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Accelerating CNS Drug Development Using Biomarkers · Mind the Methods

• 0:01
  SPEAKER_00: Welcome to the Mind the Methods Podcast, brought to you by the International Society for CNS Clinical Trials and Methodology, your gateway to the latest insights, innovations, and conversations at the forefront of central nervous system clinical research.
• 0:14
  SPEAKER_00: This series dives into the challenges, progress, and people shaping the future of CNS therapeutics development and trial methodology.
• 0:22
  SPEAKER_00: In this first season, we'll explore innovations in CNS trial design, from digital endpoints and adaptive protocols to patient-centric models and generative AI.
• 0:32
  SPEAKER_00: Here we bring together researchers, clinicians, regulators, and industry leaders to discuss the challenges and breakthroughs shaping the future of CNS therapeutics development.
• 0:41
  SPEAKER_00: From advancing trial methodology to improving outcomes for patients, our conversations dive deep into the science and strategy behind CNS research.
• 0:50
  SPEAKER_00: Thanks for joining us.
• 0:51
  SPEAKER_00: Let's get started.
• 0:52
  SPEAKER_01: Mind the Methods brought to you by the International Society for CNS Trials and Methodology.
• 1:01
  SPEAKER_03: Welcome to today's ISCTM Mind the Methods podcast.
• 1:05
  SPEAKER_03: I'm joined today by Sean Ratcliffe SmithHurst, who is president-elect of the ISCTM.
• 1:11
  SPEAKER_03: Sean, welcome back to the podcast.
• 1:13
  SPEAKER_03: Thank you.
• 1:14
  SPEAKER_03: Today we'll discuss two related questions.
• 1:17
  SPEAKER_03: First, how can biomarkers accelerate drug development in neuroscience without creating false confidence?
• 1:24
  SPEAKER_03: And second, what practical methods can sponsors use to create regulatory flexibility while preserving scientific rigor?
• 1:32
  SPEAKER_03: So, Sean, I'd like to start with some terminology.
• 1:35
  SPEAKER_03: We use the word biomarker so broadly sometimes, and it can obscure more than it clarifies.
• 1:42
  SPEAKER_03: How should we be thinking about defining the term a biomarker as drug developers?
• 1:48
  SPEAKER_02: Really important question, Kemi.
• 1:50
  SPEAKER_02: And this is where I'll reference the FDA NIH best framework.
• 1:55
  SPEAKER_02: That framework is for biomarkers, endpoints, and other tools.
• 1:58
  SPEAKER_02: And this framework helps to define a biomarker as a measurable characteristic that indicates a normal biological process, a disease process, or a response to an exposure or intervention.
• 2:10
  SPEAKER_02: It can be molecular, imaging-based, histologic, physiologic, or digital.
• 2:16
  SPEAKER_02: Importantly, a biomarker is not itself a direct assessment of how a patient feels, functions, or survives.
• 2:23
  SPEAKER_02: That latter category really belongs to clinical outcome assessments and clinical endpoints.
• 2:29
  SPEAKER_03: Thank you so much.
• 2:30
  SPEAKER_03: You know, that category matters quite a bit because not all biomarkers are being asked to do the same job, correct?
• 2:36
  SPEAKER_03: Absolutely.
• 2:37
  SPEAKER_02: The best framework includes susceptibility or risk, diagnostic, monitoring, prognostic, predictive, pharmacodynamic or response and safety biomarkers.
• 2:49
  SPEAKER_02: And what's been fantastic is that advances in neuroimaging, electrophysiology, fluid biomarkers, neurochemical biomarkers, and physiologic measures have really opened up new possibilities, particularly in CNS clinical trial development.
• 3:06
  SPEAKER_02: Great examples with functional MRI patterns of activation in certain circuits, such as in the prefrontal cortex, the amygdala, and default mold network, can predict response to antidepressants, psychotherapy, or neuromodulation.
• 3:22
  SPEAKER_02: And EEG signatures such as alpha, asymmetry, theta activity, and event-related potentials can be linked to response in depression, ADHD, anxiety, and other psychological conditions.
• 3:35
  SPEAKER_02: A single bar marker might fit more than one category, but every regulatory discussion should be anchored to one proposed use in one defined population and stage of development.
• 3:47
  SPEAKER_02: That's really critical.
• 3:48
  SPEAKER_03: Well, thank you so much.
• 3:50
  SPEAKER_03: I think about the context of use principle, your point about proposing the use in a particular population that's predefined and a particular stage of development.
• 4:01
  SPEAKER_02: Absolutely.
• 4:02
  SPEAKER_02: I think that context of use is really critical because it describes what the biomarker is, the population and setting in which it will be measured, what decision it will inform, and how the results should be interpreted.
• 4:14
  SPEAKER_02: And something that we'll refer to later on in the podcast is neurofilament light.
• 4:20
  SPEAKER_02: Saying neurofilament light is a biomarker is not a sufficient development plane per se.
• 4:25
  SPEAKER_02: Plasma neurofilament light measured by a specific assay at a specific time will support pharmacodynamic interpretation in adults with a defined neurodegenerative disease is much closer to a usable context of use.
• 4:39
  SPEAKER_02: So, Sean, where do surrogate endpoints fit into this hierarchy?
• 4:44
  SPEAKER_02: A surrogate endpoint is particularly special because it really has a much higher stakes use of a biomarker.
• 4:51
  SPEAKER_02: In the context of surrogate endpoints, this is substituting for a direct clinical outcome in an approval decision because it is either known to predict clinical benefit or is considered reasonably likely to predict clinical benefit under accelerated approval.
• 5:07
  SPEAKER_02: Many biomarkers are excellent development tools without actually meeting this standard of being able to suffice as a surrogate endpoint.
• 5:16
  SPEAKER_03: Yeah, that's a great point.
• 5:18
  SPEAKER_03: One of the discipline checks really for development teams is to stop asking if a biomarker is validated.
• 5:25
  SPEAKER_03: And rather than asking that question, you may want to really think about validated for what decision and in which population and which assay and what are the consequences if we are wrong.
• 5:38
  SPEAKER_02: Absolutely, 100%.
• 5:39
  SPEAKER_02: That's exactly the right question.
• 5:41
  SPEAKER_02: Analytical validity, biological plausibility, clinical association, responsiveness to treatment, and surrogacy are related, but they're not all interchangeable.
• 5:53
  SPEAKER_03: So, Sean, let's let's get more granular.
• 5:55
  SPEAKER_03: I like this example and discuss the many uses of neurofilament light chain.
• 6:01
  SPEAKER_03: Why do you think NFL has become so prominent across ALS, MS, and even other neurodegenerative diseases?
• 6:10
  SPEAKER_02: Yeah, this is really an exciting use case of both bar marker being able to meet that evidentiary standard of a surrogate endpoint.
• 6:19
  SPEAKER_02: So neurofilament light is a structural protein in large myelinated axons.
• 6:24
  SPEAKER_02: When axons are injured, neurofilament light is released into cerebrospinal fluid and then into blood.
• 6:31
  SPEAKER_02: The practical appeal is that blood-based assays can provide a relatively scalable and dynamic measure of neuronal injury in this way.
• 6:41
  SPEAKER_02: The limitation is that neurofilament light is not disease fit per se because it's a marker of damage to these long neurons.
• 6:48
  SPEAKER_02: An elevated value will tell us that injury is occurring, but it doesn't necessarily say why it is occurring or where it is occurring.
• 6:55
  SPEAKER_03: Yeah, that's a great point.
• 6:57
  SPEAKER_03: Potentially many use cases, but definitely not a specific unless you really predefine what the context of use is.
• 7:05
  SPEAKER_03: I think neurofilament is potentially powerful either as a monitoring or pharmacodynamic biomarker, but that its interpretation requires the exact clinical context, reference data, standardized sampling across either blood or CSF and an assay that has an adequate amount of precision.
• 7:23
  SPEAKER_02: Correct.
• 7:24
  SPEAKER_02: Age, comorbidities, acute neurologic events, sample handling, assay platform, and the timing of measurement can all influence interpretation.
• 7:33
  SPEAKER_02: So it is really key for development programs to prospectively define what magnitude and timing of change would be considered biologically meaningful rather than simply measuring neurofilament light and deciding later what the result means.
• 7:48
  SPEAKER_02: It really is that predefinition and putting all of those components in context.
• 7:53
  SPEAKER_03: Exactly, exactly.
• 7:55
  SPEAKER_03: And the most important regulatory example is with TOFersin, which is currently marketed as Calcity Pasad1 Associated ALS.
• 8:05
  SPEAKER_03: Sean, can you walk us through why that particular Toeferson case is relevant here?
• 8:10
  SPEAKER_03: Absolutely.
• 8:10
  SPEAKER_02: And for those of you who have attended one of our ISCTM meetings in the last year, we did have some discussion of this across two different panels.
• 8:19
  SPEAKER_02: So this might be familiar to some.
• 8:20
  SPEAKER_02: So forgive me going all the way back to the beginning, but Tofersin is an antisense oligonucleotide or an ASO that's designed to reduce SOD1 messenger RNA and SOD1 protein.
• 8:33
  SPEAKER_02: SOD1 here being superoxide dismutase one.
• 8:37
  SPEAKER_02: In a randomized trial conducted by Biogen called Valor, 108 participants were assigned two to one to Tofersin or placebo.
• 8:47
  SPEAKER_02: At 28 weeks, the primary clinical endpoint, the change in ALS functional rating scale in the faster progressing subgroup was not statistically significant.
• 8:56
  SPEAKER_02: However, tofersin reduced both CSF SOD1 and produced a substantial reduction in plasma neurofilament light compared to placebo.
• 9:07
  SPEAKER_03: That's such an important nuance to point out that even though this population seems to have been enriched for a faster progressing subgroup of patients, they still didn't meet their primary endpoint in terms of the clinical endpoint.
• 9:21
  SPEAKER_03: However, the mechanistic as well as the biomarker moved in the expected direction.
• 9:26
  SPEAKER_02: Yeah, absolutely.
• 9:27
  SPEAKER_02: And those are key pieces, really, when we think about the biomarker in the context of both disease biology as well as a meaningful change that goes with sort of target engagement as well.
• 9:37
  SPEAKER_02: And based on this, FDA granted accelerated approval in April 2023, based on this reduction in the plasma neurofilament light, concluding that the biomarker effect was reasonably likely to predict clinical benefit in this specific genetic form of AMS.
• 9:53
  SPEAKER_03: So, Sean, what made the NFL argument more persuasive for the FDA than a generic association between just having a lower NFL and better outcomes?
• 10:03
  SPEAKER_02: Absolutely.
• 10:04
  SPEAKER_02: And this is where the totality of evidence really comes in.
• 10:07
  SPEAKER_02: There was a genetically defined disease, a therapy directed at the causal pathway, evidence of target engagement through lower CSFs, odd one, a downstream injury marker that moved strongly and consistently, natural history evidence linking neurofilament light to disease activity and prognosis, and ultimately longer-term observations that were directionally more favorable with earlier treatment.
• 10:34
  SPEAKER_02: The regulatory conclusion was not that every neurofilament light reduction equals clinical benefit.
• 10:40
  SPEAKER_02: It was that this particular chain of evidence in this population and with a confirmatory plan to confirm the clinical benefit downstream, that was what supported accelerated approval in this case.
• 10:52
  SPEAKER_03: Yeah, thanks for elaborating on that.
• 10:54
  SPEAKER_03: But the totality of evidence seems to have been favorable in this particular instance.
• 10:59
  SPEAKER_03: Absolutely.
• 11:00
  SPEAKER_02: I think that those are key points.
• 11:02
  SPEAKER_02: It's a precedent for really a context-specific reasoning and very clearly laid out, but it's not a universal surrogacy for neurofilament like for all broad ALS, not until it's been studied in that way.
• 11:15
  SPEAKER_02: A sponsor developing a treatment for sporadic ALS, MS, or other conditions can't simply cite this example and assume that it'll have the same regulatory status.
• 11:25
  SPEAKER_02: It's really important for those sponsors to work through the totality of evidence in the same way it was laid out for Calcity.
• 11:32
  SPEAKER_02: I think something that is encouraging, however, it does open the door for other areas where neurofilament light might also play a role.
• 11:40
  SPEAKER_02: And a great example here is the growing body of evidence in SMA, spinal muscular atrophy.
• 11:47
  SPEAKER_02: You know, however, there are some considerations here because neurofilament light is most informative in infants and young children where levels dramatically elevate before treatment and fall rapidly with effective treatment.
• 12:01
  SPEAKER_02: The magnitude of decline really correlates with clinical improvement on the motor milestones and motor endpoints, as well as the chop-in 10 scores, which are sort of around development milestone acquisition.
• 12:12
  SPEAKER_02: However, you know, if we look across older age groups, older children and adults with SMA, neurofilament light is less often less useful in that regard because it's often lower or near normal.
• 12:24
  SPEAKER_02: So you haven't got that ability to sort of really discern the treatment effect.
• 12:28
  SPEAKER_02: And so this is another great example, even within a disease or an illness, where one biomarker has a very age-specific context that needs to be taken into account.
• 12:38
  SPEAKER_03: Yeah, I agree.
• 12:39
  SPEAKER_03: That's another excellent example.
• 12:41
  SPEAKER_03: Thank you so much for that.
• 12:42
  SPEAKER_03: So let's contrast NFL with amyloid lowering and Alzheimer's disease.
• 12:48
  SPEAKER_03: Amyloid can be used diagnostically for enrichment or as a pharmacodynamic measure.
• 12:54
  SPEAKER_03: And in some settings, as a surrogate point, what should listeners take from that history of amyloid and NAD?
• 13:01
  SPEAKER_02: Absolutely.
• 13:02
  SPEAKER_02: And this is another one that's really exciting, and we had a good chance to explore in one of our recent panels.
• 13:07
  SPEAKER_02: Again, I think one of the key lessons is that one biomarker can serve several functions in the same program.
• 13:13
  SPEAKER_02: Amyloid PET or CSF biomarkers can confirm the underlying pathology.
• 13:18
  SPEAKER_02: So they can be diagnostic as well as enrich the study population.
• 13:22
  SPEAKER_02: Serial amyloid pet over time can demonstrate target engagement and it can quantify plaque removal.
• 13:29
  SPEAKER_02: So this is where you have multiple ways in which this biomarker can function.
• 13:34
  SPEAKER_02: And under the accelerated approval paradigm, reduction in amyloid plaque here was accepted as a surrogate endpoint that's reasonably likely to predict clinical benefit because it also shows the removal of the amyloid plaques part of the disease hallmark.
• 13:49
  SPEAKER_03: Yeah, exactly.
• 13:50
  SPEAKER_03: And Lakinabab is particularly instructive here because this drug moved from accelerated to traditional approval, correct?
• 13:58
  SPEAKER_02: Absolutely.
• 13:58
  SPEAKER_02: Absolutely.
• 13:59
  SPEAKER_02: This is another great example, very similar to the Toferson example we shared earlier.
• 14:04
  SPEAKER_02: Lakembi initially received accelerated approval based on amyloid plaque reduction.
• 14:09
  SPEAKER_02: And then based on data from the Clarity AD trial that showed benefit on the clinical measures of cognition as well as function, that this approval then became a traditional approval with that confirmatory evidence from the Clarity AD trial.
• 14:25
  SPEAKER_02: And I think what this tells us is having this sequence of an accelerated approval and then further confirming it in a longer and bigger study is a great way to provide patient access sooner and earlier and shows the regulatory flexibility to do that.
• 14:41
  SPEAKER_03: I think the confirmatory evidence is critical to point out here because often we're so excited to think about what the surrogate biomarker is going to be and getting that accelerated approval.
• 14:52
  SPEAKER_03: But along with that comes commitments to make sure that that confirmatory evidence is really gathered and supports the accelerated approval.
• 14:59
  SPEAKER_03: So thinking about DanaMab, this offers a slightly different design lesson than Lacanomab, correct?
• 15:05
  SPEAKER_02: Absolutely, yeah.
• 15:06
  SPEAKER_02: And this is sort of where that kind of growth of evidence in the amyloid lowering pathway, I think, really helped the Donanomab program, who were able to receive traditional approval, which is in the US marketed as consumer.
• 15:20
  SPEAKER_02: This was because those studies showed both amyloid lowering as well as statistically significant slowing cognitive and functional decline.
• 15:29
  SPEAKER_02: So those studies were able to demonstrate both the effect on the biomarker, but it also showed the effect on clinical outcomes.
• 15:37
  SPEAKER_02: Amyloid PET was still very central in these trials.
• 15:40
  SPEAKER_02: It confirmed pathology, measured pharmacodynamic effect, and it was used in the trial to also stop active treatment when participants had reached a certain pre-specified low amyloid level.
• 15:51
  SPEAKER_02: The approval case was really grounded in both those components as well as the clinical outcomes and the amyloid aspect has been leveraged in the label to inform who to treat, whether the drug engaged its target, and when treatment could be discontinued.
• 16:05
  SPEAKER_02: So slightly different development path and outcome to Lacanomat.
• 16:10
  SPEAKER_03: So let's pivot a little bit here to digital biomarkers.
• 16:14
  SPEAKER_03: So this includes wearables, sensors from smartphones, voice, ectigraphy, and other continuously collected measures.
• 16:24
  SPEAKER_03: How should a sponsor begin to address this particular type of firework?
• 16:29
  SPEAKER_02: Oh, absolutely.
• 16:30
  SPEAKER_02: And this I think is really central to really begin with the clinical concept, not the device.
• 16:35
  SPEAKER_02: Many of these come in a form of a device, and that's not the starting point.
• 16:39
  SPEAKER_02: The real starting point is what aspect of disease or function is being measured, why the digital measure is better or complementary to an established assessment, and what decision will it inform?
• 16:51
  SPEAKER_02: A digital health technology is a data acquisition system.
• 16:55
  SPEAKER_02: The digital endpoint or biomarker is the interpretable measure that's derived from those data.
• 17:01
  SPEAKER_02: So those two concepts are related, but they're also not the same thing.
• 17:05
  SPEAKER_03: Correct me if I'm wrong, FDA has a guidance on remote data acquisition that emphasizes fit-for-purpose selection and validation, correct?
• 17:13
  SPEAKER_02: Correct, yeah.
• 17:13
  SPEAKER_02: And this is a really helpful guidance because it really outlines how sponsors should address verification of the sensor or the software function, the analytical validation of the derived measures, clinical validation where appropriate, usability in the intended population, data transmission and storage, as well as missing data, algorithm version control as well, which can be really important, privacy as well as participant burden.
• 17:41
  SPEAKER_02: So all of that is covered in that guidance.
• 17:43
  SPEAKER_02: A consumer wearable can be appropriate, but only if its performance is adequate for the proposed context of use.
• 17:50
  SPEAKER_02: And you mentioned ectigraphy as one of those examples, risk-worn activity device has a number of different great uses across a number of different conditions.
• 17:59
  SPEAKER_02: But again, it has to be a very specific context of use because if you're measuring ambulation and foot strides, that has a in non-ambulatory patients, that could be very different.
• 18:09
  SPEAKER_03: Yeah, that's a very good point.
• 18:12
  SPEAKER_03: I'm thinking about our audience, uh, Sean, a lot of uh people who work with ICTM are involved in psychiatry clinical trials.
• 18:19
  SPEAKER_03: And this really is an attractive use case for digital biomarkers because episodic clinic visits typically miss changes in sleep, mobility, social interaction, other things routinely occurring in daily life.
• 18:33
  SPEAKER_03: Absolutely.
• 18:34
  SPEAKER_02: And I think that's the promise of passive sensing with that improved ecological validity.
• 18:39
  SPEAKER_02: There are some great examples, including the cost check program, which combines self-report and smartphone-derived measures on activity, mobility, communication, and device use in people with schizophrenia spectrum disorders.
• 18:54
  SPEAKER_02: And it demonstrated that there are individualized changes around relapse events.
• 18:59
  SPEAKER_02: It also illustrated some challenges that these patterns can be highly person-specific.
• 19:05
  SPEAKER_02: Adherence and data completeness can vary, and small observational data sets can produce unstable algorithms.
• 19:12
  SPEAKER_02: So I think this is helpful as it gives us some key lessons that we can take forward in other programs.
• 19:18
  SPEAKER_03: Yeah, so the lesson here is that digital biomarkers can be valuable for exploratory signal detection and even endpoint development, but sponsors should resist converting an algorithm into a pivotal endpoint before its measurement properties and its interpretability are fully established.
• 19:36
  SPEAKER_03: So let's switch gears and talk a little bit about prognostic adjustment and statistical methods.
• 19:42
  SPEAKER_03: We recently discussed prognostic adjustment and other digital twin methods at our last ISCTM meeting.
• 19:50
  SPEAKER_03: What is the cleanest way to explain the distinction?
• 19:53
  SPEAKER_02: A prognostic model uses baseline information to predict a participant's likely outcome under standard of care or placebo, because it's largely been built based on longitudinal data set.
• 20:06
  SPEAKER_02: In a randomized trial, that prediction can be included as a pre-specified baseline prognostic covariate.
• 20:13
  SPEAKER_02: If the prediction is really strongly associated with the observed outcome, this prognostic adjustment of the analysis can produce a more precise treatment effect estimate and a narrower confidence interval while preserving randomization.
• 20:29
  SPEAKER_02: So it can really, it's an individual patient, a digital twin built from a prognostic model.
• 20:36
  SPEAKER_02: So hopefully that can help explain to a degree.
• 20:39
  SPEAKER_03: Yeah, absolutely.
• 20:40
  SPEAKER_03: And this is aligned with FD's final guidance, encouraging pre-specified adjustment for prognostic baseline covariates.
• 20:48
  SPEAKER_02: Absolutely.
• 20:49
  SPEAKER_02: And and it and just sort of as I introduced there, it has an important caveat that 2023 guidance doesn't specifically endorse machine learning or digital twin methods, but it really covers that broader statistical principle that well-chosen prognostic covariates can improve trial efficiency, whether that is through then generating a digital twin score that fits and this will fit if the model is locked before I'm blinding.
• 21:17
  SPEAKER_02: It's externally trained, adequately validated and calibrated, and supported by sensitivity analysis as well.
• 21:24
  SPEAKER_03: Yeah.
• 21:25
  SPEAKER_03: So that's quite different from saying that a digital twin is going to replace a concurrent placebo participant.
• 21:31
  SPEAKER_02: Exactly.
• 21:32
  SPEAKER_02: And I think you highlight here sort of the words digital twin often get used to mean multiple different things.
• 21:39
  SPEAKER_02: And so it really is important to clarify what is being conveyed and meant by a digital twin.
• 21:44
  SPEAKER_02: And what I've been describing here is this prognostic score as an individual patient's digital twin to improve the precision of estimate in the trial.
• 21:53
  SPEAKER_02: Once you're leveraging a digital twin to replace a control arm, or if you're using historical Data set to replace a control arm, the design becomes vulnerable to differences in patient selection, standards of care, endpoint assessment, calendar time, missing data, and unmeasured confounding.
• 22:11
  SPEAKER_02: And so this is where actually following FDA's draft guidance on externally controlled trials is really key.
• 22:19
  SPEAKER_02: It makes it very clear that the comparability and data quality need to be really central with that external control or historic data set that are being leveraged and that they can carry greater risk of bias than concurrent randomized controls.
• 22:34
  SPEAKER_02: However, you know, this is a really important guidance because it also paves the way for being able to use large historic data sets as you know historical control arms, very important in rare disease and rare CNS disease in particular.
• 22:49
  SPEAKER_03: Yeah.
• 22:49
  SPEAKER_03: And I'm thinking about one particular example in a prevalent disease in Alzheimer's.
• 22:54
  SPEAKER_03: There was a in 2025 a data set with an AI digital twin model that harmonized historical data from over 6,000 patients that were treated and evaluated in a 450-plus phase two trial.
• 23:11
  SPEAKER_03: And the predicted projectories for placebo actually correlated modestly with the observed outcomes and they supported a potential use as a prognostic covariate.
• 23:22
  SPEAKER_03: So not as an individual counterfactual truth and not as a regulatory approval precedent, but as a prognostic covariate.
• 23:30
  SPEAKER_02: Absolutely.
• 23:30
  SPEAKER_02: And I think it's a great interpretation.
• 23:33
  SPEAKER_02: I think digital twins prognostic school models in this regard are most defensible today as either precision-enhancing covariates, scenario planning tools, possibly components of a Bayesian or adaptive design.
• 23:46
  SPEAKER_02: And I think again, are very much something that the agencies, both EMA and FDA, are willing to talk about and encourage for use, particularly in phase two trials, and definitely need to see discussions on how they will be used in pivotal studies if that's the direction that would be taken.
• 24:05
  SPEAKER_02: And I think it's, you know, again important that they're not necessarily a synthetic patient that eliminates the need for actual controls, unless there truly is the strength of evidence and regulatory agreement that's very strong in that regard.
• 24:18
  SPEAKER_02: So always consult with the agencies when you're planning to sort of leverage this in your trials.
• 24:24
  SPEAKER_03: I wholeheartedly agree with that.
• 24:26
  SPEAKER_03: And while we could talk for another hour, Sean, I'm conscious of the time.
• 24:31
  SPEAKER_03: So maybe let's just close this discussion with some practical approaches.
• 24:35
  SPEAKER_03: So if a sponsor wants flexibility from regulators, what should the team development team do before the pivotal file in terms of planning?
• 24:45
  SPEAKER_02: I think, you know, consult early, I think is really key.
• 24:48
  SPEAKER_02: I think we've talked about a couple of guidances here today with prognostic modeling, the use of external control arms.
• 24:56
  SPEAKER_02: And we've also talked about surrogate endpoints as a way to drive earlier access to treatment through the accelerated regulatory pathways.
• 25:04
  SPEAKER_02: So really important to consult early, define the decision in the context of use if you're going for a biomarker as a surrogate endpoint.
• 25:13
  SPEAKER_02: Really, that context of use should be well articulated before finalizing the protocol, be linked to the assay plan and the statistical analysis plan.
• 25:23
  SPEAKER_02: The biomarker plan should really state what the measure will be measuring.
• 25:27
  SPEAKER_02: Will it be measured in all participants, select participants, really confirm the mechanism, choose dose, support the monitoring, any adjustment to the analysis, or whether it will ultimately contribute to an approval endpoint.
• 25:41
  SPEAKER_02: Really getting all of that clarity up front with an early consultation because ultimately, you know, ambiguity at the beginning really moves downstream more as multiplicity and interpretability problems at the end.
• 25:55
  SPEAKER_03: Yeah.
• 25:56
  SPEAKER_03: And I would I would add also, you know, don't forget to connect the biomarker to the mechanism and to the ultimate clinical meaning of that biomarker in the context of use.
• 26:07
  SPEAKER_02: Absolutely, absolutely.
• 26:08
  SPEAKER_02: And whenever we've spoken about these on our panels, it's been very, very clear to really you need to use that triangulated evidence package, non-clinical data, target engagement, dose response, longitudinal natural history, treatment associated biomarker changes, and relationships to clinically meaningful outcomes.
• 26:28
  SPEAKER_02: You can't rely solely on a single correlation in this regard.
• 26:32
  SPEAKER_02: And, you know, one of the things that machine learning has given us an advantage of here in biomarker discovery and prediction is that machine learning approaches can really deconvolute and uncover complex patterns.
• 26:44
  SPEAKER_02: You know, you can look at high-dimensional data sets, so you get many more correlations than a single correlation.
• 26:50
  SPEAKER_02: And this is where, you know, model aspects such as the feature selection or dimensionality reduction with principal components analysis and/or predictive modeling using these model validation are really important aspects to also include in this triangulated evidence package.
• 27:09
  SPEAKER_02: The confirmatory question really should not be postponed until after approval.
• 27:13
  SPEAKER_02: It really needs to be at thought a priori and that plan underway as you go through discussions for accelerated approval.
• 27:20
  SPEAKER_03: And I just thought about one more thing, just making sure that the data is generalizable, because biomarkers can unfortunately sometimes unintentionally narrow participation if you have, you know, reference range differences, algorithms, or thresholds that are developed in unrepresented populations, these can have knock-on effects in the development program and ultimately the intended users of the drug.
• 27:43
  SPEAKER_02: Absolutely, absolutely.
• 27:44
  SPEAKER_02: And this is, you know, it's a scientific issue, not only an equity issue as well, a bar marker that performs differently across age, sex, ancestry, language, geography, disability, device ownership or comorbidity can really undermine the internal validity and that generalizability.
• 28:02
  SPEAKER_02: So really any subgroup performance and calibration should be part of that development planning right from the get-go and right from the beginning.
• 28:10
  SPEAKER_03: Well, Sean, it's been fantastic speaking with you.
• 28:13
  SPEAKER_03: This is an exciting time for CNS clinical trials, where advances in validated biomarkers are providing objective measures of treatment response.
• 28:21
  SPEAKER_03: And they're really paving the way for what we call precision medicine and improved trial efficiency and ultimately supporting regulatory decision making.
• 28:29
  SPEAKER_03: Thank you again for joining me today.
• 28:31
  SPEAKER_03: Thank you, Kemi.
• 28:34
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