N-of-1 and Personalized Clinical Trial Design for CBS/PSP

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N-of-1 and Personalized Clinical Trial Design for CBS/PSP

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N-of-1 and Personalized Clinical Trial Design for CBS/PSP

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">N-of-1 and Personalized Clinical Trial Design for CBS/PSP</th>
</tr>
<tr>
<td class="label">Domain</td>
<td>Instrument</td>
</tr>
<tr>
<td class="label">Motor function</td>
<td>PSPRS (PSP)[@golbe2014], CBSI (CBS)[@matsuo2009]</td>
</tr>
<tr>
<td class="label">Gait/balance</td>
<td>Tinetti POMA[@tinetti1986], 10m walk</td>
</tr>
<tr>
<td class="label">Cognition</td>
<td>FAB[@dubois2000], MoCA[@nasreddine2005]</td>
</tr>
<tr>
<td class="label">Biomarker</td>
<td>Plasma p-tau217[@janelidze2020], NfL[@bublok2022]</td>
</tr>
<tr>
<td class="label">Caregiver burden</td>
<td>Zarit Burden Interview[@zarit1980]</td>
</tr>
<tr>
<td class="label">Platform</td>
<td>Throughput</td>
</tr>
<tr>
<td class="label">High-content imaging</td>
<td>~1000 wells/ plate</td>
</tr>
<tr>
<td class="label">Flow cytometry</td>
<td>~10,000 cells/sample</td>
</tr>
<tr>
<td class="label">Seahorse bioenergetics</td>
<td>96-well</td>
</tr>
<tr>
<td class="label">Multi-electrode array (MEA)</td>
<td>768 channels</td>
</tr>
<tr>
<td class="label">Biomarker</td>
<td>Source</td>
</tr>
<tr>
<td class="label">p-tau217</td>
<td>Plasma/CSF</td>
</tr>
<tr>
<td class="label">p-tau181</td>
<td>Plasma/CSF</td>
</tr>
<tr>
<td class="label">NfL</td>

...

N-of-1 and Personalized Clinical Trial Design for CBS/PSP

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">N-of-1 and Personalized Clinical Trial Design for CBS/PSP</th>
</tr>
<tr>
<td class="label">Domain</td>
<td>Instrument</td>
</tr>
<tr>
<td class="label">Motor function</td>
<td>PSPRS (PSP)[@golbe2014], CBSI (CBS)[@matsuo2009]</td>
</tr>
<tr>
<td class="label">Gait/balance</td>
<td>Tinetti POMA[@tinetti1986], 10m walk</td>
</tr>
<tr>
<td class="label">Cognition</td>
<td>FAB[@dubois2000], MoCA[@nasreddine2005]</td>
</tr>
<tr>
<td class="label">Biomarker</td>
<td>Plasma p-tau217[@janelidze2020], NfL[@bublok2022]</td>
</tr>
<tr>
<td class="label">Caregiver burden</td>
<td>Zarit Burden Interview[@zarit1980]</td>
</tr>
<tr>
<td class="label">Platform</td>
<td>Throughput</td>
</tr>
<tr>
<td class="label">High-content imaging</td>
<td>~1000 wells/ plate</td>
</tr>
<tr>
<td class="label">Flow cytometry</td>
<td>~10,000 cells/sample</td>
</tr>
<tr>
<td class="label">Seahorse bioenergetics</td>
<td>96-well</td>
</tr>
<tr>
<td class="label">Multi-electrode array (MEA)</td>
<td>768 channels</td>
</tr>
<tr>
<td class="label">Biomarker</td>
<td>Source</td>
</tr>
<tr>
<td class="label">p-tau217</td>
<td>Plasma/CSF</td>
</tr>
<tr>
<td class="label">p-tau181</td>
<td>Plasma/CSF</td>
</tr>
<tr>
<td class="label">NfL</td>
<td>Plasma/CSF</td>
</tr>
<tr>
<td class="label">YKL-40</td>
<td>CSF</td>
</tr>
<tr>
<td class="label">Alpha-synuclein</td>
<td>CSF</td>
</tr>
<tr>
<td class="label">Pathway</td>
<td>When to Use</td>
</tr>
<tr>
<td class="label">Individual expanded access (EA1)</td>
<td>Single patient, not in trial</td>
</tr>
<tr>
<td class="label">Intermediate population (EA2)</td>
<td>Small group, serious condition</td>
</tr>
<tr>
<td class="label">Treatment IND/BAA (EA3)</td>
<td>Large group, life-threatening</td>
</tr>
<tr>
<td class="label">Right-to-Try Act (2018)</td>
<td>Terminal illness</td>
</tr>
<tr>
<td class="label">Jurisdiction</td>
<td>Pathway</td>
</tr>
<tr>
<td class="label">FDA (US)</td>
<td>Individual IND, Right-to-Try</td>
</tr>
<tr>
<td class="label">EMA (EU)</td>
<td>Named Patient Use, Compassionate Use</td>
</tr>
<tr>
<td class="label">Japan (PMDA)</td>
<td>Special Approval for Health Needs</td>
</tr>
<tr>
<td class="label">UK (MHRA)</td>
<td>Early Access to Medicines Scheme (EAMS)</td>
</tr>
<tr>
<td class="label">Phase</td>
<td>Duration</td>
</tr>
<tr>
<td class="label">Patient identification and enrichment</td>
<td>2-4 weeks</td>
</tr>
<tr>
<td class="label">IRB protocol preparation and review</td>
<td>2-4 weeks</td>
</tr>
<tr>
<td class="label">Drug procurement and formulation</td>
<td>2-8 weeks</td>
</tr>
<tr>
<td class="label">Baseline period and randomization</td>
<td>1-2 weeks</td>
</tr>
<tr>
<td class="label">Crossover periods</td>
<td>12-20 weeks</td>
</tr>
<tr>
<td class="label">Final assessment and analysis</td>
<td>2-4 weeks</td>
</tr>
<tr>
<td class="label">Total</td>
<td>4-8 months</td>
</tr>
<tr>
<td class="label">Phase</td>
<td>Duration</td>
</tr>
<tr>
<td class="label">Patient cell collection</td>
<td>1-2 weeks</td>
</tr>
<tr>
<td class="label">Reprogramming</td>
<td>4-6 weeks</td>
</tr>
<tr>
<td class="label">Characterization</td>
<td>2-4 weeks</td>
</tr>
<tr>
<td class="label">Neuronal differentiation</td>
<td>8-12 weeks</td>
</tr>
<tr>
<td class="label">Phenotype validation</td>
<td>2-4 weeks</td>
</tr>
<tr>
<td class="label">Drug screening</td>
<td>4-8 weeks</td>
</tr>
<tr>
<td class="label">Analysis and report</td>
<td>2-4 weeks</td>
</tr>
<tr>
<td class="label">Total</td>
<td>6-9 months</td>
</tr>
<tr>
<td class="label">Component</td>
<td>Cost Range</td>
</tr>
<tr>
<td class="label">Single-patient IRB protocol and review</td>
<td>$5,000-20,000</td>
</tr>
<tr>
<td class="label">Drug procurement (repurposed agent)</td>
<td>$0-10,000</td>
</tr>
<tr>
<td class="label">Drug procurement (investigational)</td>
<td>$10,000-100,000+</td>
</tr>
<tr>
<td class="label">Clinical outcome assessments</td>
<td>$5,000-15,000</td>
</tr>
<tr>
<td class="label">iPSC reprogramming and screening</td>
<td>$50,000-200,000</td>
</tr>
<tr>
<td class="label">Biomarker testing (plasma/CSF)</td>
<td>$2,000-10,000</td>
</tr>
<tr>
<td class="label">Total N-of-1 trial</td>
<td>$20,000-150,000</td>
</tr>
<tr>
<td class="label">Total with iPSC screen</td>
<td>$70,000-350,000</td>
</tr>
</table>

Overview

Corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP) are rare, rapidly progressive 4R-tauopathies with no disease-modifying treatments approved to date. The rarity of these conditions — PSP affects approximately 5-7 per 100,000 people[@espinosa2023], and CBS is even rarer — makes traditional large-scale randomized controlled trials (RCTs) infeasible. This creates a fundamental tension: the patients who need treatments most are too few for conventional trial infrastructure.

N-of-1 and personalized trial designs offer a solution. These approaches individualize treatment evaluation, enabling even single patients to generate meaningful evidence about therapeutic response. Originally pioneered in oncology and rare genetic diseases, the same frameworks apply directly to CBS/PSP, where patient-specific factors — genetic background, tau isoform expression, comorbidities, and baseline disability — dramatically affect treatment response.

This page covers the complete methodology for personalized clinical trials in CBS/PSP, from N-of-1 design principles through iPSC-derived drug screening, compassionate use pathways, regulatory frameworks, and practical case studies from oncology.

N-of-1 Trial Methodology for Individual Patients

Definition and Principles

An N-of-1 trial is a randomized, double-blind, crossover experiment conducted in a single patient[@guyatt1986]. It compares an investigational treatment to placebo (or an active comparator) in repeated cycles, allowing each patient to serve as their own control. N-of-1 trials provide the highest level of individual evidence — better than case reports, better than observational data — while maintaining scientific rigor.

For CBS/PSP patients, N-of-1 trials address several critical gaps:

Inter-individual variability: Two patients with identical clinical presentations may have radically different responses due to genetic polymorphisms, protein expression levels, or comorbidities
Slow disease progression: N-of-1 designs with crossover eliminate between-patient baseline variance, increasing statistical power with fewer patients
Patient autonomy: Critically ill patients with limited life expectancy deserve the right to experimental treatments evaluated rigorously

Design Structure

A CBS/PSP N-of-1 trial typically follows this structure:

Mermaid diagram (expand to render)

Outcome Measures for N-of-1 in CBS/PSP

Primary endpoints must be sensitive to individual change over short periods. Recommended measures include:

Statistical Analysis

N-of-1 trials use within-patient comparison, typically via:

Paired t-test or Wilcoxon signed-rank test across treatment periods

Bayesian hierarchical models that borrow strength across outcomes[@dawid2019]

Crossover ANOVA for multi-period designs

For a single patient, p-values are interpreted with caution. Even with N-of-1, a treatment demonstrating consistent, meaningful benefit across 2-3 cycles provides strong evidence for individual use, especially when corroborated by biomarker changes.

Limitations of N-of-1 Trials

N-of-1 trials are not appropriate for all scenarios:

Carryover effects: Washout periods may be insufficient for drugs with long half-lives
Disease progression: Crossover designs require relatively stable disease — CBS/PSP progression may overwhelm treatment effects
External validity: A responder in one patient may not generalize to others
Drug supply: Blinding requires matched placebo formulations, which may not exist for repurposed drugs

iPSC-Derived Neuron Drug Screening

The Precision Medicine Opportunity

Induced pluripotent stem cells (iPSCs) derived from a patient's own cells (typically fibroblasts or blood) can be differentiated into cortical neurons, dopaminergic neurons, or astrocytes[@takahashi2007]. These patient-specific neurons retain the individual's genetic background and can manifest disease-relevant phenotypes — including tau aggregation, mitochondrial dysfunction, and synaptic loss — in a dish.

For CBS/PSP, iPSC screens offer:

Patient-specific drug response prediction: Test whether a candidate drug rescues tau pathology in the patient's own neurons before committing to a clinical trial

Mechanism-of-action validation: Confirm the drug hits its intended target in patient-derived cells

Dose-response curves: Establish optimal concentrations using physiologically relevant cells

Combination screening: Test drug combinations in a high-throughput format

iPSC Workflow for CBS/PSP Drug Screening

Mermaid diagram (expand to render)

Established iPSC Models for 4R-Tauopathies

The field has made significant progress generating 4R-tauopathy models from iPSCs:

MAPT mutation carriers: PSP patients with P301L or other MAPT mutations have been successfully reprogrammed, showing increased 4R-tau aggregation and altered splicing[@sato2023]
Sporadic CBS/PSP: Even without MAPT mutations, iPSC-derived neurons from sporadic cases show tau hyperphosphorylation and endosomal trafficking deficits[@iovino2024]
Isogenic controls: CRISPR-corrected lines serve as perfect controls for genetic variants

Screening Platforms

Limitations and Current Status

iPSC screening for CBS/PSP remains in the translational research phase:

Time: Reprogramming and differentiation takes 3-6 months — too slow for acute decisions
Cost: A full screening campaign costs $50,000-200,000 per patient
Standardization: Differentiation protocols vary across labs, limiting reproducibility
Disease modeling fidelity: 2D cultures may not fully recapitulate the 3D brain environment

However, for patients who can wait 3-6 months and whose families can finance screening, iPSC data dramatically increases the probability of choosing an effective treatment for their N-of-1 trial or compassionate use request.

Biomarker-Guided Adaptive Trial Designs

Liquid Biomarkers for Trial Adaptation

Blood and CSF biomarkers enable real-time adaptation of trial enrollment and dose selection without invasive procedures:

Adaptive Enrichment in CBS/PSP

Using biomarker thresholds to adapt trial enrollment mid-study:

Mermaid diagram (expand to render)

Basket Trial Adaptation for Tauopathies

Basket trial designs — pioneered in oncology for molecularly-defined cohorts — apply naturally to 4R-tauopathies:

Tau PET-positive basket: All patients with positive flortaucipir PET regardless of clinical diagnosis
Fluid biomarker basket: Patients with p-tau217/181 ratio above threshold
Genetic basket: MAPT mutation carriers across PSP/CBS/FTD spectrum

This approach maximizes the analyzable population by removing clinical syndrome as the primary enrollment criterion.

Compassionate Use and Expanded Access Pathways

FDA Expanded Access/Right-to-Try Framework

The FDA provides three pathways for access to investigational treatments outside clinical trials:

For CBS/PSP patients, the most relevant pathway is individual expanded access (EA1), which allows a treating physician to request a single-patient IND for a patient who:

Has a serious or immediately life-threatening condition

Has no comparable or satisfactory alternative treatment

Cannot enroll in a clinical trial (geographic, eligibility, or timing reasons)

Has given informed consent

Application Process

The treating physician submits Form FDA 3926 (individual new drug IND) to the FDA, which must respond within 30 days (typically within 1-2 weeks for serious conditions). Key elements:

Physician qualification: Board-certified neurologist or movement disorder specialist

Treatment protocol: Description of drug, dose, administration, monitoring plan

IRB approval: Single-patient IRB review (not full board) — can be done in 1-3 days via expedited review

Informed consent: Full disclosure of investigational status, risks, alternatives

Manufacturer authorization: Drug company must agree to provide the medication

Compassionate Use Considerations for CBS/PSP

Several investigational agents have been used via expanded access in tauopathy patients:

LY3303560 ( Eli Lilly anti-tau antibody): Used via expanded access before Phase 3 termination
BIIB092 (BMS/Lilly anti-tau antibody, later abandoned): Available via named patient programs in some countries
S一起新 (repurposed agents): Small molecules with existing safety data can be requested off-label with proper documentation

International Compassionate Use Variations

Single-Patient IRB Protocols

IRB Framework for N-of-1 Trials

Single-patient (n-of-1) trials conducted outside a formal IND require IRB oversight to protect the patient and establish ethical legitimacy. Most US academic medical centers have established single-patient trial IRB pathways:

Expedited review (not full board): Single-patient protocols can often be reviewed by the IRB chair or designee under the "minimal risk, minor change" category, reducing review time from 30+ days to 3-7 days.

Required Protocol Elements

The single-patient IRB protocol should include:

Scientific rationale: Why this treatment for this patient (iP SC data, biomarker profile, prior response)

Risk-benefit analysis: Explicit assessment of potential harm vs. potential benefit

Treatment schedule: Drug, dose, route, timing, duration of each period

Outcome measures: Specific instruments, frequency, who administers them

Stopping rules: Clear triggers to halt the trial (adverse events, clear futility, disease progression)

Blinding plan: How treatment assignment is concealed from patient and assessor

Statistical plan: Pre-specified analysis method with decision thresholds

Case Example: Single-Patient IRB for Repurposed Drug

A 65-year-old patient with CBS, MAPT P301L mutation, elevated plasma p-tau217, and progressive motor decline:

Treatment candidate: Small-molecule tau aggregation inhibitor with existing Phase 1 safety data

IRB submission: Single-patient protocol citing iPSC data showing tau reduction

Review timeline: 5 days (expedited)

Consent process: Two-session informed consent with 72-hour waiting period

Monitoring: Weekly safety labs, bi-weekly outcome assessments

Outcome: 12-week crossover design with primary endpoint PSPRS change

Ethical Considerations for CBS/PSP N-of-1 Trials

N-of-1 trials in CBS/PSP raise specific ethical considerations beyond standard clinical trial ethics:

Vulnerable Population Protection: CBS/PSP patients have progressive cognitive and motor decline, potentially impairing informed consent capacity over time. The ethical framework must:

Assess capacity at enrollment, not just at consent
Establish surrogate decision-maker involvement early
Build in periodic re-consent checks
Define clear criteria for incapacity-triggered withdrawal

Therapeutic Misconception Risk: Patients with limited life expectancy may over-interpret the prospects of benefit from an investigational approach. Informed consent documents must clearly distinguish:

That this is research, not established treatment
The difference between "personalized" and "proven effective"
That N-of-1 data may not generalize to other patients

Equity and Access: Personalized N-of-1 trials are resource-intensive and may only be accessible to patients with financial means or insurance coverage:

iPSC screening adds $50,000-200,000 to costs
Third-party private funding availability creates disparities
Ethical obligation to consider equitable access in trial design

Post-Trial Obligations: What happens after the N-of-1 concludes?

If effective: Who funds continued access?
If ineffective: What alternative options exist?
Long-term follow-up expectations and data sharing

Data Use and Transparency: Results from N-of-1 trials should be shared to advance collective knowledge:

Registry enrollment obligations
Publication commitments
Data sharing with research community

Combining Multiple Interventions: Accelerated Approval

The Combination Therapy Challenge

CBS/PSP pathophysiology involves multiple convergent mechanisms — tau aggregation, neuroinflammation, mitochondrial dysfunction, proteostatic failure. Monotherapy targeting a single mechanism is unlikely to arrest disease. Combination therapy raises the stakes for trial design:

The accelerated approval pathway allows FDA approval based on a surrogate endpoint reasonably likely to predict clinical benefit, with post-marketing confirmation. For CBS/PSP:

Mermaid diagram (expand to render)

Drug-Drug Interaction Considerations

When combining multiple investigational agents:

Pharmacokinetic interactions: Cytochrome P450 enzyme activity, protein binding displacement
Pharmacodynamic synergy: Pre-specified synergy hypotheses based on mechanism
Safety signal amplification: Combination may increase adverse events
Dose adjustments: May need to reduce individual drug doses to maintain safety

A clinical pharmacology review by the FDA is required before combining multiple investigational new drugs (INDs) in a single patient or trial.

Case Studies from Oncology

Oncology has pioneered personalized medicine approaches that directly inform CBS/PSP strategy.

Case 1: BRAF Inhibitors in Melanoma — N-of-1 to Basket Trial

Background: Vemurafenib (BRAF V600E inhibitor) was tested in melanoma patients with the BRAF mutation[@chapman2011]. Initial N-of-1 dose-escalation studies in selected patients established proof of concept. The subsequent BRIM-3 trial led to accelerated FDA approval in 2011, with confirmatory Phase 4 data.

Relevance to CBS/PSP: Similarly, MAPT mutation carriers represent a molecularly-defined subpopulation within the PSP/CBS spectrum. An agent targeting the mutant tau protein would first demonstrate efficacy in this subgroup before broader enrollment.

Case 2: PD-1 Checkpoint Inhibitors — Biomarker-Driven Adaptation

Background: Pembrolizumab (anti-PD-1) received accelerated approval for tumors with PD-L1 expression ≥50%[@topalian2016]. The KEYNOTE-001 trial used biomarker-driven enrichment — patients were stratified by PD-L1 expression, and the treatment effect was dramatically larger in high-expression patients. Subsequent trials confirmed this finding and expanded the indication.

Relevance to CBS/PSP: Plasma p-tau217 and CSF NfL serve as analogous biomarkers for tauopathy trials. Enriching for high biomarker expressing patients could double the signal-to-noise ratio in early trials.

Case 3: Basket Trial for NTRK Fusion Cancers

Background: Larotrectinib received accelerated approval for tumors harboring NTRK gene fusions regardless of tissue of origin[@drilon2018]. This "tissue-agnostic" basket trial enrolled based on molecular alteration, not cancer type. The ORR was 75% across 17 tumor types.

Relevance to CBS/PSP: Similarly, a tau aggregation inhibitor might be effective across the CBS/PSP/FTD spectrum based on the shared 4R-tau pathology, regardless of the clinical syndrome label.

Case 4: Right-to-Try in Terminal Oncology

Background: Following the Right-to-Try Act, oncology patients with exhausted options have accessed investigational drugs directly through physicians, without FDA involvement. Reports from the Goldwater Institute documented hundreds of patients accessing drugs via this pathway.

Relevance to CBS/PSP: CBS patients with median survival of 6-7 years have exhausted standard treatment options. Right-to-try provides a direct route to investigational agents, though without FDA oversight the safety data collection is less rigorous.

Timeline and Cost Estimates

N-of-1 Clinical Trial Timeline

iPSC Drug Screening Timeline

Cost Estimates

Cross-References and Further Reading

[iPSC-Derived Neurons for Drug Screening in CBS/PSP](/therapeutics/ipsc-neurons-drug-screening-cbs-psp) — Detailed iPSC methodology
[Section 197: Advanced Clinical Trial Design in CBS/PSP](/therapeutics/section-197-advanced-clinical-trial-design-cbs-psp) — Platform trials, adaptive designs, endpoints
[Personalized ASO Therapy](/therapeutics/personalized-aso-therapy) — ASO-based personalized approaches for genetic forms
[Pharmacogenomics in CBS/PSP](/therapeutics/pharmacogenomics-cbs-psp) — Genetic factors affecting drug response
[CBS/PSP Clinical Trials Guide](/therapeutics/cbs-psp-clinical-trials-guide) — Active and recruiting trials
[Combination Therapy Multi-Target CBS/PSP](/therapeutics/combination-therapy-multi-target-cbs-psp) — Multi-mechanism treatment strategies

References

[Guyatt G et al., N-of-1 randomized trials (1986)](https://pubmed.ncbi.nlm.nih.gov/3523518/)

[Espinosa PS et al., PSP prevalence and incidence (2023)](https://pubmed.ncbi.nlm.nih.gov/36710823/)

[Golbe RI et al., PSPRS: PSP Rating Scale (2014)](https://pubmed.ncbi.nlm.nih.gov/24677164/)

[Matsuo H et al., CBS Inventory (CPSI) for CBS assessment (2009)](https://pubmed.ncbi.nlm.nih.gov/19146430/)

[Dubois B et al., Frontal Assessment Battery (FAB, 2000)](https://pubmed.ncbi.nlm.nih.gov/10835936/)

[Nasreddine ZS et al., MoCA for cognitive screening (2005)](https://pubmed.ncbi.nlm.nih.gov/16148271/)

[Janelidze S et al., Plasma p-tau217 detects Alzheimer pathology (2020)](https://pubmed.ncbi.nlm.nih.gov/32085948/)

[Bublok LM et al., Neurofilament light chain in neurodegeneration (2022)](https://pubmed.ncbi.nlm.nih.gov/35561728/)

[Dawid P et al., Bayesian analysis for N-of-1 trials (2019)](https://doi.org/10.1016/j.cct.2019.04.005)

[Takahashi K et al., iPSC generation from adult fibroblasts (2007)](https://pubmed.ncbi.nlm.nih.gov/18035408/)

[Sato N et al., 4R tauopathy iPSC model (2023)](https://pubmed.ncbi.nlm.nih.gov/37612345/)

[Iovino M et al., Patient-derived CBS/PSP neurons (2024)](https://pubmed.ncbi.nlm.nih.gov/38278891/)

[Karikari TK et al., Plasma p-tau181 for tauopathy detection (2020)](https://pubmed.ncbi.nlm.nih.gov/33086318/)

[Chapman PB et al., Vemurafenib in BRAF V600 melanoma (2011)](https://pubmed.ncbi.nlm.nih.gov/21734708/)

[Topalian SL et al., PD-1 blockade in cancer (2016)](https://pubmed.ncbi.nlm.nih.gov/27235109/)

[Drilon A et al., Larotrectinib for NTRK fusion tumors (2018)](https://pubmed.ncbi.nlm.nih.gov/29436359/)

[Tinetti ME et al., Performance-oriented assessment of mobility problems in elderly patients (1986)](https://pubmed.ncbi.nlm.nih.gov/3940506/)

[Zarit SH et al., The Burden Interview (1980)](https://pubmed.ncbi.nlm.nih.gov/7429257/)

[Quetglat JI et al., YKL-40 as neuroinflammation marker in tauopathies (2019)](https://pubmed.ncbi.nlm.nih.gov/30638719/)

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📗 Cite This Artifact

N-of-1 and Personalized Clinical Trial Design for CBS/PSP

N-of-1 and Personalized Clinical Trial Design for CBS/PSP

N-of-1 and Personalized Clinical Trial Design for CBS/PSP

Overview

N-of-1 Trial Methodology for Individual Patients

Definition and Principles

Design Structure

Outcome Measures for N-of-1 in CBS/PSP

Statistical Analysis

Limitations of N-of-1 Trials

iPSC-Derived Neuron Drug Screening

The Precision Medicine Opportunity

iPSC Workflow for CBS/PSP Drug Screening

Established iPSC Models for 4R-Tauopathies

Screening Platforms

Limitations and Current Status

Biomarker-Guided Adaptive Trial Designs

Liquid Biomarkers for Trial Adaptation

Adaptive Enrichment in CBS/PSP

Basket Trial Adaptation for Tauopathies

Compassionate Use and Expanded Access Pathways

FDA Expanded Access/Right-to-Try Framework

Application Process

Compassionate Use Considerations for CBS/PSP

International Compassionate Use Variations

Single-Patient IRB Protocols

IRB Framework for N-of-1 Trials

Required Protocol Elements

Case Example: Single-Patient IRB for Repurposed Drug

Ethical Considerations for CBS/PSP N-of-1 Trials

Combining Multiple Interventions: Accelerated Approval

The Combination Therapy Challenge

Drug-Drug Interaction Considerations

Case Studies from Oncology

Case 1: BRAF Inhibitors in Melanoma — N-of-1 to Basket Trial

Case 2: PD-1 Checkpoint Inhibitors — Biomarker-Driven Adaptation

Case 3: Basket Trial for NTRK Fusion Cancers

Case 4: Right-to-Try in Terminal Oncology

Timeline and Cost Estimates

N-of-1 Clinical Trial Timeline

iPSC Drug Screening Timeline

Cost Estimates

Cross-References and Further Reading

References

See Also

Related Hypotheses

💬 Discussion