Biomarker Validity, Milestones, BMx Milestone Matrix

clinic to compare results in humans and mice	Plot A — y-axis: Total %BWL (0–45); x-axis: Beloranib Cavg (ng/mL) (0 to ~2). Plot B — y-axis: Avg %Occupancy (0–75); x-axis: Beloranib Cavg (ng/mL). Plot C — y-axis: Total %BWL; x-axis: Avg % Occupancy. Legend: BIW sim, QD sim, BIW in DIO, QD in DIO, Human equivalent. Annotation: same Cavg →. - we calculated the mouse-equivalent exposures for the doses given to humans (0.6, 1.2, and 2.4 mg) using the reported human plasma concentration, → We then plotted the corresponding human weight loss achieved after 12 weeks against the mouse-equivalent beloranib concentrations → we simulated the average MetAP2 occupancy for the human regimens at the mouse-equivalent exposures	more MetAP2 occupancy and more efficacy than a higher dose given twice-weekly
- Dosing interval?

[BIOMARKER]

Validity

Construct validity	the degree of similarity between the mechanisms underlying behavior in the model and that underlying the behavior in the condition, which is being modeled.
Face validity	the degree of descriptive similarity between, for example, the behavioral dysfunction seen in an animal model and in the human affected by a particular neurobehavioral disorder.
Predictive validity	An animal model with high predictive validity (also called criterion validity; [57]) predicts behavior in the situation it is supposed to model, i.e. it allows extrapolation of the effect of a particular experimental manipulation from one species to other species, including humans, and from one condition (e.g. the laboratory) to the other (e.g. the 'Real World'), or from one testing timepoint to another [57]. Predictive validity may share components of generalizability (or external validity; see below) of a model.
measurement validity	is the biomarker proposed as a surrogate capable of being measured objectively and reproducibly in a given case, and does it measure an objective, quantifiable characteristic successfully?
the internal or study validity	within the study, can the biomarker be measured not just with precision and reproducibility, but also with accuracy within this study population and situation, does the biomarker correlate strongly with the clinical endpoint for which it is serving as a surrogate?
external validity	can this surrogate be shown to have similar predictive power in other populations or in other related treatment studies
Analytical validation	validation of the test's, tool's, or instrument's technical performance, but not validation of the item's usefulness
Clinical validation	Establishing that the test, tool, or instrument acceptably identifies, measures, or predicts the concept of interest.

Types of biomarkers

Integral biomarkers	Integrated biomarkers	Exploratory biomarkers
	a high priority scientific question and for which there is a clear statistically testable hypothesis, there are prespecified protocols for specimen collection, biomarker testing and statistical analysis, but the trial could proceed without the biomarker.

Type of BM

Type of BM	BM Value correlate with		Cut point
Diagnostic	Yes or No	AUC on ROC curve	0.7
Prognostic (Herceptin)	이 경우는 bm status 일수 있음.
Predictive (drug response)
Pharmacodynamic/Response	biomarker used to show that a biological response has occurred in an individual who has been exposed to a medical product or an environmental agent.
Monitoring (disease progression)	A biomarker measured serially for assessing status of a disease or medical condition or for evidence of exposure to (or effect of) a medical product or an environmental agent. Disease severity (eg. UPDRS)	Correlation coefficient	0.7

• 위 source: FDA-NIH Biomarker Working Group, BEST (Biomarkers, EndpointS, and other Tools) Resource
• 어느 경우에도 통계학적 방법이 존재하고, 통계상담 받으면 될 것임.

Milestones

Proposed flow in MBMIG

Process flow (top-to-bottom, with Development phase covering steps before A&P runs and Qualification phase covering steps from A&P runs):

• BPS: Procure antibodies, reference standard (recombinant protein), etc
• ↓ Screen of antibody pairs in MSD format
• ↓ Generate calibration curve and determine buffer-based LLOQ
• BPS-1: Determine MRD in primary-target biofluid (pooled) and Re-calculate LLOQ according to MRD
• BFA: Prepare aliquots of QCs and perform A&P runs
• ↓ Test individual donor specimens, Confirm response of drug-treatment in e.g. cellular model
• BTV: Test stability (bench-top, freeze-thaw)

Side annotations:

• Development phase
• Solutions in case of failure
  • Assay parameter optimization
  • Convert to SMC assay
  • Convert to Simoa assay
  • EV enrichment
  • Addition of inhibitors
• Qualification phase
• Logo: Takeda Pharmaceutical Company Limited

Footer comment under the diagram: 바로 Clinical 용이므로, preclinical 에서 Tx response 없네!

BMx Milestone Matrix

	Stage	Molecular BMx	Neurocircuitry BM (도대체 언제 in vivo Tx response?)	Novel PET ligand	Existing Clinical (so preclinical work is not here below) IMG method (MRI or PET)
	Milestone
	BM Platform Start	In silico assessment of assay feasibility: reagents, standards, assay format	White paper on available datasets or techniques, vendors, analysis plan	PET Tracer proposal presented to PET Steering Committee (Makoto: LGE 직후면 OK)	Rationale & proposal for development
	BPS	Go/NoGo @ TDIB based on Research plan with selected vendor	Go/NoGo @ TDIB based on vendor SOW or internal PF plan;	Go/NoGo @ PET SC based on feasibility, cost, need	Go/NoGo from QTS-DDU-TAU based on feasibility, cost, need
	Feasibility Assessment	Procure & verify compatibility of reagents and assay format; verify assay sensitivity in samples	Optimization of assay or contracting with vendors	BMax assessment	Survey of available external options and/or partnerships
	BFA	Prototype assay 가 개발되었다! → PE 에서 쓰자	Prototype assay	GNG at PET SC based on Bmax assessment	Vendor or internal SOW
다, POC (Preliminary)	Technical Validation	Achieve all assay acceptance criteria in vitro, e.g. dilutional linearity, etc.	Pilot study of test-retest variability, etc.	Optimization of physical properties and non-imaging triaging of potential candidates	Vendor/collaborator/technology assessments
	BTV	Spec sheet with assay wet lab quantified parameters	Technical validation with specific protocol procedures in place	Potential PET tracer candidates identified	Candidate IMG BMx for use within Takeda
POC (Solid)	In Vivo Calibration (IVC)	In vivo BMx data package incl. PK/PD analysis in collaboration with DMPK	Preclinical testing of BxM longitudinal change & variability	In vivo PET studies in relevant preclinical species (e.g. NHP) – specific binding, dosimetry	Technical characteristics of marker in relevant population (fibroblast 를 여기 넣을수 있나? Clinical study 를 넣자) – face validity
GPT is formed by CS	BCS	Approved by MBM SC as ready for use in preclinical POC(?이제서야?) or EM study	Approved by NCB SC as ready for use in preclinical POC or EM study	Approved by PET SC as fit-for-purpose for preclinical use, It is understanding that a detailed clinical PET study is not formulated until a GPT is formed.	Approved by QTS-IMG as ready for (pre)clinical use – construct validity
Tox	Human use qualification	Human matrix assessment / patient samples	EM testing of BMx longitudinal change and variability	-GLP Tox IND-enabling studies -FIH T/RT and dosimetry	Assessment in relevant population for drug development use case – construct validity
	BFP	Approved by MBM SC as ready for clinical use in TAK study	Approved by TDIB as ready for clinical use in TAK study	Approved by PET SC as ready for clinical use in TAK study	Approved by QTS-IMG as ready for clinical use in TAK study
	BM Types	TE << PD, DR >> PS	PD, DR >> PS	TE >> PD, DR >> PS	PD, DR >> PS

Milestone: MBM Only

Stage	BDD
Milestone
BMx Project Start	In silico assessment of assay feasibility: reagents, standards, assay format
BPS (BMx Project Start)	Go/NoGo @ TST based on d/w TML & PJ team

Uncertain Spans

location	transcription	uncertainty
Beloranib Plot A axis	Total %BWL axis ticks	Tick numbers are visible but small (45, 35, 25, 15, 5); exact intermediate increments may be slightly off.
BMx matrix row label	다, POC (Preliminary)	Leftmost label cell text near Technical Validation is partly cropped at the left edge; the prefix character before POC is uncertain.
BMx matrix row label	GPT is formed by CS	Left edge is partly cropped; the abbreviation could read GPT is formed/by differently.
Plot C legend	BIW sim, QD sim, BIW in DIO, QD in DIO, Human equivalent	Legend text is small; “BIW” vs “BIW” reading is consistent, but the small-text “sim” suffix relies on context.