This is the slide deck used in my webinar that was presented on 2/1/2018 on the FDA Predictive Toxicology Roadmap. It was presented at a webinar hosted by BioIVT in my private capacity and is not an official statement of FDA policy

1. Early Phase Drug Development and the
FDA’s Predictive Toxicology Roadmap
E. DENNIS BASHAW, PHARMD
CLINICAL PHARMACOLOGY
CONSULTANT
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2. Disclaimer & Disclosures
This presentation should not be considered, in whole or in part as
being statements of policy or recommendation by the United States
Government or the US Food and Drug Administration.
This presentation is being given while I am serving as a private
consultant and in my private capacity.
The views presented here are my personal views based on my
experiences. Researchers are warned that prior to acting on any
information presented here today that they should contact the
relevant regulatory agency for guidance and concurrence before
proceeding.
Throughout the presentation representative products or
organizations may be used as examples to emphasize a point, no
endorsement is either intended or implied.
Neither BioreclaimationIVT, Qualyst, or any agent of these
companies has had any input into the content or scope of todays
presentation.
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3. THE NEED FOR BETTER PATHWAYS AND ROADMAPS
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4. Lengthy Process to Reach Market
PDUFA
4

5. Reasons for Lack of Success
in Drug Discovery
 Lack of fundamental knowledge regarding the causes
of CNS disorders
 Absence of biomarkers for diagnosing and monitoring
these conditions
 A paucity of animal models that are congruent with
the human disease state
 The likelihood that CNS conditions are multifactorial
in their etiology
These factors are true for most therapeutic areas.
They are also factors that we can IMPACT.
Williams, Michael & Enna, S J “Prospects for neurodegenerative and psychiatric disorder drug discovery” Expert Opin. Drug Discov. (2011) 6(5):457-463 5

6. Arrowsmith J, Miller P., “Trial watch: phase II and phase III attrition rates 2011-2012.”
Nat Rev Drug Discov. 2013 Aug;12(8):569. PMID: 23903212
Phase 2 Efficacy Failures
Are to be “expected”-first time in patients
Phase 2 Safety Failures
Are not “un-expected but can be minimized by proper “first in human trials”
Reasons for Attrition in Phase 2 Studies
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7. Updated Drug Development Cost Figures
J Health Econ. 2016 May;47:20-33. doi: 10.1016/j.jhealeco.2016.01.012 7

8. Predictive Toxicology Roadmap
Issued by the FDA on Dec. 6th 2017
Focused on advancing the science
surrounding lead compound
selection and drug development
Not a “guidance”
Not a “step by step” map
An example of continuing
involvement of the FDA in
promoting Science
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9. 9
Continuity With the 2011 Strategic Plan
www.fda.gov/downloads/scienceresearch/specialtopics/regulatoryscience/ucm268225.pdf
Regulatory Science
Science of developing new tools,
standards, and approaches to assess the
safety, efficacy, quality, and performance
of FDA- regulated products
Vision
FDA will advance regulatory science to
speed innovation, improve regulatory
decision- making, and get products to
people in need. 21st Century regulatory
science will be a driving force as FDA
works with diverse partners to protect
and promote the health of our nation and
the global community

10. 10
2. Stimulate Innovation in Clinical Evaluations & Personalized
Medicine to Improve Product Development and Patient Outcomes
4. Ensure FDA Readiness to Evaluate Innovative Emerging Technologies
6. Implement a New Prevention-Focused food Safety System to
Protect Public Health
5. Harness Diverse Data Through Information Sciences to Improve
Health Outcomes
7. Facilitate Development of medical Countermeasures to Protect
Against Threats to U.S. and Global Health and Security
8. Strengthen Social and Behavorial Science to Help Consumers
and Professionals Make Informed Decisions about Regulated Products
1. Modernize Toxicology to Enhance Product Safety
3. Support New Approaches to Improve Product Manufacturing
and Quality
Science Priority Areas

11. The Roadmap is Not Exclusive it is
Intended to be INCLUSIVE!
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12. Roadmap Elements-Research
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13. TGN1412
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14. Clinical Trial Chronology
TeGenero “first in human” (FIH) study of TGN1412
◦ Direct immune stimulation
Trial initiated March 13, 2006
Four single doses of 0.1, 0.5, 2.0 and 5.0 mg/kg planned in
4 groups of 8 subjects
1st cohort:
◦ 0.1 mg/kg IV at 2 mg/min to 6 subjects in the course of one hour
(i.e., one subject dosed every 10 minutes)
◦ Placebo: 2 subjects
G. Suntharalingam, et al., “Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412” NEJM, 355;10, pg 1018-1028
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15. Clinical Course
Within 90 min dosing
◦ Severe headache, lumbar myalgia, pyrexia, rigors
◦ Nausea, vomiting, diarrhea
◦ Amnestic episodes, restlessness
◦ Erythema, desquamation
◦ Peripheral vasodilation, hypotension, tachycardia
Subjects/patients admitted to ICU 12-16 hours
after dosing
◦ Multisystem failure
◦ Metabolic acidosis, Disseminated Intravascular Coagulation
◦ Respiratory failure, bilateral infiltrates
Cytokine storm
◦ Lymphopenia, monocytopenia
◦ ↑ ↑ TNF α
◦ ↑ IL-2, IL-6, IL-10
◦ ↑ IFN-γ
G. Suntharalingam, et al., “Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412” NEJM, 355;10, pg 1018-1028 15

16. Therapy
Aggressive supportive management
◦ Steroids
◦ Daclizumab (anti-IL2 receptor antagonist)
◦ Pulmonary support, dialysis, fresh frozen plasma
◦ Irradiated cells to decrease GVHD
EXPERT SCIENTIFIC GROUP ON PHASE ONE CLINICAL TRIALS, www.tsoshop.co.uk
Time Course of Immunologic Effects
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17. TGN1412-What Went Wrong?
Animal-Human Pharmacology
• Potential differences between humans and
monkeys
 CD28 structure difference in three
transmembrane residues
 CD28SA binding kinetics and calcium
response (sustained in humans)
 Immunological Synapse (IS) formation
involving CD28 crosslinking
 Greater T-cell adhesion to endothelial
cells in humans
 Greater immunoregulation in animals
Hansel, T., et al, “The Safety and Side Effects of Monoclonal Antibodies”, Nature Reviews Drug Discovery, 2010 Apr; 9(4): 325-38 17

18. General Information Flow for
Determining a FIH Dose: TGN1412
Tibbits J., et al, “Practicalapproaches to dose selection for first-in-human clinical trials with novel
biopharmaceuticals” Regulatory Toxicology and Pharmacology, Volume 58, Issue 2, 2010, 243 - 251
BIA 10-2474
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19. Moving Forward
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20. EMA First-in-Human Study Guideline
Revised July 25, 2017
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/07/WC500232186.pdf 20

21. EMA First-in-Human Study Guideline
Revised July 25, 2017
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22. Pre-Clinical Pharmacokinetics and Man
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23. Hepatic Based Safety Withdrawals (1997)
Drug Saf (2014) 37 (Suppl 1):S9–S17 DOI 10.1007/s40264-014-0182-7
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24. Hepatic Based Safety Withdrawals (1997)
Drug Saf (2014) 37 (Suppl 1):S9–S17 DOI 10.1007/s40264-014-0182-7
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25. Hy’s Law
A Regulatory “Gold” Standard
Drugs are likely to cause a high rate (10-50%) of fatal liver injury or need for
transplant in patients with acute hepatocellular injury sufficient to cause jaundice.
Translated into signals in drug development, this means that we expect serious
toxicity if there is:
• Increased rate (compared to control) of aminotransferase elevation to ≥ 3x ULN
indicating hepatocellular injury; greater elevations cause greater concern, but
alone do not predict severe toxicity (aspirin, tacrine, heparin, statins, many other
drugs).
• Total bilirubin > 2x ULN; 2 cases or even 1 case.
• Little or no cholestasis (AP close to normal).
• No other good explanation for the injury (hepatitis A, B, C, or other viral hepatic
injury, alcohol ingestion, congestive heart failure).
Patients with all 4 of these are “Hy’s Law” cases.
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26. Problems With Hy’s Law and Other
Clinically Based Markers
•A Hy’s Law case predicts severe injury at a rate of at least
1/10 of the rate of Hy’s Law cases. Thus: 1 case in 1000
suggests severe injury at a rate of 1/10,000.
• It requires exposure of relatively large numbers of subjects to
have predictive impact (thousands of patients)
•A clinically based “rule” or “law” is predicated that we have
reached Phase III trials where large numbers are exposed
• Drug failure at this point can be catastrophic to the affected patients
• Drug failure at this point (for any reason) IS catastrophic to a
company
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27. Animal-Man Extrapolation
CYP-Preservation Across Species
NOT!
http://dx.doi.org/10.5487/TR.2015.31.2.137
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28. Use of Human Hepatocytes in Drug
Development
Metabolic Profiling
Drug Drug Interaction
 Inhibition
 Induction
 Transporter Based
Drug Induced Liver Impairment (DILI)
 Cytotoxic Assays
 Toxicogenomics
These are well established uses and covered by
applicable guidance's and publications, but what
about the FUTURE
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29. In Vitro Cell Culture Systems
Broad classification of cell-culture systems used for developing liver-based
multiorgan models. (A) Multiwell plate (monInterconnected oculture,
transwell, and interconnected culture), (B) Macroscale bioreactor, (C)
microfluidic platforms and (D) Static microscale platforms.
Tissue Eng Part B Rev. 2016 Oct 1; 22(5): 383–394.
doi: 10.1089/ten.teb.2016.0031 29

30. Integrated Discrete Multiple Organ
Co-culture (IdMOC TM)
IdMOCTM consists of multiple shallow wells within a larger containing
well (chamber). Cells are plated firstly into the shallow wells (one cell
type per well) to allow attachment and growth. Upon establishment of
the cultures, the shallow wells are flooded with a co-culture medium,
allowing cells from the difference inner wells to communicate via
soluble factors.
The cells can then be challenged with different drugs or other factors to
assess either hepatocyte viability or metabolic activity and toxicity
http://dx.doi.org/10.5487/TR.2015.31.2.137
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31. Demonstration of Cytotoxicity of
Cyclophosphamide in IdMOCTM With Human
Hepatocytes and 3T3* Cells
http://dx.doi.org/10.5487/TR.2015.31.2.137
*standard fibroblast cell line
Dose dependent cytotoxicity of cyclophosphamide to 3T3 cells in the presence
of hepatocytes which are necessary to form the cytotoxic metabolite. Allowing
the screening of compounds that use metabolic activation.
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32. Success with single organ cell cultures has led to multi-organ plates that can
evaluate the interaction between more and more tissues that are pseudo-
“whole body” and are becoming commercially available:
Trademarks and images belong to the respective holders, no endorsement is implied or intended.
IdMOCTM AlvetexTM Perfusion PlateHuDMOPTM
Human Dynamic Multiple Organ Plate
Commercialization of Multi-Organ Plates

33. The Next Step
“Human Body on a Chip”
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34. International Interest and Consortia
There are multiple university-government
sponsored consortia based programs developing
“human on a chip” models that link “organs”
together to develop physiologically correct
human systems. Examples include:
 University of Pittsburg-Drug Discovery Institute
 Los Alamos National Laboratory-ATHENA Program
 Wake Forest University Institute for Regenerative Medicine
 Technische Universitat Berlin Go-Bio Initiative
 Russian Ministry of Education and Science Homunculus Program
 EC Body on a Chip Consortia
They are in fact cellular based surrogates for
physiologically based pharmacokinetic models.
http://pharmguse.net/pkdm/pbpm.jpg
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35. Images illustrate four MPS prototypes in experimental evaluation aiming to advance multi-
organ systems into miniature organisms on a chip. (A) The German “GO-Bio-MOC” program-
derived 10-organ prototype of TissUse GmbH, Germany (Courtesy of TissUse GmbH,
Germany); (B) The Russian “Homunculus” program-derived 6-organ prototype design of
Bioclinicum, Russia (Courtesy of Bioclinicum, Russia); (C) The US 10-organ prototype of
Cornell University, USA (Courtesy of Cornell University, USA); and (D) a US 4-way
PhysioMimetics prototype of the Human Physiome on a Chip Program, MIT, USA (Courtesy of
MIT, USA), developed within the framework of the US DARPA/NIH/FDA MPS initiative.
ALTEX. 2016 ; 33(3): 272–321. doi:10.14573/altex.1603161 35

36. Are We There YET?-And WHY NOT!
ALTEX. 2016 ; 33(3): 272–321. doi:10.14573/altex.1603161
Experimental Biology and Medicine 2017; 242:
1573–1578.DOI: 10.1177/1535370217700523
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37. Conclusions
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Escher-Man Image copyright Andrew Lipson, used by permission

38. Continuing Commitment to Improving the
Science, Tools, and
COLLABORATION!
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40. Development of Safe and Effective Drugs
Requires a Team Effort
Academia
Industry
International
Collaboration
Patient
Advocacy
Regulators
Benefits
To All
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41. Toxicology Roadmap and
Pre-Clinical Research
The goal of the roadmap is to encourage new methodologies and to
improve on current methods
In vitro cellular based systems using human biomaterials allows a closer
replication of the in vivo system and can be used to screen drugs for
toxicity long before the first exposure to humans
Animal testing has a role, but it is not an exact surrogate for humans,
especially metabolically where cross-species CYP-P450 preservation is
low making human hepatocyte studies crucial to development
While human testing is and will always be a necessary component of
safety testing, avoidance of toxicity thru proper candidate selection and
dose estimation can improve throughput in an increasingly complex and
expensive drug development process
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42. A New Roadmap For Drug Development
Harnessing In Vitro Multi-Organ Models
ALTEX. 2016 ; 33(3): 272–321. doi:10.14573/altex.1603161
A Challenge-Where is YOUR “ROADMAP” taking you?
Are you using the best tools you can ?
If not, WHY NOT?
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Concluding Thought
“If I had five minutes to
chop down a tree, I’d spend
the first three minutes
sharpening my axe.”
Abraham Lincoln
Rigorous preparation and Best In Class Tools are the key to success

44. Contact Information
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45. Further Reading
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