
Qualification of 3 additional rodent kidney safety biomarkers, and qualification of clinical kidney safety biomarkers
Qualification of rodent skeletal muscle safety biomarkers
Initiate nonclinical biomarker qualification of NT-proANP in rodents at EMA and FDA
Initiate biomarker qualification in rodents at EMA and FDA (Jeff Lawrence)
Initiate translational biomarker qualification in rodents at EMA and FDA
Completion of biomarker discovery phase
Presenter
Presentation Notes
What we have really concentrated on is around partnerships, so partnering with other consortia. There's no doubt that everyone in the room has heard of this idea of consortia fatigue. There's a number of consortia out there. But I think where we are at now is looking at how we can go ahead and make sure the consortia are working together, that we are not duplicating each other's efforts and that we are basically, you know, acting synergistically and propelling each other's efforts. And some of these important consortia collaborations have been with FNIH, The Hamner Institute, as well as with a more recent collaboration with IMI/SAFE‑T. We have other planned milestones, of course, looking into the future. You know, we're going to be looking at qualifying non-clinical biomarkers for cardiac hypertrophy. Jeff Lawrence is going to talk tomorrow about our efforts around qualifying additional DILI biomarkers from both a non-clinical as well as from a translational perspective. We are looking at skeletal muscle biomarkers as well as vascular injury, testicular, and some additional kidney biomarkers. We're heavily involved right now in the clinical qualification of these kidney biomarkers, and that's really where we see the greatest use of these biomarkers are actually going to occur, is in the clinical setting.
Key Collaborations
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Again, key collaborations. As I said before, I don't want to repeat myself, but, you know, this is really where it's at for consortia in my mind, is how we can best leverage each other's activities and expertise. If you look at PSTC, where we really have the most expertise is in the non-clinical and translational areas. Where we don't have the expertise is in the clinical area. So, that is where this FNIH as well as SAFE‑T collaboration is extremely important. �
Building a Translational Safety Strategy Accessible predictive (quantitative) biomarkers of tissue injury that can be used in preclinical animal models and humans
Adverse outcomes in animals
Adverse outcomes in humans
Biomarkers
Drug Exposure
Toxicometrics
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So, when we think about translation, I mean, what are we really trying to do here? We are really trying to look at adverse events in animals and trying to predict what's going to happen in humans, not as easy as it actually sounds. And we all know that, right? But probably the underlying basis for being able to do this is biomarkers. So, when we look at every biomarker that is basically qualified, we are basically laying that foundation for that translational safety strategy, and that's exactly what we're trying to do across each of our working groups.
Improve and expand our battery of qualified biomarkers that can be used to translate adverse effect from toxicology studies to the clinic
PSTC is laying the foundation for Toxicometrics with each biomarker we discover and qualify
The Predictive Safety Testing Consortium
Toxicometrics
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But I think what we have to realize, that it is not going to be a one-for-one play, right? We are going to have to take a much more holistic approach to how we are utilizing these biomarkers. So, it is just not discovering and qualifying these biomarkers, but, instead, putting these biomarkers into the appropriate models, so that we can make the best predictions. So, these models would include the underlying understanding of systems toxicology as well as, then, applying pieces like pharmacokinetic, pharmacodynamic, or toxicodynamic-type modeling as well physiological-based pharmacokinetic modeling, to go ahead and make better predictions.
This would, also, then, be supported by underlying mechanistic in vitro models as well as models that will help us understand in vitro pathways. The interesting part, this could also, then, feed into actually discovery of novel biomarkers that can be used for translation
We want to thank the Food and Drug Administration and Science Foundation Arizona for their
significant funding of our work.
SFAz Grant: SRG 0335-08 CFIC FDA Grant: U01 FD003865
Accelerating Pathways to a Healthier World
Presenter
Presentation Notes
So, with that, I would like to go ahead and thank both FDA as well as Arizona Science Foundation for their support of our work. And thank you for your attention. (Applause.)
