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InsideScientific is an online educational environment designed for life science researchers. Our goal is to aid in the sharing and distribution of scientific information regarding innovative technologies, protocols, research tools and laboratory services.
Today’s Presenters: 
R. Dustan Sarazan, DVM, PhD 
Vice President & CSO, Data Sciences International 
Steve Fox, BS 
Associate Principal Scientist, Merck & Co., Inc. 
Anna Honko, PhD 
Staff Scientist, NIH/NIAID Integrated Research Facility
years – 1984 to 2014 
Integrated Physiologic Monitoring for Life Science Research 
DSI is a pioneering research company focused on systems physiology and pharmacology. We are celebrating 30 years of advancing the field of physiologic monitoring this year. Over the past 30 years, we’ve delivered proven solutions that have been used to monitor more than 500,000 research subjects and study findings have been published in over 1000 peer-reviewed journal articles. DSI’s 200 scientists, engineers, and personnel are based out of St. Paul, MN, but we also have offices in Europe and Asia where sales and technical support staff are located to help our customers abroad.
Benefits of Telemetry 
1. 
Freely moving, conscious animals 
2. 
Eliminates exit site infections 
3. 
Chronically instrumented animals can be used sequentially as their own controls, or in several studies, thus improving animal welfare 
4. 
Decreases costs 
5. 
Enhances safety
Additional Considerations 
• 
Number of animals 
• 
Physiologic endpoints of interest 
• 
Study duration 
• 
Interventions 
• 
Data collection schedule 
• 
Data analysis
Utilizing Continuous EEG in Drug Discovery: From Mouse to Man 
Steve Fox 
Associate Principal Scientist 
Pharmacology - EEG 
Merck Research Laboratories Copyright S. Fox, Data Sciences International, and InsideScientific. All Rights Reserved.
Challenges of Drug Discovery for CNS Indications 
a 
Nature Reviews Drug Discovery 11, 191-200 (March 2012)
Increasing POS of Drug Candidates: 
1. 
Expose at the target site of action over a desired period of time 
2. 
Binding to the pharmacological target as expected for its mode of action 
3. 
Expression of pharmacological activity commensurate with the demonstrated target exposure and target binding 
For a development candidate to have potential to elicit the desired effect over the necessary period of time, three fundamental elements need to be demonstrated:
CNS Biomarkers 
Body 
Brain 
Functional 
Brain Area 
Cortex 
Mid 
- 
Brain 
Nuclei 
ms Second Minute Hour Day 
Week 
Months 
Years 
PET 
CSF 
PK 
MRI 
Genetic Traits 
Level of Anatomic Accuracy 
Cognition/Mood 
Space 
EEG
EEG Spans a Large Temporal Space 
Measure 
Pharmaco-Dynamic? 
Pharmaco-Kinetic? 
Comment: 
PET 
No 
Yes 
- 
Expensive, patient location locked to scanner 
MRI 
Yes 
No 
- Expensive, patient location locked to scanner 
Genetics 
No 
No 
- Possibly response predictive 
EEG 
Yes 
Yes 
- Patient is location and time independent 
- Spans large temporal and anatomic space 
- Inexpensive, portable, scaffold for other clinical measures
Symphony in the Brain 
• 
Tuba section 
• 
Trombone section 
• 
French horn section 
• 
Trumpet section 
EEG 
• 
Delta activity (0.5 - 4 Hz) 
• 
Theta activity (4 - 8 Hz) 
• 
Alpha activity (8 -13 Hz) 
• 
Beta activity (14 - 26 Hz) 
Beta 
Active Cognition 
Alpha 
Relaxed Wake 
Delta 
Deep Sleep 
Theta 
REM Sleep 
In Humans: Recording Brain Activity is Done Readily Using External Measurements
Sanna et al. 2004, Int J Sports Med; 25: 457-460 
Circadian Physiology 
Moore-Ede et al., 1983 NEJM 
Sleep is Assessed Using Broadly Useful Measures (EEG, EMG, EOG) 
Including: 
• 
ECG 
• 
cognition 
• 
mood 
• 
respiration 
• 
activity 
• 
body temperature 
• 
vocalization & more… 
Polysomnography
Sleep is Assessed Using Broadly Useful Measures (EEG, EMG, EOG) 
Including: 
• 
ECG 
• 
cognition 
• 
mood 
• 
respiration 
• 
activity 
• 
body temperature 
• 
vocalization & more… 
NEJM 1974, 290(9) 487
Sleep is Translational by Nature…
Pharmacological Confidence in EEG 
1. 
MRL Sleep / EEG Lab Translation 
• 
Rely on natural translation of sleep & EEG 
• 
Employ multiple species (mice, rats, dogs, monkeys & man) 
• 
Add therapeutic area specific measures 
2. 
Sleep & qEEG as Biomarkers 
• 
EEG is time scalable 
• 
Dynamic frequencies and transients 
• 
Topography 
3. 
Combine EEG, Cognition & PK 
• 
3-D drug signature 
• 
PK/PD and PD/PD estimates 
4. 
Automation to Drive Probability of Success 
• 
Data collection is easy – data analysis is hard 
• 
Alignment of pre-clinical & clinical end points
EEG patterns are conserved among mice, rats, dogs, NHP and humans 
- this approach is readily translatable among species… 
Ideal Profile for Insomnia Drug: 
- reduce sleep latency (sleep onset) and sleep fragmentation (maintenance), improve next-day performance, non-addictive
EEG Translational Strategy for Drug Discovery 
• 
Similar study designs across species 
• 
Control for environmental conditions 
• 
Standardize and optimize analytic approaches 
CNS Drug Discovery 
Improved POS 
Higher POS 
Optimal POS 
Minimal POS 
Patients 
Human PhI 
Rat 
Efficacy, PK 
Patients 
Human PhI 
Canine 
Rat 
Mouse (TG) 
NHP 
Sleep / qEEG / Pharmaco-EEG 
Efficacy, PK, Cognition, Temp, ECG, Activity 
Patients 
Human PhI 
Rat 
Mouse (TG) 
Sleep / qEEG / Pharmaco-EEG 
Efficacy, PK 
Patients 
Human PhI 
Rat 
Mouse (TG) 
Sleep / qEEG / Pharmaco-EEG 
Efficacy, PK, Cognition, Temp, ECG, Activity
1. 
Minimize stress, surgeries, possibilities for infection 
2. 
Maximize predictive ability, animal health, and model durability 
3. 
Measure continuously over multiple circadian cycles/ drug administrations 
4. 
Support discovery and development programs using automated workflows and algorithms 
Pre-clinical EEG methods are similar to human but are optimized to:
Measuring Sleep in Pre-Clinical Species 
DSI Implant 
F20/F40 EET 
Quad-ET 
D70-EEE
Standard Analytic Approaches 
for Pre-Clinical Studies 
EEG Recording V/t 
Δ φ α β γ 
Arousal State Average Across Time 
Spectral Distribution 
Spectral Band Average Across Time 
Sleep Scoring 
FFT Analysis 
Compound L 
• 
EEG + EMG + Activity 
•Polysomnography 
•Quantitative EEG (qEEG) – Fast Fourier Transform (FFT) 
•Group frequencies by bands (Delta, Theta, Alpha,…) 
•Time course of drug effect
Rat Sleep as High-Throughput PK/PD Screen 
• 
Sleep/EEG signatures of CNS compounds 
• 
Focuses target selection, lead optimization, and biomarker assessment 
• 
Wireless implants allow for additional measures in home cages 
Paroxetine 
(Paxil©) 
Buproprion 
(Wellbutrin©) 
Buspirone 
(Buspar©)
High-Throughput EEG Screen for Seizure Liability 
• 
WAG-Rij rats genetically susceptible to absence-like seizures 
• 
EEG evaluates brain penetrance and thalamic calcium channel target engagement 
• 
Automated scoring reduces cycle time while maintaining accuracy 0% After Dosing0% 20% 40% 60% 80% 100% 0246810121416182022 Percent Cumulative Seizure Time (%) Untreated (n=32) 200mpk (8)400mpk (8)Dosed50mpk 50mpk (8)ACTIVEIN-ACTIVEACTIVEHours Dosing 
5 sec 
seizure 
Automatically scored seizure 
Ethosuximide
Summary= statistically significant effects 0.05, 0.01, 0.0010246810121416OlanzapineVehicleActive WakeLight SleepDelta SleepREM SleepHours Duration (Min) Olanzapine•10 mpk, PO•Vehicle-0.5% Methylcellulose•Analysis of all nights •Dose Time=3:30•Time 0 = 3:00pm•n=8 rats & nights: 56Study details-3036912153691215510152025024681.8 hour decrease in active wake starting immediately post dose2.Increase in light sleep for 2 hours3.10.5 hour increase in delta sleep for starting 3 hours post dose4.1 hour increase in REM sleep immediately post dose; 5 hour decrease in REM starting 2 hours post dose 
0.00102468101214160246810121416OlanzapineVehicleOlanzapineVehicleActive Rat Sleep as Adverse Event Screen 
• 
Sleep, EEG, & cognition are also adverse event detection tools 
• 
Seizures also detected automatically if needed 
• 
Zyprexa causes “excessive sedation” when given PO to rats 
Rat Sleep Study: Olanzapine
Ancillary Measures Using Quad-ET in Rats 
• 
Acute and chronic changes in SC body temperature and heart rate 
• 
Indicative of adverse effects, though insomnia drugs may reduce body temperature and heart rate to sleep- phase levels 
• 
Activity data not shown, but is also analyzed 
Heart Rate 
SC Body Temperature
Innovative Research 
• 
Flexibility to design and run interesting studies 
• 
Sleep Disruption 
• 
Lights-on, Sounds 
• 
Develop new translatable analysis 
• 
Combine EEG + Cognition for residual sleep effects / arousability 0246051015051015-0.100.10.20.30.40102030 Duration (Min) REM SleepDelta Sleep IIDelta Sleep IActive WakeQuiet WakeREM Wake02468101214161820220246810121416182022 
Sleep Disruption
Human “Home Cage” EEG
Recursive Vertical Integration 
• 
PD/PK across species using common PD/PK endpoints 
• 
Improve next- generation drug quality 
• 
Decrease clinical discovery time 
Cellular Assays 
(Specificity, Potency) 
Rodent Assays 
(Safety, EEG) 
Monkey Assays 
(EEG, Cognition) 
Identify Specific Signals 
Identify Efficacy 
(Success per Year) 
2MM 
3000 
200 
3-5 
Human Assays 
(EEG, Cognition) 
+ 
ID 
+ 
ID 
+ 
ID 
30 
1 
FDA Approved!
Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival 
Sleep Lab Translational Strategy… 
Paul Morgan, Piet H. Van Der Graaf, John Arrowsmith, Doug E. Feltner, Kira S. Drummond, Craig D. Wegner and Steve D.A. Street 
Drug Discover Today – Volume 17, Number 9/10 – May 2012
EEG as a Model for CNS Drug Discovery 
1. 
Sleep & qEEG as biomarkers for CNS penetration and vertical translation to patients 
2. 
EEG is high throughput & highly translational 
3. 
Multi-species for optimal human predictions 
• 
Sleep 
• 
qEEG 
• 
Cognition 
• 
Aging 
4. 
Ambulatory PSG/EEG 
• 
FIM 
• 
CNS Penetration 
• 
Dose selection 
5. 
Database building 
• 
CNS target specific EEG signals 
• 
PK/PD & PD/PD across species 
Patients 
Human 
Non-Human Primate 
Canine 
Rat 
Mouse
Telemetry for Biodefense Research Applications 
Anna Honko, PhD 
Staff Scientist 
NIH/NIAID Integrated Research Facility 
Frederick, MD Copyright A. Honko, Data Sciences International, and InsideScientific. All Rights Reserved.
What will we cover today… 
1. 
Introduce what makes biodefense research unique from other pharm/tox or drug discovery applications in the context of disease models 
2. 
Discuss some of the different study designs where telemetry can be utilized
Biosafety Level 3 (BSL-3) 
• 
Agents associated with serious or lethal human disease for which preventive or therapeutic interventions may be available 
• 
Personnel may have to change into scrubs before entering the laboratory and take a complete shower before exiting 
• 
Other personal protective equipment may be required as well, depending on the tasks to be performed 
CDC Biosafety in Microbiological and Biomedical Laboratories (BMBL) 5th Edition
Biosafety Level 4 (BSL-4) 
• 
BSL-4 is required for work with dangerous and exotic agents that pose a high risk of aerosol-transmitted laboratory infections and life-threatening disease that is frequently fatal, for which there are no approved vaccines or treatments 
CDC Biosafety in Microbiological and Biomedical Laboratories (BMBL) 5th Edition
BSL-4 viral agents: 
Ebola virus 
Marburg virus 
Smallpox (Variola virus) 
Lassa Fever Virus 
Junin Virus 
Crimean-Congo hemorrhagic fever virus 
BSL-3 bacterial agents: 
Yersinia pestis 
Bacillus anthracis 
Francisella tularensis 
Mycobacterium tuberculosis 
BSL-3 viral agents: 
Venezuelan equine encephalitis virus 
Eastern equine encephalitis virus 
Western equine encephalitis virus 
SARS coronavirus 
Yellow Fever Virus 
West Nile Virus 
Chikungunya 
Rift Valley Fever Virus
Due to engineering design requirements of laboratory, telemetry system reliability is critical… 
1. 
Only persons whose presence in the facility or individual laboratory rooms is required for scientific or support purposes are authorized to enter 
2. 
Equipment must be decontaminated using an effective and validated method before repair, maintenance, or removal from the laboratory 
This means… 
• 
Only able to install or make major repairs when laboratory is decontaminated, or 
• 
Personnel must be able to install or make minor adjustments if necessary 
• 
Telemetry device sterilization/decontamination [Either one-time use or decontaminate and replace/exchange (factor into costs)] 
CDC Biosafety in Microbiological and Biomedical Laboratories (BMBL) 5th Edition
Sequence of Entry Rooms 
• 
Since there is frequently a physical separation between the telemetry base station and the animals being monitored, communication is critical…
Biodefense research and the FDA Animal Rule 
1. 
Non-traditional regulatory pathway for new drug approval when human efficacy studies are not ethical or feasible 
2. 
The Animal Rule states that FDA will rely on evidence from animal studies to provide substantial evidence of effectiveness only when the following four criteria are met: 
1. 
There is a reasonably well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the product; 
2. 
The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well- characterized animal model for predicting the response in humans; 
3. 
The animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity; and 
4. 
The data or information on the kinetics and pharmacodynamics of the product or other relevant data or information, in animals and humans, allows selection of an effective dose in humans. 
Paraphrased from “Guidance for Industry, Product Development Under the Animal Rule, May 2014” 
3. 
Adequate and well-controlled animal efficacy studies are required for approval under the Animal Rule = well-documented and GLP if possible
Purpose of natural history studies for rare diseases 
From a presentation by Anne R. Pariser, M.D. , former Associate Director for Rare Diseases, CDER, FDA: 
• 
“The natural course of a disease from the time immediately prior to its inception, progressing through its presymptomatic phase and different clinical stages to the point where it has ended and the patient is either cured, chronically disabled or dead without external intervention”1 
There is limited natural history data in humans for high containment diseases for a number of reasons: 
• 
Sporadic nature of the outbreaks and the remote locations of the cases, availability of resources at sites 
• 
Variability in dose, route of exposure and time to presentation for individual cases 
1Posada de la Paz M; Groft SC. 2010. Rare diseases epidemiology. Vol. 686
Benefits of natural disease progression studies in non- human primates using telemetry 
1.Studies are observational and longitudinal, allowing for the characterization of the pathophysiology of the disease in a more controlled system 
•Does the disease in nonhuman primates model the disease in humans? 
•Are we able to identify potential triggers for therapeutic intervention, biomarkers or correlates of disease?
Benefits of natural disease progression studies in non- human primates using telemetry 
2. 
Some disease manifestations that are common in human cases, such as shortness of breath or fever, are difficult to objectively measure in nonhuman primates cageside 
• 
Telemetry is considered a “refined technique” for collecting this data 
3. 
Additionally, if mortality is used as a primary endpoint, considerations must be made for the effects of euthanasia criteria 
• 
Real-time monitoring using telemetry has provided an additional means of objective euthanasia criteria, reducing observational study bias 
• 
Increasing sample integrity since terminal sample collection can occur
Study designs that benefit from telemetry data acquisition 
1. 
Longitudinal natural history studies and basic pathophysiology modeling studies 
2. 
Comparison of nonhuman primate species 
3. 
Agent dose-seeking studies 
4. 
Identification / application of therapeutic interventions, establishment of euthanasia criteria 
5. 
Efficacy trials of potential vaccine or therapeutic
Longitudinal natural history studies and basic pathophysiology modeling studies 
Characterization of disease progression differences between fatal and non-fatal viral infection 
Non-survivor 
Survivor 
1
Longitudinal natural history studies and basic pathophysiology modeling studies 
1 
Ability to match physiological parameters by telemetry with commonly collected clinical parameters 
Plasma RNA levels 
Clinical serum chemistry
Febrile response of macaques following EEE virus exposure 
Longitudinal natural history studies and basic pathophysiology modeling studies 
1
Comparisons of viral disease in different NHP models 
Comparison of Non-human Primate Species 
2
Comparison of febrile responses between dose groups of aerosol exposed macaques (WEE) 
Low Dose 
High Dose 
Agent Dose-Seeking Studies 
3
Trigger to initiate therapeutic intervention 
• 
Results of natural disease modeling studies can be used to determine triggers for treatment 
• 
In combination with RT-PCR assessment, fever as calculated by ≥1.5°C above pre- challenge baseline using remote telemetry monitoring was used to determine starting point for mAb treatment for Ebola 
Identification / application of therapeutic interventions, establishment of euthanasia criteria 
4
Comparison of vaccine efficacy: Sham-immunized controls challenged against EEEV 
Efficacy trials of potential vaccine or therapeutic 
5
Comparison of vaccine efficacy: SIN-SAEEEV vaccinated (nonprotective – 17% survival) 
Efficacy trials of potential vaccine or therapeutic 
5
Comparison of vaccine efficacy: SIN/NAEEEV vaccinated (significant protection – 82% survival) 
Efficacy trials of potential vaccine or therapeutic 
5
Summary 
Real-time monitoring of physiological parameters using less-invasive implanted telemetry devices will provide critical data for: 
1. 
Development of animal models for biodefense or emerging diseases 
2. 
Evaluation of potential vaccines and therapeutics 
3. 
Establishment of objective criteria for therapeutic interventions or endpoints
Thank You! 
For additional information on telemetry applications and various DSI solutions for continuous monitoring of physiology in pre- clinical research studies please visit: www.datasci.com
ACCESS THE RECORDING AND SUPPLIMENTARY MATERIALS FOR THIS EVENT AND OTHERS AT 
http://goo.gl/yLiXpP 
JOIN OUR GROUP ON LINKEDIN FOR INFORMATION ON UPCOMING EVENTS, ON-DEMAND WEBINARS, AND ADDITIONAL LAB RESOURCES
InsideScientific is an online educational environment designed for life science researchers. Our goal is to aid in the sharing and distribution of scientific information regarding innovative technologies, protocols, research tools and laboratory services.

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Don't Miss a Beat: Understanding Continuous, Real Time Physiologic Monitoring

  • 1.
  • 2. InsideScientific is an online educational environment designed for life science researchers. Our goal is to aid in the sharing and distribution of scientific information regarding innovative technologies, protocols, research tools and laboratory services.
  • 3. Today’s Presenters: R. Dustan Sarazan, DVM, PhD Vice President & CSO, Data Sciences International Steve Fox, BS Associate Principal Scientist, Merck & Co., Inc. Anna Honko, PhD Staff Scientist, NIH/NIAID Integrated Research Facility
  • 4. years – 1984 to 2014 Integrated Physiologic Monitoring for Life Science Research DSI is a pioneering research company focused on systems physiology and pharmacology. We are celebrating 30 years of advancing the field of physiologic monitoring this year. Over the past 30 years, we’ve delivered proven solutions that have been used to monitor more than 500,000 research subjects and study findings have been published in over 1000 peer-reviewed journal articles. DSI’s 200 scientists, engineers, and personnel are based out of St. Paul, MN, but we also have offices in Europe and Asia where sales and technical support staff are located to help our customers abroad.
  • 5. Benefits of Telemetry 1. Freely moving, conscious animals 2. Eliminates exit site infections 3. Chronically instrumented animals can be used sequentially as their own controls, or in several studies, thus improving animal welfare 4. Decreases costs 5. Enhances safety
  • 6. Additional Considerations • Number of animals • Physiologic endpoints of interest • Study duration • Interventions • Data collection schedule • Data analysis
  • 7. Utilizing Continuous EEG in Drug Discovery: From Mouse to Man Steve Fox Associate Principal Scientist Pharmacology - EEG Merck Research Laboratories Copyright S. Fox, Data Sciences International, and InsideScientific. All Rights Reserved.
  • 8. Challenges of Drug Discovery for CNS Indications a Nature Reviews Drug Discovery 11, 191-200 (March 2012)
  • 9. Increasing POS of Drug Candidates: 1. Expose at the target site of action over a desired period of time 2. Binding to the pharmacological target as expected for its mode of action 3. Expression of pharmacological activity commensurate with the demonstrated target exposure and target binding For a development candidate to have potential to elicit the desired effect over the necessary period of time, three fundamental elements need to be demonstrated:
  • 10. CNS Biomarkers Body Brain Functional Brain Area Cortex Mid - Brain Nuclei ms Second Minute Hour Day Week Months Years PET CSF PK MRI Genetic Traits Level of Anatomic Accuracy Cognition/Mood Space EEG
  • 11. EEG Spans a Large Temporal Space Measure Pharmaco-Dynamic? Pharmaco-Kinetic? Comment: PET No Yes - Expensive, patient location locked to scanner MRI Yes No - Expensive, patient location locked to scanner Genetics No No - Possibly response predictive EEG Yes Yes - Patient is location and time independent - Spans large temporal and anatomic space - Inexpensive, portable, scaffold for other clinical measures
  • 12. Symphony in the Brain • Tuba section • Trombone section • French horn section • Trumpet section EEG • Delta activity (0.5 - 4 Hz) • Theta activity (4 - 8 Hz) • Alpha activity (8 -13 Hz) • Beta activity (14 - 26 Hz) Beta Active Cognition Alpha Relaxed Wake Delta Deep Sleep Theta REM Sleep In Humans: Recording Brain Activity is Done Readily Using External Measurements
  • 13. Sanna et al. 2004, Int J Sports Med; 25: 457-460 Circadian Physiology Moore-Ede et al., 1983 NEJM Sleep is Assessed Using Broadly Useful Measures (EEG, EMG, EOG) Including: • ECG • cognition • mood • respiration • activity • body temperature • vocalization & more… Polysomnography
  • 14. Sleep is Assessed Using Broadly Useful Measures (EEG, EMG, EOG) Including: • ECG • cognition • mood • respiration • activity • body temperature • vocalization & more… NEJM 1974, 290(9) 487
  • 15. Sleep is Translational by Nature…
  • 16. Pharmacological Confidence in EEG 1. MRL Sleep / EEG Lab Translation • Rely on natural translation of sleep & EEG • Employ multiple species (mice, rats, dogs, monkeys & man) • Add therapeutic area specific measures 2. Sleep & qEEG as Biomarkers • EEG is time scalable • Dynamic frequencies and transients • Topography 3. Combine EEG, Cognition & PK • 3-D drug signature • PK/PD and PD/PD estimates 4. Automation to Drive Probability of Success • Data collection is easy – data analysis is hard • Alignment of pre-clinical & clinical end points
  • 17. EEG patterns are conserved among mice, rats, dogs, NHP and humans - this approach is readily translatable among species… Ideal Profile for Insomnia Drug: - reduce sleep latency (sleep onset) and sleep fragmentation (maintenance), improve next-day performance, non-addictive
  • 18. EEG Translational Strategy for Drug Discovery • Similar study designs across species • Control for environmental conditions • Standardize and optimize analytic approaches CNS Drug Discovery Improved POS Higher POS Optimal POS Minimal POS Patients Human PhI Rat Efficacy, PK Patients Human PhI Canine Rat Mouse (TG) NHP Sleep / qEEG / Pharmaco-EEG Efficacy, PK, Cognition, Temp, ECG, Activity Patients Human PhI Rat Mouse (TG) Sleep / qEEG / Pharmaco-EEG Efficacy, PK Patients Human PhI Rat Mouse (TG) Sleep / qEEG / Pharmaco-EEG Efficacy, PK, Cognition, Temp, ECG, Activity
  • 19. 1. Minimize stress, surgeries, possibilities for infection 2. Maximize predictive ability, animal health, and model durability 3. Measure continuously over multiple circadian cycles/ drug administrations 4. Support discovery and development programs using automated workflows and algorithms Pre-clinical EEG methods are similar to human but are optimized to:
  • 20. Measuring Sleep in Pre-Clinical Species DSI Implant F20/F40 EET Quad-ET D70-EEE
  • 21. Standard Analytic Approaches for Pre-Clinical Studies EEG Recording V/t Δ φ α β γ Arousal State Average Across Time Spectral Distribution Spectral Band Average Across Time Sleep Scoring FFT Analysis Compound L • EEG + EMG + Activity •Polysomnography •Quantitative EEG (qEEG) – Fast Fourier Transform (FFT) •Group frequencies by bands (Delta, Theta, Alpha,…) •Time course of drug effect
  • 22. Rat Sleep as High-Throughput PK/PD Screen • Sleep/EEG signatures of CNS compounds • Focuses target selection, lead optimization, and biomarker assessment • Wireless implants allow for additional measures in home cages Paroxetine (Paxil©) Buproprion (Wellbutrin©) Buspirone (Buspar©)
  • 23. High-Throughput EEG Screen for Seizure Liability • WAG-Rij rats genetically susceptible to absence-like seizures • EEG evaluates brain penetrance and thalamic calcium channel target engagement • Automated scoring reduces cycle time while maintaining accuracy 0% After Dosing0% 20% 40% 60% 80% 100% 0246810121416182022 Percent Cumulative Seizure Time (%) Untreated (n=32) 200mpk (8)400mpk (8)Dosed50mpk 50mpk (8)ACTIVEIN-ACTIVEACTIVEHours Dosing 5 sec seizure Automatically scored seizure Ethosuximide
  • 24. Summary= statistically significant effects 0.05, 0.01, 0.0010246810121416OlanzapineVehicleActive WakeLight SleepDelta SleepREM SleepHours Duration (Min) Olanzapine•10 mpk, PO•Vehicle-0.5% Methylcellulose•Analysis of all nights •Dose Time=3:30•Time 0 = 3:00pm•n=8 rats & nights: 56Study details-3036912153691215510152025024681.8 hour decrease in active wake starting immediately post dose2.Increase in light sleep for 2 hours3.10.5 hour increase in delta sleep for starting 3 hours post dose4.1 hour increase in REM sleep immediately post dose; 5 hour decrease in REM starting 2 hours post dose 0.00102468101214160246810121416OlanzapineVehicleOlanzapineVehicleActive Rat Sleep as Adverse Event Screen • Sleep, EEG, & cognition are also adverse event detection tools • Seizures also detected automatically if needed • Zyprexa causes “excessive sedation” when given PO to rats Rat Sleep Study: Olanzapine
  • 25. Ancillary Measures Using Quad-ET in Rats • Acute and chronic changes in SC body temperature and heart rate • Indicative of adverse effects, though insomnia drugs may reduce body temperature and heart rate to sleep- phase levels • Activity data not shown, but is also analyzed Heart Rate SC Body Temperature
  • 26. Innovative Research • Flexibility to design and run interesting studies • Sleep Disruption • Lights-on, Sounds • Develop new translatable analysis • Combine EEG + Cognition for residual sleep effects / arousability 0246051015051015-0.100.10.20.30.40102030 Duration (Min) REM SleepDelta Sleep IIDelta Sleep IActive WakeQuiet WakeREM Wake02468101214161820220246810121416182022 Sleep Disruption
  • 28. Recursive Vertical Integration • PD/PK across species using common PD/PK endpoints • Improve next- generation drug quality • Decrease clinical discovery time Cellular Assays (Specificity, Potency) Rodent Assays (Safety, EEG) Monkey Assays (EEG, Cognition) Identify Specific Signals Identify Efficacy (Success per Year) 2MM 3000 200 3-5 Human Assays (EEG, Cognition) + ID + ID + ID 30 1 FDA Approved!
  • 29. Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival Sleep Lab Translational Strategy… Paul Morgan, Piet H. Van Der Graaf, John Arrowsmith, Doug E. Feltner, Kira S. Drummond, Craig D. Wegner and Steve D.A. Street Drug Discover Today – Volume 17, Number 9/10 – May 2012
  • 30. EEG as a Model for CNS Drug Discovery 1. Sleep & qEEG as biomarkers for CNS penetration and vertical translation to patients 2. EEG is high throughput & highly translational 3. Multi-species for optimal human predictions • Sleep • qEEG • Cognition • Aging 4. Ambulatory PSG/EEG • FIM • CNS Penetration • Dose selection 5. Database building • CNS target specific EEG signals • PK/PD & PD/PD across species Patients Human Non-Human Primate Canine Rat Mouse
  • 31. Telemetry for Biodefense Research Applications Anna Honko, PhD Staff Scientist NIH/NIAID Integrated Research Facility Frederick, MD Copyright A. Honko, Data Sciences International, and InsideScientific. All Rights Reserved.
  • 32. What will we cover today… 1. Introduce what makes biodefense research unique from other pharm/tox or drug discovery applications in the context of disease models 2. Discuss some of the different study designs where telemetry can be utilized
  • 33. Biosafety Level 3 (BSL-3) • Agents associated with serious or lethal human disease for which preventive or therapeutic interventions may be available • Personnel may have to change into scrubs before entering the laboratory and take a complete shower before exiting • Other personal protective equipment may be required as well, depending on the tasks to be performed CDC Biosafety in Microbiological and Biomedical Laboratories (BMBL) 5th Edition
  • 34. Biosafety Level 4 (BSL-4) • BSL-4 is required for work with dangerous and exotic agents that pose a high risk of aerosol-transmitted laboratory infections and life-threatening disease that is frequently fatal, for which there are no approved vaccines or treatments CDC Biosafety in Microbiological and Biomedical Laboratories (BMBL) 5th Edition
  • 35. BSL-4 viral agents: Ebola virus Marburg virus Smallpox (Variola virus) Lassa Fever Virus Junin Virus Crimean-Congo hemorrhagic fever virus BSL-3 bacterial agents: Yersinia pestis Bacillus anthracis Francisella tularensis Mycobacterium tuberculosis BSL-3 viral agents: Venezuelan equine encephalitis virus Eastern equine encephalitis virus Western equine encephalitis virus SARS coronavirus Yellow Fever Virus West Nile Virus Chikungunya Rift Valley Fever Virus
  • 36. Due to engineering design requirements of laboratory, telemetry system reliability is critical… 1. Only persons whose presence in the facility or individual laboratory rooms is required for scientific or support purposes are authorized to enter 2. Equipment must be decontaminated using an effective and validated method before repair, maintenance, or removal from the laboratory This means… • Only able to install or make major repairs when laboratory is decontaminated, or • Personnel must be able to install or make minor adjustments if necessary • Telemetry device sterilization/decontamination [Either one-time use or decontaminate and replace/exchange (factor into costs)] CDC Biosafety in Microbiological and Biomedical Laboratories (BMBL) 5th Edition
  • 37. Sequence of Entry Rooms • Since there is frequently a physical separation between the telemetry base station and the animals being monitored, communication is critical…
  • 38. Biodefense research and the FDA Animal Rule 1. Non-traditional regulatory pathway for new drug approval when human efficacy studies are not ethical or feasible 2. The Animal Rule states that FDA will rely on evidence from animal studies to provide substantial evidence of effectiveness only when the following four criteria are met: 1. There is a reasonably well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the product; 2. The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well- characterized animal model for predicting the response in humans; 3. The animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity; and 4. The data or information on the kinetics and pharmacodynamics of the product or other relevant data or information, in animals and humans, allows selection of an effective dose in humans. Paraphrased from “Guidance for Industry, Product Development Under the Animal Rule, May 2014” 3. Adequate and well-controlled animal efficacy studies are required for approval under the Animal Rule = well-documented and GLP if possible
  • 39. Purpose of natural history studies for rare diseases From a presentation by Anne R. Pariser, M.D. , former Associate Director for Rare Diseases, CDER, FDA: • “The natural course of a disease from the time immediately prior to its inception, progressing through its presymptomatic phase and different clinical stages to the point where it has ended and the patient is either cured, chronically disabled or dead without external intervention”1 There is limited natural history data in humans for high containment diseases for a number of reasons: • Sporadic nature of the outbreaks and the remote locations of the cases, availability of resources at sites • Variability in dose, route of exposure and time to presentation for individual cases 1Posada de la Paz M; Groft SC. 2010. Rare diseases epidemiology. Vol. 686
  • 40. Benefits of natural disease progression studies in non- human primates using telemetry 1.Studies are observational and longitudinal, allowing for the characterization of the pathophysiology of the disease in a more controlled system •Does the disease in nonhuman primates model the disease in humans? •Are we able to identify potential triggers for therapeutic intervention, biomarkers or correlates of disease?
  • 41. Benefits of natural disease progression studies in non- human primates using telemetry 2. Some disease manifestations that are common in human cases, such as shortness of breath or fever, are difficult to objectively measure in nonhuman primates cageside • Telemetry is considered a “refined technique” for collecting this data 3. Additionally, if mortality is used as a primary endpoint, considerations must be made for the effects of euthanasia criteria • Real-time monitoring using telemetry has provided an additional means of objective euthanasia criteria, reducing observational study bias • Increasing sample integrity since terminal sample collection can occur
  • 42. Study designs that benefit from telemetry data acquisition 1. Longitudinal natural history studies and basic pathophysiology modeling studies 2. Comparison of nonhuman primate species 3. Agent dose-seeking studies 4. Identification / application of therapeutic interventions, establishment of euthanasia criteria 5. Efficacy trials of potential vaccine or therapeutic
  • 43. Longitudinal natural history studies and basic pathophysiology modeling studies Characterization of disease progression differences between fatal and non-fatal viral infection Non-survivor Survivor 1
  • 44. Longitudinal natural history studies and basic pathophysiology modeling studies 1 Ability to match physiological parameters by telemetry with commonly collected clinical parameters Plasma RNA levels Clinical serum chemistry
  • 45. Febrile response of macaques following EEE virus exposure Longitudinal natural history studies and basic pathophysiology modeling studies 1
  • 46. Comparisons of viral disease in different NHP models Comparison of Non-human Primate Species 2
  • 47. Comparison of febrile responses between dose groups of aerosol exposed macaques (WEE) Low Dose High Dose Agent Dose-Seeking Studies 3
  • 48. Trigger to initiate therapeutic intervention • Results of natural disease modeling studies can be used to determine triggers for treatment • In combination with RT-PCR assessment, fever as calculated by ≥1.5°C above pre- challenge baseline using remote telemetry monitoring was used to determine starting point for mAb treatment for Ebola Identification / application of therapeutic interventions, establishment of euthanasia criteria 4
  • 49. Comparison of vaccine efficacy: Sham-immunized controls challenged against EEEV Efficacy trials of potential vaccine or therapeutic 5
  • 50. Comparison of vaccine efficacy: SIN-SAEEEV vaccinated (nonprotective – 17% survival) Efficacy trials of potential vaccine or therapeutic 5
  • 51. Comparison of vaccine efficacy: SIN/NAEEEV vaccinated (significant protection – 82% survival) Efficacy trials of potential vaccine or therapeutic 5
  • 52. Summary Real-time monitoring of physiological parameters using less-invasive implanted telemetry devices will provide critical data for: 1. Development of animal models for biodefense or emerging diseases 2. Evaluation of potential vaccines and therapeutics 3. Establishment of objective criteria for therapeutic interventions or endpoints
  • 53. Thank You! For additional information on telemetry applications and various DSI solutions for continuous monitoring of physiology in pre- clinical research studies please visit: www.datasci.com
  • 54. ACCESS THE RECORDING AND SUPPLIMENTARY MATERIALS FOR THIS EVENT AND OTHERS AT http://goo.gl/yLiXpP JOIN OUR GROUP ON LINKEDIN FOR INFORMATION ON UPCOMING EVENTS, ON-DEMAND WEBINARS, AND ADDITIONAL LAB RESOURCES
  • 55. InsideScientific is an online educational environment designed for life science researchers. Our goal is to aid in the sharing and distribution of scientific information regarding innovative technologies, protocols, research tools and laboratory services.