Transcript Title of Presentation Date

Brain Interfaces: A Regulatory
Perspective
February 28, 2013
Victor Krauthamer, PhD
Acting Director, Division of Neurological and Physical Medical Devices, ODE,
and
Director, Division of Physics, OSEL
Center for Devices and Radiological Health
and
Kristen Bowsher, PhD
Electrical and Biomedical Engineer
Division of Neurological and Physical Medicine Devices
American Society for Experimental NeuroTherapeutics | 15th Annual Meeting
Disclosures
None
American Society for Experimental NeuroTherapeutics | 15th Annual Meeting
Learning Objectives
• CDRH device regulation is risk-based so that the
Benefit-to-Risk ratio is a factor for approvals
• Device classification is risk-based: Class I –III
depending on risk and ability to mitigate risk
• Human trials with significant risks require
approved investigational device exemptions
• A reasonable assurance of safety and
effectiveness is necessary for new devices
• Fundamental scientific research informs
regulatory decisions
American Society for Experimental NeuroTherapeutics | 15th Annual Meeting
Center for
Food
Safety &
Applied
Nutrition
Center for
Drug
Evaluation &
Research
Center for
Biologics
Evaluation &
Research
Center for
Tobacco
Products
Center for
Devices &
Radiological
Health
Center for
Veterinary
Medicine
National
Center for
Toxicological
Research
FDA Organizational Structure
FDA
Office of the
Commissioner
CVM
CFSAN
CDER
CBER
CDRH
CTP
NCTR
Center for Devices and Radiological Health
(CDRH)
ODE
OC
OSB
CDRH
OCER
OIR
OMO
OSEL
Office of Device
Evaluation
Division of Cardiovascular
Devices
Division of Surgical
Devices
Division of Orthopedic
Devices
Division of Ophthalmic
and ENT Devices
8 Branches
4 Branches
5 Branches
4 Branches
Division of
Neurological and
Physical Medicine
Devices
Neurostimulation
Devices Branch
CDRH/ODE
Reorganization
November 1, 2012
Neurodiagnostic and
Neurosurgical
Devices Branch
Physical Medicine
and
Neurotherapeutic
Devices Branch
Division of Reproductive,
Gastro-Renal and
Urological Devices
Division of
Anesthesiology, General
Hospital, Infection,
Dental Devices
4 Branches
6 Branches
Division of Neurological and Physical Medicine Devices
Division Director
Victor Krauthamer, PhD (acting)
Deputy Director
Joyce Whang, PhD (acting)
NSDB
Neurostimulation Devices Branch
Chief – vacant
Cortical Stimulators
Deep Brain Stimulators (DBS)
Peripheral Nerve Stimulators
(PNS)
Spinal Cord Stimulators (SCS)
Vagus Nerve Stimulations (VNS)
Other cranial nerve stimulators
NNDB
Neurodiagnostic and
Neurosurgical Devices Branch
Chief - Quynh Hoang
Cranioplasty devices
Dural Sealants
Dura mater substitutes
Electroencephalogram
(EEG)
Dx Electromyography
Neurodiagnostic devices
Neuroendoscopes
Nerve locators/monitors
Neurosurgical drills
Neurosurgical instruments
Neurovascular devices
RF ablation devices
Stereotaxic devices
Clot retrievers
PNDB
Physical Medicine and
Neurotherapeutic Devices Branch
Chief – vacant
Brain-Computer Interfaces
Cranial/limb/truncal orthoses
Exoskeletons
Cranial Electrotherapy Stimulator
Diathermy
Electroconvulsive Therapy (ECT)
Functional Electrical Stimulators
Iontophoresis devices
Powered muscle stimulators
Transcranial Magnetic Stimulators
(TMS)
Transcutaneous Electrical Nerve
Stimulators (TENS)
Therapeutic massagers/vibrators
Wheelchairs
Walkers
Patient lifts
Neurological and Phys Med
Devices Review Expertise
• Medical Officers: Neurologists, Neurosurgeons,
Psychiatrist, Neuropsychologist
• Physical Therapist
• Engineers: Biomedical, Electrical, Mechanical, Software,
Chemical, etc.
• Toxicologist
• Microbiologist
• Neuroscientists
• Statisticians
9
Neurological Device Classification
• Class I General Controls e.g., Manual Surgical
Instruments, Tuning Fork, Neurosurgical Chair,
External Limb Prosthetics, Orthotics
• Class II Special Controls e.g., EEG, Cutaneous
Electrodes, Cortical Electrodes (< 30 days),
Depth Electrodes (<30 days), Shunts, Clot
Retrievers, Motorized Wheelchairs
• Class III Premarket Approval e.g., Vagus Nerve
Stimulation, Spinal Cord Stimulation, Deep
Brain Stimulation, Stents
Medical Device Paths to Market
Law  Regulation  Guidance
Investigational Device Exemption
Code of Federal Regulations (21 CFR):
– Part 812 - IDE Regulation
– Part 50 - Protection for Human Subjects,
Informed Consent Regulation
– Part 54 – Financial Disclosure of Investigators
– Part 56 - Institutional Review Boards (IRBs)
Regulation
Practice of Medicine
“Nothing in this Act shall be construed to limit or
interfere with the authority of a health care
practitioner to prescribe or administer any
legally marketed device to a patient for any
condition or disease within a legitimate health
care practitioner-patient relationship….”
From Section 906 of the FD&C Act
Differences between Devices and Drugs
•
•
•
•
•
•
•
•
Devices are often tools or diagnostics
Blinding may be difficult – placebo testing
Mechanisms may not be known, especially for CAM devices
Small companies
Effects usually more specific and localized for devices
Small clinical trials
Risks are highly variable, class I – class III
No requirement for device sponsor to cover cost of
investigational device
• “… whether the available evidence, when taken as a whole,
is adequate to support a determination that there is
reasonable assurance that the device is safe and effective
for its conditions of use.” - 21 CFR 860.7(d)
Stages of Medical Device Studies
• Exploratory Stage – first in human and feasibility/pilot
studies, iterative learning and product development
• Pivotal Stage – definitive study to support the safety
and effectiveness evaluation of the medical device for its
intended use
• Postmarket Stage – includes studies intended to better
understand the long-term effectiveness and safety of the
device, including rare adverse events
When Are Clinical Data Needed?
To support:
• PMA, PDP or HDE (almost always)
• 510(k) (10 – 15%*, usually involving new technology
that could affect safety of effectiveness or a new
population)
• New indication for an approved device (e.g., new
indications for DBS)
• Significant change to device, especially Class III
devices
*for all devices
When clinical trials may not be justified?
• When Causal Effects are Known
– to evaluate a scalpel: cuts because it is sharp
– to evaluate a sterilizer: temperature and pressure
– mathematical models used to support safety of a metallic
implants in MR imaging in a PMA
• Codified use of prior information: section 510(k).
The better the prior information, the less justified the
randomized placebo-control study.
26
Treatment Effect? or Placebo Effect? or
Regression to the Mean?
24
baseline
Pain Severity
22
no treatment
20
sham treatment
18
treatment
16
14
hypothetical 3-arm study
of a pain treatment device
12
10
0
1
Time
Fundamental science provides the
necessary context of a clinical trial.
Is the empirical trial enough?
• Willingness to infer causality
• Willingness to accept uncertainty, α≤ 5%
• Trials are never perfect
• Real practice is different from clinical trial
• Demographic differences
• Duration of study
• Patient drop-out
• Blinding issues
• Unknown covariates
• Unknown interactions
Electrical Stimulation Safety in CNS
• Reviewers use standards, guidance documents and literature as a reference
when evaluating files
• Examples:
– Stimulation from macro electrodes in nervous system
• No recognized standard or guidance
• Shannon criteria (charge vs. charge density)
• McCreery et al. 1990, Agnew et al. 1989, etc.
• DBS (assuming 0.06 cm2
surface area electrode)
= 30 µC/cm2/phase; 1.8 µC/phase
BMI-Relevant Research in CDRH/OSEL
Division of Physics
Neural implant lab:
Invasive electrophysiology;
cellular pathology; animal models
Functional performance lab:
Noninvasive electrophysiology;
human performance
64-channel EEG
surface EMG
Cristin Welle
Gene Civillico
Pavel Takmakov
James Coburn
Finn Donaldson
Kelliann Wachrathit
Stanley Huang
eye tracking
motion capture
Technical Approaches
In vivo physiology - DP
Electrophysiology
Longitudinal measurements of signal quality
Optogenetic assessment of neural health
Impedance spectroscopy
Motor behavior analysis
Wireless electrophysiology system
Computerized behavioral detection
Motor output correlation
Imaging cell morphology
Two-photon imaging of neurite growth
patterns and branching
Histology with confocal microscopy
uCT in vivo
Biointerface and materials
Device failure analysis
Evaluating electrode integrity before and
after implantation in animal
Includes following metrics:
SEM
Impedance spectroscopy
Optical microscopy
ICP-MS
Voltammetry
Accelerated aging analysis - ‘Artificial Brain’
Simulated in vivo environment
Identify materials and design factors to
increase device longevity
Validate with in vivo results
Electrodes
headstage
preamplifier
Implanted
electrode
Electrodes implanted in motor cortex of mouse
Electrophysiological recordings performed from awake, behaving animal
Document signal longevity for various electrodes in mouse animal model
Project example: long-term performance of
intracranial electrodes in mouse motor cortex
Event rate (Hz)
Days postimplant
Event size (µV)
Cristin Welle, Ph.D.
Gene Civillico, Ph.D.
Kelliann Wachrathit
1 month
Days postimplant
Supported by
DARPA RE-NET
Models Used for Assurance of Device Safety and Effectiveness
Human
Trial
Animal
Model
In Vitro Model
(phantom)
Computer
Model
cost
very high
moderate
low
low (after
development)
time
long
moderate
short
short
ability to vary
parameters
not easy
limited
limited
high (good
learning tool)
testing involving
harm
no,
unethical
restricted
yes
yes
simplifying
assumptions
none
none
many and
always
always (limiting)
relevance
direct
variable
(species)
limited
variable
(depends on
validation)
testing of disease
state
yes
difficult
simplified states
yes
experimental
control
difficult
good
high
high
interpretation of
data and ability to
predict
not easy
yes
limited
Yes – can predict
device and drug
interactions
Questions
• Cristin G. Welle, PhD, OSEL
cristin.welle.fda.hhs.gov
• Kristen Bowsher, PhD, ODE
kristen.bowsher.fda.hhs.gov
• Victor Krauthamer, PhD, OSEL/ODE
[email protected]
http://www.fda.gov/cdrh/
devadvice/