Functional Indications for Invasive Brain-Computer Interface Development: Ensuring Equitable Access Through Evidence-Based Eligibility Criteria

DRAFT WHITE PAPER: Prepared for the Implantable Brain-Computer Interface Collaborative Community (iBCI-CC)

Executive Summary

As invasive brain-computer interface (iBCI) technologies advance toward FDA approval and clinical implementation, the regulatory framework chosen today will determine access for decades. This white paper advocates for functional indications based on objective biomarkers of cortical integrity rather than disease-specific etiologies. Such an approach ensures equitable access while satisfying both FDA safety/effectiveness standards and CMS evidence requirements for reimbursement.

Key Recommendations:

• Pursue functional indications defining eligibility by measurable motor/communication deficits and objectively verified cortical integrity

• Implement tiered biomarker strategies appropriate to different regulatory stages (IDE, PMA) and payer requirements

• Leverage non-invasive neurophysiological assessments (TMS-EEG, fNIRS, quantitative EEG) to demonstrate voluntary cortical modulation capacity

• Structure clinical trials to establish biomarker-based responder criteria that CMS can adopt for coverage determinations

1. The Problem: Disease-Specific Indications Create Barriers

1.1 Current Trajectory

Most iBCI companies are targeting pivotal trials at specific etiologies: amyotrophic lateral sclerosis (ALS), high cervical spinal cord injury (SCI), and brainstem stroke. While this simplifies initial trial design, it creates immediate exclusion of equally appropriate candidates the moment FDA approval is granted.

Patients excluded under disease-specific indications include:

• Duchenne muscular dystrophy (DMD) with quadriplegia

• Advanced spinocerebellar ataxias with complete upper extremity paralysis

• Severe Charcot-Marie-Tooth disease

• Multiple sclerosis with locked-in syndrome

• Traumatic brain injury with persistent motor deficits

• Guillain-Barré syndrome sequelae

• Other rare neuromuscular and neurological disorders conditions

These patients often represent ideal candidates—younger, cognitively intact, highly motivated, with stable conditions and long life expectancies that maximize benefit from iBCI systems.

1.2 The Regulatory Reality

FDA historically prefers precedent-driven approvals. When companies pursue disease-specific indications for expedited approval, subsequent etiology-agnostic expansion becomes arduous, expensive, and time-consuming. Meanwhile, patients with rare conditions wait years or decades for access.

1.3 The Financial Imperative

If reimbursement ranges up to $150,000-$300,000 per implant, every eligible patient matters for company sustainability and continued technology development. Artificial exclusions based on diagnostic labels rather than functional capacity unnecessarily constrain the patient population and threaten long-term viability.

2. The Solution: Functional Indications with Objective Biomarkers

2.1 Regulatory Precedents Support Functional Approaches

The FDA has established clear precedent for functional indications in neurorehabilitation devices:

NuedEXta (Dextromethorphan/Quinidine): Approved for pseudobulbar affect—the symptom itself, regardless of underlying etiology (ALS, MS, stroke, TBI).

MyoPro (Myomo Inc.): FDA cleared for "upper extremity weakness" enabling individuals with neuromuscular impairment to self-initiate movement using residual muscle signals. The indication does not specify stroke versus brachial plexus injury versus SCI.

InterStim (Medtronic): Approved for urinary urgency/frequency and fecal incontinence as functional problems across etiologies.

FES Foot Drop Devices: Multiple devices approved for the functional impairment of foot drop, not for the diseases causing it.

Indego Exoskeleton: Indications state it "is intended to enable individuals with spinal cord injury at levels T3 to L5 to perform ambulatory functions," notably encompassing both traumatic and non-traumatic SCI etiologies.

Powered Wheelchairs: FDA guidance focuses on functional mobility needs, not specific diagnoses.

These precedents demonstrate that FDA can and does approve devices based on functional deficits when the mechanism of action targets a final common pathway.

3. FDA Guidance for iBCI Development

3.1 Current FDA Framework

The FDA published comprehensive guidance in 2021: Implanted Brain-Computer Interface (BCI) Devices for Patients with Paralysis or Amputation - Non-clinical Testing and Clinical Considerations.

This guidance provides recommendations for:

• Investigational Device Exemption (IDE) feasibility studies

• Pivotal clinical studies

• Non-clinical testing requirements

• Study design considerations

Critically, the guidance focuses on "patients with paralysis" as the population, not specific disease etiologies.

3.2 Regulatory Pathway Considerations

IDE Stage (Early Feasibility):

• Smaller patient populations acceptable (n=3-10 typically)

• Focus on safety and preliminary evidence of effectiveness

• Can include heterogeneous etiologies to demonstrate broad applicability

• Human factors validation typically not required

PMA Stage (Pivotal Trials):

• Requires substantial evidence of safety and effectiveness

• Larger patient populations (n=30-100+)

• Must demonstrate benefit-risk profile justifies approval

• Clinical outcome assessments must be validated for intended population

• Evidence standards similar to Phase III drug trials

510(k) Pathway:

• Requires substantial equivalence to predicate device

• Less likely for novel iBCI systems without clear predicates

• Potentially relevant for incremental improvements

3.3 FDA-NIH Collaborative Efforts

The September 2024 FDA-NIH Joint Workshop focused on developing clinical outcome assessments (COAs) for iBCI effectiveness evaluation. Key themes:

• Need for standardized COAs with generalizability to home environments

• Recognition that functional communication and motor control in real-world settings must be measured

• Challenge of heterogeneous populations with varying functionality

• Importance of measuring clinically meaningful outcomes

4. Proposed Functional Indication Framework

4.1 Core Functional Criteria

Indication for Use:

"For adults with severe upper extremity motor impairment who have:

1. Functional Deficit Criteria:

   • Bilateral upper extremity dysfunction (Action Research Arm Test score <10 in both hands, or equivalent functional assessment)

   • Inability to perform activities of daily living requiring hand function

   • Preserved cognitive capacity sufficient for device training and use (Montreal Cognitive Assessment ≥18 or equivalent)

2. Cortical Integrity Criteria (see Section 4.2):

   • Demonstrated capacity for voluntary cortical modulation as evidenced by objective neurophysiological assessment

   • Sufficient cortical signal quality for decoding based on pre-implant evaluation"

4.2 Objective Biomarkers of Cortical Integrity

The critical innovation is establishing objective, pre-implant assessments proving the patient has intact cortical substrate capable of modulation. This addresses both FDA requirements (appropriate patient selection) and CMS requirements (evidence of likely benefit).

4.2.1 TMS-EEG (Transcranial Magnetic Stimulation with Electroencephalography)

QuantalX Delphi MD System:

The Delphi MD platform represents a clinically validated approach for assessing cortical network integrity. The system has received:

• FDA Breakthrough Device Designation (twice)

• FDA 510(k) clearance for nerve stimulation diagnostic applications

• Dedicated CPT reimbursement code (0858T)

Technical Approach:

The Delphi MD system uses focused transcranial magnetic stimulation (fTMS) combined with simultaneous EEG to generate TMS-evoked potentials (TEPs). This methodology measures:

1. Cortical Reactivity: The ability of cortical networks to respond to external stimulation

2. Network Connectivity: Interhemispheric and intracortical connectivity patterns

3. Cortical Excitability: Baseline and evoked cortical activation levels

4. Wide-Waveform Adherence: Similarity to healthy cortical response patterns

Academic Foundation - Mark Hallett's Pioneering Work:

Dr. Mark Hallett at the NIH National Institute of Neurological Disorders and Stroke has published extensively on TMS as a tool for assessing motor cortex excitability and voluntary modulation capacity. Key contributions include:

• Demonstrating that single-pulse TMS produces measurable motor-evoked potentials (MEPs) that reflect cortical excitability and voluntary control capacity

• Establishing paired-pulse TMS paradigms to assess intracortical inhibition and facilitation

• Showing that voluntary movement modulates ipsilateral motor cortex excitability in time-dependent patterns

• Developing methods to assess surround inhibition and intracortical circuits essential for fine motor control

• Characterizing how repetitive TMS can modulate cortical excitability beyond stimulation duration

These foundational studies established that TMS-derived measures provide quantitative, objective assessments of motor cortex function—exactly what is needed to determine iBCI candidacy.

Application to iBCI Eligibility:

For iBCI candidates, Delphi MD assessment can objectively demonstrate:

• Presence of voluntary cortical modulation capacity (preserved TEP responses)

• Intact motor cortex networks capable of generating decodable signals

• Adequate cortical excitability for signal acquisition

• Absence of severe cortical dysfunction that would preclude iBCI benefit

Critical Advantage:

TMS-EEG can be performed non-invasively at the bedside in 30-45 minutes without requiring patient cooperation beyond remaining still. For ventilator-dependent, non-verbal patients, this is transformative—proving neural capacity without the risks of prolonged MRI or need for behavioral responses.

4.2.2 Functional Near-Infrared Spectroscopy (fNIRS)

fNIRS offers complementary assessment capabilities with distinct advantages:

Technical Capabilities:

• Measures hemodynamic responses (oxygenated/deoxygenated hemoglobin) during attempted or imagined movement

• Provides spatial localization of motor cortex activation

• Demonstrates ~90% classification accuracy for motor imagery, ~100% for real movements

• Portable, bedside-compatible, no contraindications for metallic implants

• Resistance to motion artifacts compared to fMRI

• Higher temporal resolution than fMRI for detecting cortical activation

Evidence Base: Multiple studies demonstrate fNIRS can:

• Detect motor cortex activation during voluntary movement and motor imagery

• Differentiate between left/right hand movements based on hemispheric lateralization

• Identify preserved consciousness and voluntary modulation in minimally conscious patients

• Serve as a biomarker for neurorehabilitation potential after stroke and TBI

Application for iBCI:

fNIRS can objectively demonstrate:

• Presence of motor cortex activation during attempted movement

• Hemispheric specificity of motor intention

• Capacity for voluntary modulation of cortical hemodynamics

• Baseline signal quality predictive of BCI performance

Integration with Other Measures:

fNIRS complements TMS-EEG by:

• Providing functional activation patterns during attempted movement (not just responsiveness to stimulation)

• Offering a second modality for patients with suboptimal TMS or EEG signals

• Confirming spatial localization of motor networks

4.2.3 Quantitative EEG Measures

Sensorimotor Rhythm (SMR) Modulation:

• Measure 8-13 Hz oscillations over motor cortex

• Assess modulation during movement attempts or motor imagery

• Event-related desynchronization (ERD) demonstrates intact motor planning circuits

Motor-Related Cortical Potentials:

• Bereitschaftspotential (readiness potential) preceding movement attempts

• Demonstrates preserved motor intention signaling

• Can be measured even without overt movement

Perturbational Complexity Index (PCI):

• Derived from TMS-EEG responses

• Quantifies cortical complexity and integration

• Validated marker of conscious processing capacity

• Distinguishes minimally conscious from vegetative states

4.2.4 Specific Motor-Evoked Potentials (MEPs)

For patients with incomplete paralysis:

• TMS-evoked MEPs in remaining functional muscles

• Demonstrates preserved corticospinal pathway function

• Correlation with residual voluntary control

NOTE: Vendors sponsoring trials must VALIDATE any number of the above biomarkers because absence of proof is not proof of absence and what both FDA and CMS need is a biomarker that is specific like that, eg a biomarker that if negative IS indeed evidence that the person should NOT receive an iBCI. Vendors might consider combining them, eg, a person has at least one of those biomarkers present to qualify, or put another way, CMS can only decline coverage if the person has none of those biomarkers present.

4.2.5 What NOT to Require: fMRI Limitations

Why fMRI is problematic for iBCI eligibility screening:

1. Risk for Ventilator-Dependent Patients:

   • Prolonged supine positioning during extended scanning

   • Challenges maintaining ventilation in MRI environment

   • Medical risk often outweighs diagnostic benefit for screening

2. Not Necessary for Eligibility Determination:

   • Purpose is proving cortical integrity and modulability, not surgical targeting

   • Surgical targeting can use intraoperative mapping, CT-MRI fusion, or other methods

   • iBCI arrays sample broadly; precise preoperative localization less critical than for lesioning procedures

3. Accessibility and Cost:

   • fMRI requires specialized facilities, longer scan times

   • TMS-EEG and fNIRS are bedside-capable, more accessible

When fMRI may Be Appropriate:

• Pre-surgical planning when additional anatomical detail needed

• Research protocols investigating neural mechanisms

• When contraindications to TMS exist (seizure history, metallic implants)

5. Addressing the CMS Coverage Challenge

5.1 FDA Approval vs. CMS Coverage: Different Standards

FDA Standard: Safe and effective for intended use populationCMS Standard: Reasonable and necessary for Medicare beneficiaries

Historically, FDA approval takes 6-12 months for devices not requiring external technology assessment or MEDCAC review. CMS National Coverage Determinations (NCDs) require an additional 6-9 months minimum, with an average of 17 months from FDA approval to final coverage determination.

5.2 CMS Evidence Requirements Are More Stringent

CMS evaluates:

1. Quality of Individual Studies:

   • Randomized controlled trials strongly preferred

   • Evidence of effectiveness in Medicare-relevant population (typically 65+, multiple comorbidities)

   • Long-term durability of benefit (not just acute efficacy)

2. Relevance to Medicare Population:

   • Trial participants must reflect Medicare beneficiaries

   • Evidence of effectiveness in older adults with comorbidities

   • Consideration of differential risk-benefit by subgroup

3. Strength of Body of Evidence:

   • Multiple studies from independent research groups preferred

   • Consistency of findings across studies

   • Magnitude and clinical significance of benefit

5.3 Coverage with Evidence Development (CED)

CMS may impose Coverage with Evidence Development requiring:

• Device use only within CMS-approved clinical studies

• Ongoing data collection to assess appropriateness

• Reconsideration of coverage after evidence accumulation

Risk: CED is expected to severely limit patient access while generating additional evidence.

5.4 Local Coverage Determinations (LCDs)

Without a National Coverage Determination, access depends on geographic location:

• Medicare Administrative Contractors (MACs) make local coverage decisions

• Significant regional variation in coverage policies

• "Coverage lottery" based on where patient lives

• Example: DEKA Arm has inconsistent Medicare coverage across jurisdictions

5.5 The Biomarker Solution for CMS

CMS wants to pay only for patients who will benefit. The challenge is defining who will benefit using objective criteria.

Strategy:

1. Establish Validated Biomarker Criteria:

   • Include TMS-EEG, fNIRS, or qEEG assessments in pivotal trials

   • Demonstrate correlation between pre-implant biomarkers and clinical outcomes

   • Create objective eligibility criteria based on cortical integrity measures

2. Build Evidence of Biomarker-Outcome Relationships:

   • Show that patients meeting biomarker thresholds achieve clinically meaningful benefit

   • Demonstrate that patients NOT meeting thresholds have poor outcomes

   • Provide CMS with clear "appropriate candidate" criteria

3. Avoid One-Size-Fits-All Disease Trials:

   • Rather than attempting trials that "scoop up every rare disease" (logistically impossible)

   • Focus on functional criteria plus biomarkers that work across etiologies

   • Demonstrate principle that cortical integrity—not disease label—predicts success

4. Facilitate Coverage Determination:

   • CMS can adopt biomarker-based criteria in coverage policies

   • Clear objective measures reduce coverage denials based on subjective judgments

   • Reduces administrative burden for CMS, payers, and providers

6. Stratified Evidence Requirements Across Regulatory Stages

6.1 IDE Stage: Feasibility and Safety

Primary Goals:

• Demonstrate acceptable safety profile

• Preliminary evidence of device performance

• Establish feasibility of approach

Patient Population Strategy:

• Include diverse etiologies (2-3 patients per condition minimum)

• Document functional deficits consistently across etiologies

• Perform biomarker assessments on all participants

• Demonstrate device works regardless of underlying disease

Evidence Generated:

• Safety data across diverse etiologies

• Preliminary effectiveness signals

• Biomarker-outcome correlations (preliminary)

• Proof of principle for functional indication approach

6.2 PMA Stage: Pivotal Evidence

Primary Goals:

• Establish substantial evidence of safety and effectiveness

• Validate clinical outcome assessments

• Generate sufficient data for CMS consideration

Patient Population Strategy:

• Enroll based on functional criteria, not disease labels

• Stratify by baseline functional status and biomarker profile

• Ensure adequate representation of Medicare-age patients (if pursuing CMS coverage early)

• Power study for primary effectiveness endpoint across full cohort

• Plan secondary analyses by etiology if needed

Key Design Elements:

• Pre-specify biomarker eligibility criteria

• Include biomarker substudies with outcome correlation

• Validate functional outcome measures

• Document real-world benefit (home use, caregiver burden, quality of life)

• Plan long-term follow-up (2-5 years) for CMS consideration

Evidence Generated:

• Substantial evidence of safety across etiologies

• Effectiveness data supporting functional indication

• Validated biomarker-based eligibility criteria

• Evidence package suitable for NCD application

6.3 Post-Approval: Real-World Evidence

Ongoing Evidence Generation:

• Post-market surveillance studies

• Registry data across diverse patient populations

• Long-term durability and reliability data

• Health economics and quality of life data

Purpose:

• Support LCD development by individual MACs

• Provide evidence for indication expansion

• Demonstrate benefit in underrepresented populations

• Support international regulatory submissions

7. Specific Biomarker Implementation Recommendations

7.1 Tiered Assessment Approach

Tier 1 (Minimum for All Candidates):

• Quantitative EEG with assessment of sensorimotor rhythms

• Motor imagery task with ERD/ERS quantification

• Clinical assessment of cognitive capacity and motivation

Tier 2 (Standard Assessment):

• TMS-EEG assessment (Delphi MD or equivalent)

  • Motor cortex reactivity

  • Interhemispheric connectivity

  • Cortical complexity index

• OR fNIRS assessment

  • Motor cortex activation during attempted movement

  • Hemispheric lateralization

  • Motor imagery response

Tier 3 (Comprehensive/Research):

• Both TMS-EEG and fNIRS

• Additional MEP testing if residual motor function present

• Multimodal integration for optimal candidate selection

7.2 Threshold Criteria Development

Pilot Phase (IDE):

• Establish feasibility of biomarker assessments

• Collect preliminary data on biomarker-outcome relationships

• Refine assessment protocols

• Identify candidate threshold values

Pivotal Phase (PMA):

• Pre-specify biomarker eligibility criteria based on pilot data

• Validate thresholds prospectively

• Demonstrate positive predictive value of meeting criteria

• Document outcomes for patients not meeting criteria (if enrolled)

Post-Approval:

• Refine criteria based on expanded real-world experience

• Potentially relax initial conservative thresholds

• Identify patient subgroups with exceptional benefit

7.3 Biomarker Assessment Protocol Standards

Standardization Requirements:

• Validated, reproducible protocols

• Quality control procedures

• Operator training and certification

• Inter-rater reliability assessment

• Equipment calibration standards

Documentation:

• Raw data archiving

• Analysis methods pre-specified

• Blinded assessment when possible

• Independent core lab review for pivotal trials

8. Addressing Counterarguments and the Critical Device vs. Disease Risk Distinction

8.1 "Different Etiologies Have Different Surgical Risks" - The Core Fallacy

The FDA Tendency:

FDA reviewers may request additional safety data for patients with specific etiologies, arguing: "DMD patients have cardiomyopathy that increases anesthesia risk, therefore we need separate safety studies for this population."

THIS LOGIC MUST BE FORCEFULLY REJECTED. HERE IS WHY:

The Fundamental Distinction:

There are exactly TWO types of risk:

1. Device-Specific Risk: Risks directly caused by the device itself (electrode failure, infection from implant, neural damage from stimulation)

2. Patient-Specific/Disease-Specific Risk: Pre-existing patient conditions affecting any surgery (cardiac status, coagulopathy, immune suppression)

FDA's Proper Role:

FDA is charged with evaluating DEVICE safety and effectiveness. The agency's statutory authority under the Federal Food, Drug, and Cosmetic Act is to ensure medical devices are safe and effective for their intended use. This means:

• Does the device itself pose unacceptable risks?

• Does the device work for its intended purpose?

FDA's Improper Role (Practicing Medicine):

FDA is NOT authorized to:

• Determine which patients can safely undergo surgery

• Make individual risk-benefit determinations for specific patient populations

• Exclude patients based on general surgical risks unrelated to the device

The DMD Example:

A DMD patient's cardiomyopathy creates anesthesia risk for:

• Orthopedic surgery

• Dental extractions under general anesthesia

• Appendectomy

• Spinal fusion

• AND iBCI implantation

The cardiac risk is NOT caused by the iBCI device. The cardiac risk is caused by DMD. Skilled anesthesiologists manage these patients through surgery daily. This is standard medical practice.

If FDA Logic Were Applied Consistently:

Following FDA's potential reasoning to its logical conclusion:

• Wheelchairs couldn't be indicated for DMD patients (pressure ulcer risk due to poor tissue perfusion)

• Deep brain stimulators couldn't be indicated for Parkinson's patients with cardiac disease

• Pacemakers couldn't be indicated for elderly patients with multiple comorbidities

• Every device would require separate trials for every possible comorbidity

This is absurd and unworkable.

8.2 The Pushback Strategy: What Companies MUST Do

In Pre-Submission Meetings:

Companies must explicitly state and request written confirmation:

"We understand that FDA's role is to assess device-specific safety and effectiveness, not to practice medicine by determining which patients can safely undergo surgery. Perioperative risks that vary by patient comorbidity—such as anesthesia risk in patients with cardiac disease—should not dictate device indication boundaries when the device mechanism itself addresses a common functional deficit. We propose that such considerations be addressed in the 'Warnings and Precautions' section as clinical considerations for physicians and anesthesiologists, NOT as exclusions from the Indications for Use. Question for FDA: Does the agency agree that patient-specific surgical risks (cardiac comorbidities, coagulopathy, etc.) that are not caused by or exacerbated by the device itself should not result in exclusion of entire patient populations from the indication for use?"

Demand Written Response:

This question must be asked formally in Pre-Sub meetings and the FDA response documented in writing. This creates a record that can be:

• Referenced in future regulatory submissions

• Cited by other companies

• Used in advocacy efforts

• Appealed if FDA later contradicts its own guidance

Cite FDA's Own Policy:

FDA guidance documents repeatedly emphasize:

• "FDA does not practice medicine"

• "Physicians retain clinical judgment for individual patient selection"

• Device labeling should not constrain appropriate physician decision-making

Companies should quote these exact phrases back to FDA when pushback occurs.

8.3 The Labeling Strategy: Neutering CMS's Weaponization

The Problem:

Even if FDA agrees in principle that disease-specific surgical risks shouldn't exclude populations, FDA reviewers will want SOMETHING in the labeling about these risks. If poorly written, CMS will weaponize this language:

BAD LABELING (CMS Will Exploit):

❌ "Warnings: Patients with cardiomyopathy are at increased risk during device implantation"

How CMS Will Use This:

• "The manufacturer warns against use in patients with cardiomyopathy"

• "Coverage denied - patient has DMD-related cardiomyopathy"

• "Not medically reasonable and necessary per manufacturer's own warnings"

GOOD LABELING (Defangs CMS):

✅ "Clinical Considerations: As with any neurosurgical procedure requiring general anesthesia, patients with significant cardiac comorbidities require careful perioperative management. Standard anesthetic monitoring and cardiology consultation should be employed as clinically indicated. These considerations apply to all neurosurgical procedures and are not specific to this device."

Why This Works:

• Acknowledges the issue (satisfies FDA)

• Frames as "clinical consideration" not "warning" or "contraindication"

• Explicitly states this is NOT device-specific

• Puts responsibility on clinical team (where it belongs)

• Difficult for CMS to twist into exclusion criterion

8.4 Building the Evidentiary Record

What Companies Should Do in Pivotal Trials:

1. Explicitly Track Device-Specific vs. Patient-Specific Adverse Events:

Create adverse event categorization:

• Device-Related: Infection, electrode migration, hemorrhage at implant site

• Procedure-Related (Non-Device): Anesthesia complications, positioning injury, wound healing

• Disease-Related: Disease progression, comorbidity exacerbation

• Document That Device-Specific Safety Is Consistent Across Etiologies:

Analysis showing:

• Infection rates similar in ALS vs. DMD vs. SCI patients

• Device malfunction rates similar across etiologies

• Neural tissue response similar across etiologies

• ONLY the procedure-related (non-device) complications vary by comorbidity

• Include High-Risk Patients in Pivotal Trials:

Intentionally enroll DMD patients with cardiomyopathy, demonstrate successful perioperative management, document outcomes. Show that:

• With appropriate anesthetic management, surgery is safe

• Device outcomes are excellent regardless of cardiac comorbidity

• Any complications are managed per standard protocols

The Compelling Narrative:

"Our pivotal trial included 5 patients with DMD and known cardiomyopathy. All underwent successful implantation with cardiology consultation and specialized anesthetic protocols. There were zero device-related complications in this subgroup. One patient experienced transient hypotension during anesthesia (managed successfully), which would occur in this patient during ANY surgery requiring general anesthesia. Device functionality and clinical outcomes in DMD patients were equivalent to other etiologies. This demonstrates that appropriate patient selection and perioperative management—not exclusion from access—is the appropriate clinical approach."

8.5 The Precedent Argument: Other High-Risk Device Implants

Examples to Cite in FDA Meetings:

Deep Brain Stimulation (DBS):

• Indicated for Parkinson's disease and essential tremor

• Many elderly patients with cardiac comorbidities

• No separate trials required for patients with cardiac disease

• Labeling includes standard perioperative considerations

• Outcome: Physicians manage individual risk-benefit; FDA doesn't exclude populations

Cardiac Resynchronization Therapy (CRT) Devices:

• Patients BY DEFINITION have severe heart failure

• Extremely high perioperative risk population

• FDA doesn't require separate trials for different causes of heart failure (ischemic vs. non-ischemic cardiomyopathy)

• Outcome: Functional indication (heart failure with specific criteria), not etiology-specific

Ventricular Assist Devices (VADs):

• Highest-risk patient population possible (end-stage heart failure)

• Includes patients with diabetes, renal failure, coagulopathy

• Not restricted to specific cardiac diagnoses

• Outcome: Functional criteria (stage D heart failure), comorbidity management expected

Spinal Cord Stimulators:

• Indicated for chronic pain regardless of etiology

• Used in patients with bleeding disorders, cardiac disease, immunosuppression

• Individual risk assessment expected

• Outcome: Functional indication, physician discretion on risk management

The Consistent Principle:

Across all precedent devices, FDA recognizes that:

1. General surgical/medical comorbidities are managed by the clinical team

2. Device indications focus on the condition the device treats

3. Warnings/Precautions address clinical considerations without excluding populations

4. Physician judgment determines individual appropriateness

8.6 The Congressional/Policy Angle

If needed, the iBCI-CC and patient advocacy groups could consider:

Formal Citizen Petition to FDA:

Requesting clarification that:

• Device indications should not be restricted based on general surgical risks

• Perioperative management of patient comorbidities is not within FDA's regulatory purview

• Labeling should support physician clinical judgment, not constrain it

Engagement with Congressional Oversight Committees:

If FDA continues to demand disease-specific trials based on non-device risks:

• This creates access barriers for rare disease patients

• This conflicts with FDA's stated policy of not practicing medicine

• This imposes unnecessary costs ($millions per additional trial)

• This delays access for vulnerable populations

Public Comment During Regulatory Proceedings:

When iBCI NCDs are under CMS consideration:

• Patient advocates should submit comments emphasizing the device/disease risk distinction

• Clinicians should explain standard perioperative risk management

• Professional societies should provide expert testimony

8.7 The Existential Importance of Getting This Right

If FDA Succeeds in Conflating Device and Disease Risk:

The consequences are catastrophic:

• Every etiology requires separate safety trials (impossible for rare diseases)

• CMS will deny coverage based on labeling warnings

• Only "clean" patients with no comorbidities qualify (virtually no one)

• The entire functional indication framework collapses

If The iBCI Community Successfully Defends the Distinction:

The benefits cascade:

• Functional indications work as intended

• Physicians retain clinical judgment

• Patients with complex medical histories can access technology

• Precedent established for all future neurotechnology

This is not a minor regulatory technicality. This is THE central battle that will determine whether iBCI technology serves all who could benefit, or only a narrow slice of "perfect" patients who don't exist.

The time to fight this battle is NOW, in Pre-Sub meetings, before language gets locked into pivotal trial designs and FDA review precedents.

8.2 "FDA Wants Disease-Specific Evidence"

Response:

FDA guidance for iBCI focuses on "patients with paralysis," not specific diseases. FDA has approved numerous functional indications in neurorehabilitation. The Pre-Submission (Pre-Sub) process allows sponsors to formally request feedback on functional indication language with supporting precedent.

Action Items:

• Leverage Pre-Sub process proactively

• Request formal meetings with senior review staff

• Cite multiple functional indication precedents (MyoPro, NuedEXta, InterStim, Indego)

• Request written documentation of any concerns about functional approaches

8.3 "Heterogeneous Trials Are Too Complex"

Response:

Properly designed functional indication trials are MORE scientifically rigorous, not less:

Scientific Advantages:

• Demonstrates mechanism targets common neurophysiological pathway

• Proves concept works regardless of etiology (stronger evidence of validity)

• Tests device in clinically representative population

• Biomarker-based eligibility ensures homogeneity where it matters (cortical capacity)

Practical Advantages:

• Broader recruitment accelerates enrollment

• More generalizable results

• Single trial supports broader indication

• Better reflects real-world clinical use

Statistical Approach:

• Primary analysis on full cohort meeting functional criteria

• Pre-specified subgroup analyses by etiology if needed

• Stratification by baseline functional severity and biomarker profile

• Adequate power for primary endpoint across full cohort

8.4 "CMS Won't Cover Without Disease-Specific Evidence"

Response:

CMS wants evidence that the treatment is "reasonable and necessary" for Medicare beneficiaries. What matters is:

1. Objective Selection Criteria: Biomarkers provide this

2. Evidence of Benefit: Demonstrated in pivotal trials

3. Durability: Long-term follow-up data

4. Clinical Significance: Real-world functional improvement

CMS increasingly recognizes value of biomarker-based precision medicine approaches. Clear eligibility criteria reduce inappropriate use and coverage disputes.

9. The Labeling Strategy: Indications vs. Warnings

9.1 The FDA-CMS Labeling Paradox

FDA and CMS use device labeling fundamentally differently:

FDA Perspective:

• Ensure safety and effectiveness for appropriate population

• Does not practice medicine

• Expects physicians to make individual patient assessments

CMS/Payer Perspective:

• Mine labeling for coverage denial justifications

• Interpret warnings/precautions as contraindications

• Use language to argue "not medically necessary" for specific patients

9.2 Strategic Labeling Approach

Indications for Use (Broad): "For adults with severe upper extremity motor impairment from any etiology who meet specified functional and cortical integrity criteria."

Warnings/Precautions (Carefully Crafted):

• Avoid language that can be weaponized for coverage denials

• Frame as clinical considerations, not exclusions

• Example: "Special Considerations for Patients with Cardiac Comorbidities" rather than "Contraindicated in patients with cardiac disease"

Patient Selection (Objective Criteria):

• Functional deficit thresholds (ARAT <10)

• Biomarker requirements (TMS-EEG, fNIRS, or equivalent)

• Cognitive capacity minimums

• Clear inclusion/exclusion criteria based on safety, not disease labels

9.3 Learning from Precedent Labeling

DEKA Arm Issues:

• "18 years or older" rather than "skeletally mature" (unnecessarily restrictive)

• "Amputation" versus "congenital limb deficiency" rather than "absent limb" (diagnostic unnecessarily)

• "To assist in activities of daily living" (vague, gave CMS latitude for arbitrary denial)

Better Example - Indego:

• "Individuals with spinal cord injury at levels T3 to L5"

• Encompasses traumatic AND non-traumatic etiologies

• Functional specification (ambulatory functions)

Optimal Approach:

• Functional deficit specification

• Objective eligibility biomarkers

• Etiology-agnostic language

• Clear patient selection criteria that satisfy both FDA and CMS

10. Community and Stakeholder Engagement

10.1 The iBCI-CC Role

The Implantable Brain-Computer Interface Collaborative Community, established in 2024 with FDA participation, represents a critical forum for:

• Developing consensus on functional indication frameworks

• Coordinating industry efforts toward common regulatory goals

• Engaging FDA proactively on policy questions

• Patient and caregiver advocacy

• Clinical outcome assessment development

Key Opportunity:

FDA has largely delegated iBCI policy development to iBCI-CC. The community must proactively advocate for functional indication approaches rather than accepting disease-specific defaults.

10.2 Formal Mechanisms for Influencing Policy

Pre-Submission (Pre-Sub) Process:

• Every company should use Pre-Sub strategically

• Request specific feedback on functional indication language

• Cite precedents comprehensively

• Request senior reviewer involvement

• Obtain written responses for the record

Public Workshops:

• Request FDA workshops specifically on functional vs. disease-specific indications for neurorehabilitation

• Engage NIH, CMS, patient advocates, clinicians, and industry

• Rather than requesting FDA, may be faster and more productive for iBCI-cc itself to host a public workshop!

Medical Device Development Tools (MDDT):

• Qualify biomarker assessment tools through MDDT program

• Establish TMS-EEG, fNIRS protocols as qualified methods

• Create regulatory precedent for biomarker-based eligibility

Citizen Petitions:

• Formal requests for FDA guidance on functional indications

• Typically slow but create public record: unlikely to be feasible in 2025 and 2026

• Can be supplemented with stakeholder meetings

10.3 Patient and Caregiver Leadership

Critical Insight:

Patients with disabilities, families, and treating physicians must lead this conversation. FDA and CMS are fundamentally reactive agencies responding to public health needs as articulated by stakeholders.

Action Items:

• Patient advocacy organizations should formally petition for functional indications

• Families should submit public comments during NCD processes

• Clinicians should provide expert testimony on the clinical rationale

• Professional societies should develop position statements

11. Implementation Roadmap

11.1 Immediate Actions (Next 6 Months)

For Industry:

• Conduct Pre-Sub meetings with FDA focusing on functional indication feasibility

• Cite this white paper and all precedent devices

• Request formal written responses to functional indication proposals

For iBCI-CC:

• Develop consensus statement on functional indications

• Engage FDA in formal dialogue

• Coordinate multi-company advocacy

• Develop standardized biomarker assessment protocols

For Researchers:

• Design IDE studies incorporating diverse etiologies

• Implement biomarker assessment protocols

• Generate preliminary biomarker-outcome data

• Publish methodology and rationale

For Patient Advocates:

• Submit formal comments to FDA and CMS supporting functional indications

• Participate in iBCI-CC meetings and working groups

• Connect with Congressional representatives on access issues

11.2 Near-Term Actions (6-18 Months)

For Industry:

• Incorporate functional criteria and biomarkers into pivotal trial designs

• Engage CMS Early Feedback Program for parallel review discussions

• Develop comprehensive evidence packages supporting functional indications

For iBCI-CC:

• Host public workshop on functional indications with FDA/CMS participation

• Develop guidance documents on biomarker-based eligibility assessment

• Coordinate outcome assessment tool validation across studies

For CMS:

• Provide early feedback on evidentiary requirements for NCD

• Consider parallel review for promising technologies

• Develop framework for biomarker-based coverage criteria

11.3 Long-Term Goals (18+ Months)

Regulatory Milestones:

• First iBCI approval with functional indication

• Establishment of qualified biomarker assessment methods via MDDT

• FDA guidance document on functional indications for neurotechnology

Coverage Milestones:

• NCD with biomarker-based eligibility criteria

• Widespread LCD adoption across MACs

• International regulatory approvals based on functional framework

Clinical Implementation:

• Standardized biomarker assessment available at iBCI centers

• Training programs for assessment performance and interpretation

• Real-world evidence demonstrating equitable access across etiologies

12. Conclusion: The Path Forward

The first iBCI approval will establish regulatory precedent for decades. Disease-specific indications will create access barriers the moment they are granted, orphaning patients with rare conditions who could benefit equally.

The stakes are clear:

• Accept narrow indications for short-term regulatory expediency, OR

• Advocate for functional indications that serve all appropriate patients

The evidence is compelling:

• FDA has approved functional indications for comparable neurorehabilitation devices

• Objective biomarkers can identify appropriate candidates regardless of etiology

• TMS-EEG, fNIRS, and quantitative EEG provide non-invasive assessment of cortical integrity

• CMS coverage can be facilitated through clear, biomarker-based eligibility criteria

• Scientific rigor is enhanced, not compromised, by functional approaches

The opportunity is time-limited:

Regulatory frameworks established during initial approvals become entrenched. Expanding narrow indications requires separate trials, regulatory submissions, and years of delay. Meanwhile, patients with rare conditions wait—or never gain access.

The call to action:

• iBCI Companies: Use Pre-Sub process to formally propose and defend functional indications

• iBCI-CC: Develop community consensus and coordinate advocacy with FDA/CMS

• FDA: Provide clear guidance supporting functional indications when scientifically justified

• CMS: Engage early through parallel review; adopt biomarker-based coverage frameworks

• Researchers: Design trials incorporating diverse etiologies and validated biomarkers

• Clinicians: Advocate for patient-centered indications reflecting clinical reality

• Patients and Families: Lead the charge for equitable access; participate in regulatory processes

The principle is simple:

Define success by function, not disease label. The technology does not discriminate by diagnosis. Neither should the indication for use.

13. References and Resources

13.1 FDA Guidance Documents

1. Implanted Brain-Computer Interface (BCI) Devices for Patients with Paralysis or Amputation - Non-clinical Testing and Clinical Considerations (2021)https://www.fda.gov/regulatory-information/search-fda-guidance-documents/implanted-brain-computer-interface-bci-devices-patients-paralysis-or-amputation-non-clinical-testing

2. Guidance Document for the Preparation of Premarket Notification [510(k)] Applications for Mechanical and Powered Wheelchairshttps://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-document-preparation-premarket-notification-510k-applications-mechanical-and-powered

3. Content of Premarket Submissions for Device Software Functions (2023)Referenced in BCI guidance for software validation requirements

4. Information to Support a Claim of Electromagnetic Compatibility (EMC) for Electrically Powered Medical DevicesCritical for implanted device submissions

5. Design Considerations for Devices Intended for Home UseRelevant for iBCI systems used in community settings

13.2 FDA Public Workshops and Proceedings

1. FDA-NIH Joint Workshop: Developing Implanted Brain-Computer Interface Clinical Outcome Assessments (September 2024)

   
   

   https://www.fda.gov/news-events/fda-meetings-conferences-and-workshops/public-workshop-food-and-drug-administrationnational-institutes-health-joint-workshop-developing

   
   

   Transcript available at regulations.gov, Docket No. FDA-2024-N-2976

13.3 CMS Coverage Resources

1. Coverage with Evidence Development Guidance (Updated August 2024)https://www.cms.gov/medicare/coverage/evidence

2. Medicare Coverage Determination Processhttps://www.cms.gov/medicare/coverage/determination-process

3. National Coverage Determination Process & Timelinehttps://www.cms.gov/cms-guide-medical-technology-companies-and-other-interested-parties/coverage/national-coverage-determination-process-timeline

4. Medicare Coverage Databasehttps://www.cms.gov/medicare-coverage-database/

5. NIH SEED Program - Reimbursement Knowledge Guide for Medical DevicesComprehensive resource on Medicare coverage pathways

13.4 Regulatory Precedent Devices

1. MyoPro (Myomo Inc.) - K113149510(k) clearance for upper extremity weakness, etiology-agnostic

2. Indego Exoskeleton - Product Code PHLSpinal cord injury (traumatic and non-traumatic etiologies)

3. DEKA Arm - DEN120016510(k) summary illustrating labeling challenges

4. InterStim (Medtronic)Functional indication for urinary/bowel dysfunction

5. NuedEXta (Avanir Pharmaceuticals)Drug approval for pseudobulbar affect across etiologies

13.5 Biomarker Assessment Technologies

1. QuantalX Delphi MD Systemhttps://quantalx.com/delphi-md/

   • FDA Breakthrough Device Designation

   • FDA 510(k) clearance (nerve stimulation)

   • CPT Code: 0858T

2. TMS-EEG Academic References:

   • Hallett M. Transcranial magnetic stimulation: a primer. Neuron 2007;55(2):187-199

   • Chen R, Hallett M. The time course of changes in motor cortex excitability associated with voluntary movement. Can J Neurol Sci 1999;26(3):163-169

   • Sohn YH et al. Excitability of the ipsilateral motor cortex during phasic voluntary hand movement. Brain Res 2003;962(1-2):176-181

   • Leodori G, Hallett M. Intracortical inhibition and surround inhibition in the motor cortex: A TMS-EEG study. Front Neurosci 2019

3. fNIRS Academic References:

   • Leff DR et al. Assessment of the cerebral cortex during motor task behaviours in adults: a systematic review of functional near infrared spectroscopy (fNIRS) studies. Neuroimage 2011;54(4):2922-2936

   • Functional near-infrared spectroscopy for detecting consciousness after acute severe brain injury. PNAS 2024;121(35)

   • Sensor-level classification of motor-related brain activity using fNIRS. Sensors 2020;20(8):2362

13.6 iBCI-CC and Stakeholder Organizations

1. Implantable Brain-Computer Interface Collaborative Community (iBCI-CC)Established March 2024 by Mass General Brigham with FDA participationhttps://www.massgeneralbrigham.org/en/about/newsroom/press-releases/implantable-brain-computer-interface-collaborative-community

2. NIH BRAIN Initiative10 years of funding supporting paradigm-shifting neurotechnology research

3. BCI SocietyInternational organization for BCI research and development

13.7 Additional Scientific and Policy Resources

1. GAO Report: Brain-Computer Interfaces - Science & Tech Spotlight (GAO-25-106952)Comprehensive overview of BCI landscape, regulatory challenges, and policy considerations

2. Evidence supporting FDA approval and CMS national coverage determinations for novel medical products, 2005-2016Cross-sectional study comparing FDA and CMS evidence requirementsAnn Intern Med 2018

3. Precision Neuroscience FDA Clearance (April 2025)Recent example of iBCI regulatory pathway for intraoperative use

4. ONWARD Medical - ARC-BCI Breakthrough Device Designation (February 2024)Combined BCI and spinal cord stimulation approach

13.8 Key Academic Research on Patient Selection

1. Mark Hallett's Research Portfolio (NINDS)

   • Transcranial magnetic stimulation methodologies

   • Motor cortex excitability assessment

   • Voluntary movement neurophysiology

   • Intracortical inhibition and facilitation

   • Surround inhibition mechanisms

2. QuantalX Academic Publications:

   • Zifman et al. Direct electrophysiological imaging (DELPHI) methodology. Front Aging Neurosci 2019

   • Levy-Lamdan et al. White matter integrity evaluation using DELPHI. Front Aging Neurosci 2020

   • Meidan et al. DELPHI in Parkinson's disease diagnosis. Parkinsonism Relat Disord

   • TMS-evoked potentials in early Parkinson's disease. npj Parkinson's Dis 2024

Appendix A: Sample Functional Indication Language

Option 1: Comprehensive Functional Indication

INDICATIONS FOR USE:

The [Device Name] is indicated for use in adults (18 years and older) with severe bilateral upper extremity motor impairment from any neurological etiology who meet the following criteria:

Functional Criteria:

• Bilateral upper extremity dysfunction with Action Research Arm Test (ARAT) score ≤10 in both upper extremities, OR equivalent validated functional assessment demonstrating inability to perform activities of daily living requiring hand function

• Preserved cognitive capacity sufficient for device training and use (Montreal Cognitive Assessment ≥18 or equivalent)

• Motivated to participate in device training and long-term use

Cortical Integrity Criteria: Patient must demonstrate preserved capacity for voluntary cortical modulation as evidenced by ONE OR MORE of the following:

• TMS-evoked potentials (TEP) demonstrating cortical reactivity and connectivity within specified parameters as measured by validated TMS-EEG assessment

• Functional near-infrared spectroscopy (fNIRS) demonstrating motor cortex activation during attempted or imagined movement

• Quantitative EEG demonstrating sensorimotor rhythm modulation during motor imagery tasks

• Other validated neurophysiological assessment demonstrating preserved cortical signal generation capacity

Option 2: Streamlined Functional Indication

INDICATIONS FOR USE:

The [Device Name] is indicated to restore communication and/or control capabilities in adults with severe motor impairment who have:

• Documented inability to perform functional hand movements (ARAT ≤10 bilaterally or equivalent)

• Preserved cognitive capacity (MOCA ≥18 or equivalent)

• Objective evidence of cortical integrity and voluntary modulation capacity as demonstrated by validated neurophysiological assessment

The device is intended for use regardless of the underlying neurological etiology causing the motor impairment.

Option 3: Precedent-Based Language (Following MyoPro Model)

INDICATIONS FOR USE:

The [Device Name] is an assistive device that restores communication and motor control for individuals with severe upper extremity paralysis from any neurological cause. The user's cortical neural activity is decoded by the system to control external devices or communication interfaces. The device is indicated for adults with:

• Bilateral upper extremity motor impairment preventing functional hand use

• Preserved cognitive capacity for device operation

• Demonstrated cortical signal generation capacity via pre-implant neurophysiological assessment

Appendix B: Biomarker Assessment Protocol Template

B.1 TMS-EEG Assessment Protocol

Equipment Requirements:

• TMS-compatible EEG system (≥32 channels)

• FDA-cleared TMS stimulator with figure-8 coil

• Stereotactic neuronavigation system (optional but recommended)

Participant Preparation:

• Screen for TMS safety contraindications

• Position comfortably in reclining chair

• Apply EEG cap with impedances <5kΩ

• Determine motor hotspot and resting motor threshold (RMT)

Stimulation Protocol:

• Target: Bilateral primary motor cortex (M1)

• Intensity: 80-120% RMT

• Inter-stimulus interval: >5 seconds to avoid carryover

• Number of trials: 100-200 per hemisphere

• Additional targets: Dorsolateral prefrontal cortex (DLPFC), premotor cortex

Data Acquisition:

• Sampling rate: ≥5000 Hz

• Recording duration: 500ms pre-stimulus, 1000ms post-stimulus

• Concurrent EMG recording from target muscles

• Document adverse events

Analysis Parameters:

• TEP components: P30, N45, P60, N100, P180 latencies and amplitudes

• Cortical reactivity: Global mean field power (GMFP)

• Connectivity: Interhemispheric coherence, phase synchrony

• Complexity: Perturbational Complexity Index (PCI)

Quality Control:

• Artifact rejection criteria pre-specified

• Independent blinded review of 10% of studies

• Inter-rater reliability assessment

• Equipment calibration verification

B.2 fNIRS Assessment Protocol

Equipment Requirements:

• Continuous-wave or frequency-domain fNIRS system

• Minimum 20 channels covering bilateral motor cortex

• Source-detector separation: 3cm

• Wavelengths: 760nm and 850nm (minimum)

Participant Preparation:

• Position comfortably with head stabilized

• Apply optodes over bilateral sensorimotor cortex

• Verify signal quality on all channels

• Instruct on motor imagery tasks

Task Protocol:

• Block design: 20-30 second blocks

• Conditions: Rest, attempted right hand movement, attempted left hand movement, motor imagery

• Repetitions: 10-15 blocks per condition

• Cues: Visual or auditory prompts

Data Acquisition:

• Sampling rate: ≥10 Hz

• Recording duration: 10-15 minutes total

• Concurrent monitoring of physiology (heart rate, respiration)

• Video recording of participant (optional)

Analysis Parameters:

• Oxygenated hemoglobin (HbO) concentration changes

• Deoxygenated hemoglobin (HbR) concentration changes

• Hemispheric lateralization index

• Peak amplitude and time-to-peak

• Classification accuracy for left vs. right movements

Eligibility Thresholds (Example):

• HbO increase ≥0.5 μM during motor attempt

• Hemispheric lateralization index ≥1.5

• Task-related activation in ≥50% of motor cortex channels

B.3 Quantitative EEG Protocol

Equipment Requirements:

• High-density EEG system (≥64 channels preferred)

• Sampling rate ≥1000 Hz

• Impedances <5kΩ

Recording Protocol:

• Resting state: 5 minutes eyes closed, 5 minutes eyes open

• Motor imagery: Cued tasks (right hand, left hand, both hands, feet)

• Attempted movement: If any residual motor function

Analysis Parameters:

• Sensorimotor rhythm (8-13 Hz) event-related desynchronization

• Motor-related cortical potential (Bereitschaftspotential)

• Coherence across motor networks

• Power spectral density in motor cortex regions

Eligibility Criteria (Example):

• Demonstrable ERD during motor imagery (≥20% power reduction)

• Presence of Bereitschaftspotential prior to movement attempt

• Normal or near-normal background EEG (absence of severe slowing)

Appendix C: Comparative Analysis of Regulatory Pathways

C.1 Disease-Specific vs. Functional Indication Timelines

Milestone	Disease-Specific Approach	Functional Approach
Initial Approval	ALS-only indication	Functional deficit + biomarker
Timeline to first approval	3-5 years	3-5 years (similar)
Initial addressable population	~5,000 patients/year (US)	~50,000 patients/year (US)
First Expansion	Add SCI indication	Already included
Additional timeline	+2-3 years, new trial	N/A
Second Expansion	Add MS indication	Already included
Additional timeline	+2-3 years, new trial	N/A
Rare Disease Access	Requires HDE or off-label	Included if meet criteria
Timeline	Never, or 10+ years	Immediate

C.2 Evidence Requirements Comparison

Regulatory Stage	Disease-Specific	Functional + Biomarker
IDE Feasibility	Single etiology, n=3-10	Multiple etiologies, n=6-15
Evidence generated	Safety in one disease	Safety across etiologies
PMA Pivotal	Single etiology, n=30-100	Functional criteria, n=50-150
Primary endpoint	Function improvement in disease X	Function improvement in severe UE impairment
Subgroup analysis	Limited	By etiology, biomarker, baseline severity
Generalizability	Limited to one disease	Broad across causes
Post-Market	Separate studies for each expansion	Registry data across all etiologies

C.3 Cost-Benefit Analysis

Disease-Specific Approach Costs:

• Initial pivotal trial: $20-40M

• Each expansion trial: $15-30M

• Total for 3 indications: $65-130M

• Timeline: 9-15 years for full access

• Patients served in decade 1: ~50,000

Functional Approach Costs:

• Single pivotal trial: $30-50M (larger, more complex)

• Biomarker validation substudies: $5-10M

• Post-market registry: $10-20M

• Total: $45-80M

• Timeline: 3-5 years for full access

• Patients served in decade 1: ~500,000

ROI Considerations:

• Broader initial market access

• Single regulatory submission

• Reduced time-to-market for full population

• Stronger scientific foundation

• Better alignment with precision medicine principles

Appendix D: Patient Vignettes Illustrating Need for Functional Indications

Case 1: Duchenne Muscular Dystrophy

Patient: 28-year-old male with DMD, ventilator-dependent, quadriplegicCognitive Status: Intact, college-educated, motivatedCurrent Capability: Eye gaze only communicationUnder Disease-Specific Indication: Excluded (not ALS/SCI/stroke)Under Functional Indication: Eligible - meets functional criteria, excellent TMS-EEG biomarkers demonstrating preserved motor cortexBenefit Potential: High - young, stable disease, long life expectancy with iBCI

Case 2: Multiple Sclerosis (Locked-In)

Patient: 45-year-old female with progressive MSPresentation: Severe brainstem involvement, quadriplegia, anarthriaCurrent Capability: Yes/no with eye movements onlyUnder Disease-Specific Indication: Excluded (not primary target disease)Under Functional Indication: Eligible - functional deficits meet criteria, fNIRS shows robust motor cortex activationBenefit Potential: High - cognitively intact, motivated, caregiver support

Case 3: Charcot-Marie-Tooth Disease

Patient: 35-year-old male with severe CMTPresentation: Complete hand paralysis, proximal weakness progressingEmployment: Software engineer unable to workUnder Disease-Specific Indication: Excluded (peripheral neuropathy, not CNS disease)Under Functional Indication: Eligible - meets functional criteria, excellent qEEG showing strong motor imagery signalsBenefit Potential: Exceptional - could return to gainful employment, young, stable

Case 4: Spinocerebellar Ataxia

Patient: 52-year-old female with SCA3Presentation: Severe ataxia, inability to use hands for any functional taskCurrent Status: Dependent for all ADLsUnder Disease-Specific Indication: Excluded (cerebellar disease)Under Functional Indication: Potentially eligible - meets functional criteria; biomarker assessment would determine cortical integrityBenefit Potential: Moderate-high if motor cortex preserved

Case 5: Post-Cardiac Arrest Anoxic Brain Injury

Patient: 62-year-old male with anoxic injuryPresentation: Spastic quadriplegia, preserved consciousnessCognitive Status: Variable, requires careful assessmentUnder Disease-Specific Indication: Excluded (not standard etiology)Under Functional Indication: Biomarker assessment determines eligibility - TMS-EEG would reveal extent of cortical preservationBenefit Potential: Variable - depends on cortical integrity, but shouldn't be excluded a priori

Closing Statement

This white paper represents a call to action for the entire iBCI community. The regulatory decisions made in the next 2-3 years will determine whether these transformative technologies serve all who could benefit, or only those whose diseases happen to match narrow indication labels.

The path forward requires:

• Courage to challenge regulatory defaults and advocate for functional approaches

• Rigor in developing and validating biomarker-based eligibility criteria

• Collaboration across industry, academia, advocacy, and regulatory agencies

• Commitment to equitable access as a founding principle

The technology is ready. The scientific foundation exists. The regulatory precedents are established. What remains is the will to pursue the harder path now, to serve all patients tomorrow.

For further information or to contribute to this effort, please contact:

Document Version: 1.0 (Draft to be reviewed by iBCI-CC Review)

Date: ???

Authors: iBCI Community Stakeholders ???

Contact: [To be determined by iBCI-CC] ???

DRAFT: This white paper is intended to facilitate discussion and does not represent official guidance from FDA, CMS, or any regulatory authority. Companies should consult with regulatory affairs professionals and conduct formal Pre-Submission meetings with FDA before finalizing regulatory strategies. ???