Transcript Presentation - American Society for Experimental NeuroTherapeutics

DNPMD
CDRH/ODE
Preclinical Science and Clinical Device Trials
February 20, 2014
Victor Krauthamer, PhD
Director, Division of Physics
Office of Science and Engineering Labs
Center for Devices and Radiological Health
Food and Drug Administration
American Society for Experimental NeuroTherapeutics | 16th Annual Meeting
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Disclosure
Name of Commercial
Interest
none
Type of Financial
Relationship
n/a
American Society for Experimental NeuroTherapeutics | 16th Annual Meeting
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CDRH 2014-2015 Strategic Priorities
• Increase the number of early feasibility/firstin-human IDE studies submitted to FDA and
conducted in the U.S.
• Improve the efficiency, consistency, and
predictability of the IDE process to reduce
the time and number of cycles needed to
reach appropriate IDE full approval for
medical devices, in general, and for devices
of public health importance, in particular.
American Society for Experimental NeuroTherapeutics | 16th Annual Meeting
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Placebo-Controlled Randomized Trials
• Orthodoxy developed from drug trials
– Sugar-pill placebo is identical to experimental drug minus the
pharmacological effects
• Other possible confounders (e.g., regression to the mean) should be the same
in both treatment and sham arms
• Blinding of study subject and investigator as to identity prevents bias
(conscious or unconscious)
– Randomized trial is best way to compare treatment to placebo
• Null hypothesis is that new treatment is equivalent to placebo
• Null hypothesis can be refuted with known confidence (based upon difference
in size of effect and variance)
– Multiple drug trials can be compared against a presumed similar
placebo effect
• For drugs, placebos are easy to implement, always the
same, and placebo controlled randomized trials can give
“unambiguous” answers
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Design Considerations for Pivotal Clinical
Investigations for Medical Devices – 11/7/2013
(21CFR§314.126)
Generally, four types of comparisons are recognized;
(a ) No treatments. Where objective measurements of effectiveness are available and
placebo effect is negligible, comparison of the objective results in comparable groups of
treated and untreated patients;
(b ) Placebo control. Where there may be a placebo effect with the use of a device,
comparison of the results of use of the device with an ineffective device used under
conditions designed to resemble the conditions of use under investigation as far as
possible;
(c ) Active treatment control. Where an effective regimen of therapy may be used for
comparison, e.g., the condition being treated is such that the use of a placebo or the
withholding of treatment would be inappropriate or contrary to the interest of the patient;
(d ) Historical control. In certain circumstances, such as those involving diseases with
high and predictable mortality or signs and symptoms of predictable duration or severity, or
in the case of prophylaxis where morbidity is predictable, the results of use of the device
may be compared quantitatively with prior experience historically derived from the
adequately documented natural history of the disease or condition in comparable patients
or populations who received no treatment or who followed an established effective regimen
(therapeutic, diagnostic, prophylactic).
In addition to the four types of controls identified in the CFR, this guidance also considers a
fifth, “Subject Serving as Own Control.” In this guidance the term “intervention” will be used
instead of “treatment” when describing a control in (a) and (c) above since this term applies
to clinical outcome studies for diagnostic interventions, as well as for therapeutic and
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aesthetic interventions. (Similar to an historical control – presumes intrinsic decline).
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When Placebo Controls for Devices May Be
Inappropriate (“matter of taste”)
• Effects with “placebo” devices – e.g., surgical implantation
of “sham” device in CNS can affect CNS function – can
lead to false negative
• Mis-Matching of the sensation – can lead to false positive
– Vibration instead of electrical stimulation; e.g., paresthesia from
spinal cord stimulation
– Low-dose vs. high-dose: Is stimulation once every three hours
really a placebo compared to stimulation once every five minutes?
(More manipulation generally heightens placebo effect.)
• Different varieties of placebo controls do not permit intercomparisons to treatments; comparisons with other
treatments are indirect and could falsely presume an equal
placebo effect in all trials
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Impact of OSEL Regulatory
Science on Clinical Devices
•Regulatory science sets context for
device trials (preclinical & clinical)
•Improves the efficiency, consistency,
and predictability of regulatory
requirements
•Reduces need for clinical data through
engineering analyses and modeling
•Promotes innovation through
collaboration with sources of innovation
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Division of Physics
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staff
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Neural Interfaces lab – Cristin G. Welle
Human Performance – Gene Civillico
Clinical Studies – David G. Strauss
Optics Labs – Dan X. Hammer, Ilko Ilev, Josh Pfefer
Electromagnetics – Howard Bassen
MRI – Sunder Rajan
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fellows
fields
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Division of Physics Research Domains
Director – Victor Krauthamer, PhD
Dep. Director – Brian Beard, PhD
Dep. Director – Dan X. Hammer, PhD
MRI
Sunder Rajan, PhD,
David Soltysik, PhD
BuSik Park, PhD*
Cardiac Electrophysiology
Ksenia Blinova, PhD
Dulciana Chan, BSE
Richard Gray, PhD
Jayna Stohlman, MS
David Strauss, MD, PhD
Loriano Galeotti, PhD*
Lars Johannesen, MD*
Krystal Lansdowne, BA*
Pras Pathmanathan, PhD*
Christopher Scully, PhD*
Jose Vicente, MS*
Galen Wagner, MD*
Robbert Zusterzeel, MD*
Electrical Engineering and
Electromagnetics
Leonardo Angelone, PhD
Howard Bassen, MS
Brian Beard, PhD
Joshua Guag, BS
Wolfgang Kainz, PhD
Seth Seidman, MS
Donald Witters, MS
Gonzalo Mendoza, BS**
Esther Akinnagbe, BS*
Omar Bekdash, MS*
Maria Iacono, PhD*
Nick LaSorte, PhD*
Elena Lucano, MS*
Amir Oskoui, BS*
Neuroscience
Erkinay Abliz, PhD
Eugene Civillico, PhD,
Ethan Cohen, PhD
Victor Krauthamer, PhD
Cristin Welle, PhD
Jonathan Fisher, PhD*
Noah Greenbaum, B.S*
Taylor Hearn, BS*
Stanley Huang, PhD*
Anjuli Jain, BS*
Joseph Majdi, MS*
Maira Malik*
Kiersten Ruda, B.S*
Nicolas Vivaldi*
Meijun Ye, PhD*
Optical Physics
Anant Agrawal, MS
Daniel X. Hammer, PhD
Ilko Ilev, PhD,
Robert James, MS
Do-Hyun Kim, PhD
Xin (Sofia) Tan, PhD
Darrell Tata, PhD
Joshua Pfefer, PhD,
Quanzeng Wang, PhD
Moinuddin Hassan, PhD**
Jigesh Baxi, BS*
William Calhoun, BS*
Taylor Gould, B.S.*
Andrea Lozzi, MS*
Paweena U-Thainual, PhD*
William Vogt, PhD*
Bennett Walker, PhD*
Yi Yang, PhD*
Biomechanics
James Coburn, MS
Finn Donaldson, PhD*
Hanniebey Wiyor, PhD*
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CDRH/ODE
Current Research Related to Neurotherapeutics
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Neural Interfaces Lab – Cristin Welle, Gene Civillico
a)
Platform for in vivo electrophysiology, anatomy, vascularization, optical stimulation, motor
function and behavior
b)
Comprehensive technology being developed in conjunction with translational research
c)
Interagency agreement with DARPA RE-NET program
Magnetic resonance safety of active implants through computer modeling – Wolfgang Kainz,
Leonardo Angelone, Howard Bassen
a)
Electromagnetic models, including “Virtual Family”
b)
Worst case validations
c)
Sensitivity analysis
d)
First MR conditional spinal cord stimulator – we worked from the beginning with the company
to approval – with over 2 million simulations and no clinical trial!
Clinical trial research group - David Strauss (generalizing from cardiovascular), David Soltysik
a)
Leveraging existing clinical trial data with hypothesis driven post-hoc studies – e.g.,
combining trials for under-represented women in CRT trials
b)
Personalized medicine based on patient differentiated stem cells to predict therapeutic
response
c)
Smart monitoring – develop criteria for improvements on seizure diaries
d)
fMRI endpoints for neurological trials
Computer models for neural recording and detection – Leonardo Angelone (first guidance
document on modeling issued in 2014)
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Understanding tissue response: Electrodes in mouse forelimb motor cortex
In summary….
Single neuron firing
Firing rate of neurons
from DP neural interfaces lab - Welle
Signal decline across all electrode
types in rodent model!
Many neurons on 16 electrodes over time
Days after implantation
surface
depth
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Thank you!
[email protected]
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Science Non-Fiction in Neurotherapeutics
Panel Discussion
American Society for Experimental NeuroTherapeutics | 16th Annual Meeting
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