This is the companion talk to one I posted yesterday. This is the Third of the talks that I gave in Asia back in May. Both this talk and the "Making Every Patient Count" presentation were part of a larger program at the DIA China Annual meeting.

1. Optimizing Clinical Trials
with Advanced Tools
CAPT E. Dennis Bashaw, Pharm.D.
Dir. Division of Clinical Pharmacology-3
Office of Clinical Pharmacology
Office of Translational Sciences
US Food and Drug Administration
Session 901:STRATEGY OF CLINICAL DEVELOPMENT

2. 2
• The presentation today should not be
considered, in whole or in part as being
statements of policy or recommendation
by the US Food and Drug Administration.
• Throughout the talk, representative
examples of commercial products will be
mentioned. No commercial endorsement
is either implied or intended.

3. 3
Outline
• 21st Century Challenges in Drug
Development
• Beyond Classical PK/PD
• Case Studies
–Secukinumab
–Edoxaban
• Lessons Learned
• Conclusions and Closing Thoughts

4. 4
21ST CENTURY CHALLENGES IN
DRUG DEVELOPMENT

5. 5
Current Snapshot
https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM536693.pdf

6. 6
Lengthy Process to Reach Market

7. 7
Updated Drug Development Cost Figures
J Health Econ. 2016 May;47:20-33. doi: 10.1016/j.jhealeco.2016.01.012

8. 8
The Cost of Research vs Ease of Conduct
High
Low
Single Center Randomized Trials
Low
Single Case
Reports
Cohort Studies
Case-Control Studies
Case Series
HighEase of conduct
Multi-Center Randomized Trials
Cost

9. 9
Why Replicate Trials?
• Guidance for Industry-Providing Clinical Evidence of
Effectiveness for Human Drugs and Biological Products
– Congress adopted the 1962 Drug Amendments, Section 505(d) of the Act uses
the plural form in defining “substantial evidence” as “adequate and well-
controlled investigations, including clinical investigations.” See also use of
“investigations” in section 505(b) of the Act, which lists the contents of a new
drug application. which included a provision requiring manufacturers of drug
products to establish a drug’s effectiveness by "substantial evidence." Substantial
evidence was defined in section505(d) of the Act as “evidence consisting of
adequate and well-controlled investigations, including clinical investigations, by
experts qualified by scientific training and experience to evaluate the
effectiveness of the drug involved, on the basis of which it could fairly and
responsibly be concluded by such experts that the drug will have the effect it
purports or is represented to have under the conditions of use prescribed,
recommended, or suggested in the labeling or proposed labeling thereof.”

10. 10
BEYOND CLASSICAL PK/PD
Patrick Muller and Mark Milton, “The Determination and Interpretation of the Therapeutic Index in Drug Development”
Nature Reviews Drug Discovery, 2012, vol. 11, pg 751-751

11. 11
The Triad of Drug Innovation
• Knowledge Management
– Leveraging information
• Biomarker Qualification
• Disease History
• Innovative Trial Designs
– Moving away from the “2 replicate trials” standard
• Innovative Analysis
– Pharmacometrics
• Modeling and Simulation
– Pharmcogenomics
• Patient Factors
– Pharmacovigilance

12. 12
Tools vs Utility
• In the last 20yrs, the term “precision medicine” has been
growing in the literature as a goal to real patient
individualization
• Ideally precision medicine should include not only patient care
but also encompass drug development
– Identify and include actionable information on patient
factors
– Empower the physician to use state of the art diagnostics
and biomarkers
Huang S-M, Temple R, Clin Pharmacol Ther. 2008

13. 13
Linkage of Patient Factors
to PK and PD

14. 14
• Post Marketing
Commitments
• Post Marketing
Requirements
• Pediatric
• Special Populations
• Line Extensions
• Product Life-Cycle
• Model Refinement?
Parallel Tracks
Post
Marketing
Phase
3
Phase
2
Phase
1
Pre-
Clinical
EOP2IND Filed EOP2a
Preliminary PD
Markers
LEARN!Confirm Refine
Pharmacodynamic & Biomarker
Development And Qualification
NDA Filed

15. 15
SECUKINUMAB
DOSE RANGING-PHASE II TO PHASE III

16. 16
Psoriasis and Inflammatory Cascade
• Psoriasis is a complex inflammatory disease that occurs in genetically susceptible
individuals. It is a common, immune-mediated disease, affecting 7.4 million
adults. In these patients there are many cytokines whose levels are elevated,
including TNF-α, IFN-γ, IL-6, IL-8, IL-12, IL-18, and IL-17.3 The IL-17 family consists
of subtypes A–F, with IL-17A having the most prominent role in host defense and
autoimmunity.
https://www.dovepress.com/long-term-safety-of-biologics-in-the-treatment-of-psoriasis-peer-reviewed-fulltext-article-PTT#F1

17. 17
Case 1: Secukinumab
• Human interleukin-17A antagonist indicated for the
treatment of moderate to severe plaque psoriasis in
adult patients who are candidates for systemic therapy
or phototherapy
– adults with psoriatic arthritis
– adults with active ankylosing spondylitis
• Dose-ranging in Phase II can help identify subgroups
who may benefit from altered dosing

18. 18
Phase II Dose-Ranging Study

19. 19
Phase II Study Results
• Subgroup analysis showed an increased benefit with
regardless of body weight, but highest response was
in patients with body weight <90 kg
• Results from this trial and other sources support
benefit of exploring a higher 300 mg dose in Phase III
Endpoint Placebo
Secukinumab
25 (x1) mg 25 (x3) mg 75 (x3) mg 150 (x3) mg
PASI 75 9% 3% 19% 57% 82%
IGA 0/1 9% 0% 12% 33% 48%
Papp et al, 2012

20. 20
Phase III Confirms Benefit of
Higher Dose
• A significant difference in efficacy between two weight strata was
observed.
• Difference between weight group within each dose is similar to the
difference between doses
• Dose can be optimized for best risk/benefit accordingly for each
weight group
Dose 150 mg 300 mg
Weight Group ≥ 90 kg
(N=215)
< 90 kg
(N=355)
≥ 90 kg
(N=209)
< 90 kg
(N=359)
PASI 75 132 (61%) 261 (74%) 152 (73%) 297 (83%)
IGA 0/1 98 (46%) 194 (55%) 119 (57%) 243 (68%)
http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DermatologicandOphthalmicDrugsAdvisoryCommittee/ucm404866.htm

21. 21
Case 1: Outcome
• Phase III trial results support safety and efficacy of
both doses
• Patients with higher body weight or those that are
non-responsive at the 300 mg dose may benefit from a
further increase in dosing
• Sponsor agreed to conduct a post-marketing study to
evaluate a higher dose

22. 22
Secukinumab Development Timeline
https://www.dovepress.com/secukinumab-for-rheumatology-development-and-its-potential-place-in-th-peer-reviewed-fulltext-article-DDDT

23. 23
A “Quiver” of Arrows
https://www.fda.gov/downloads/AdvisoryCommittees/UCM419023.pdf

24. 24
EDOXABAN
Edoxaban
Factor Xa Inhibitor

25. 25
Case 2: Edoxaban
• Indicated to reduce the risk of stroke and systemic embolism in
patients with non-valvular atrial fibrillation
– Also indicated for treatment of deep vein thrombosis and
pulmonary embolism
• Edoxaban inhibits free factor Xa and prothrombinase activity
and inhibits thrombin-induced platelet aggregation. Inhibition of
factor Xa in the coagulation cascade reduces thrombin
generation and thrombus formation.
• Anti-coagulant class associated with steep bleeding and stroke
dose and exposure-response curves

26. 26
Phase II Edoxaban: 30 and 60 mg
QD based on study in patients
with atrial fibrillation
Salazar et al., Thromb Haemost, 2012
Dose selection for Phase III based
on bleeding event rate

27. 27
Phase II Edoxaban: Doses selected to
achieve less bleeding than warfarin
Salazar et al., Thromb Haemost, 2012

28. 28
Dose Response Is Evident
For Stroke & Major Bleeding Events
mITT population,
on-treatment events

29. 29
Renal Clearance is the
Major Edoxaban Elimination Pathway
• 60% of systemic edoxaban cleared
by the kidneys
• AUC increased 32%, 74%, and
72% for mild, moderate, and
severe impairment
• Patients with moderate renal
impairment received a 50% dose
reduction in the Phase 3 ENGAGE
AF study
Applicant: CSR U-120, Table 11.2, Edoxaban 60 mg; CSR U-301, Tables 14.2.5.2, 14.5.3.24, Edoxaban 60 mg
ModerateMildNormal
Edoxaban Ctrough (ng/mL)
50% Dose Reduction
High Dose Arm

30. 30
Patients with Normal Renal Function
with 60 mg Edoxaban had a Higher Risk
for Stroke/SEE Relative to Warfarin
Applicant: CSR U-120, Table 11.2, Edoxaban 60 mg; CSR U-301, Tables 14.2.5.2, 14.5.3.24, Edoxaban 60 mg
Stroke/SEE
Renal Function Category Hazard Ratio (95% CI) Hazard Ratio (95% CI)
Edoxaban Better Warfarin Better
Major Bleeds
30

31. 31
Case 2: Outcome
• Concerns identified with stroke event rate in patients with
normal renal function
• Such subjects would have lower exposure given edoxaban’s
primary route of elimination
• Boxed warning included in labeling based on renal function >90
mL/min

32. 32
Labeling Outcome

33. 33
PD Knowledge Driven Development
https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovascularandrenaldrugsadvisorycommittee/ucm420704.pdf
Biomarker Well Understood
IND May 2007 NDA Jan 2014
Type “C” Sept 2013
Pre-NDA Mtg. Feb 2012
EOP2 Aug 2008

34. 34
LESSONS LEARNED

35. 35
Time for Development
• Although both Edoxaban and Secukinumab were developed by
different companies and were reviewed by different divisions at
the FDA they share at least two things in common:
– They both were approved in 7yrs from the time of initial IND
filing.
– They both leveraged information from biomarkers
• The clotting cascade for Edoxaban
• The discovery of IL-17’s role for Secukinumab

36. 36
36
Biomarkers and Modeling
Adapted from S. McCune, Dep Dir., Office of Translational Sciences, Pediatric Advisory Committee-Neonatal Subcommittee Mtg. March 2013

37. 37
Biomarkers Are the Present
and the Future
• Biomarkers
– Expand understanding of the disease and its progression
– Provide insight into FUTURE drug development
– Provide the potential for clinician based individualization
(i.e., bleeding time vs IL-17A)
– Provide a path forward to a more optimized drug
development program
– Provide opportunities for collaboration with regulatory
bodies

38. 38
FDA Partnership in Qualification
https://www.fda.gov/drugs/developmentapprovalprocess/drugdevelopmenttoolsqualificationprogram/

39. 39
FDA Qualified Biomarkers
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/BiomarkerQualificationProgram/ucm535383.htm

40. 40
CONCLUSIONS AND
CLOSING THOUGHTS

41. 41
The Future
• It is easy to say that we are on the edge of a revolution in drug
development
– We have ALWAYS been on the EDGE!
– Only the tools and our perspective of them have changed
• Patient factors are being recognized more and more as the key
to individualizing not only drug therapy but expectations of
therapy.

42. 42
Communicating the Future
• As new advances are made, they must be reflected both in
regulatory policy and in patient care
• While we rightly focus on the population, we must not lose sight
of the individual patient and the individual physician, nurse, and
pharmacist as well
– Biomarkers can allow us to link the patient, their genetics, the
ontology of the disease, and the healthcare system into a “holistic”
treatment approach
• Clinical Pharmacology can help identify populations and
broaden patient utility and safety
• Only by selecting the right biomarkers and identifying the
proper dose for the patient population can we make “every
patient count” as every patient is a teaching opportunity for us

43. 43
Combining the Workstreams
Biomarker Selection
Utilize in vitro and in
vivo systems to probe
and qualify biomarkers
PBPK Modeling
Build models based on
observed knowledge with a
“learn and confirm” strategy.
Classical PK/PD
Synthesize the
available PK/PD data
on Drug Metabolism
Develop
Actionable
Information
Informed labeling for the
prescriber
Pharmacogenomics
Utilize in vitro systems
to identify relevant
genetic factors to
enhance patient safety
and selection
Patient Selection
Understand the pathology
of the disease to select
the needed diversity in the
affected population

44. 44
Development of Safe and Effective
Drugs For ALL Requires a Team Effort
Academia
Industry
International
Collaboration
Patient
Advocacy
Regulatory
Science
Benefits
To All
Good Science is Everybody’s Business!

45. 45
Contact Information
CAPT Edward D. Bashaw, PharmD.
Director, Div. of Clinical Pharmacology-3
US FDA
10903 New Hampshire Ave
Building 51, Rm 3134
Edward.Bashaw@fda.hhs.gov

46. 46
Acknowledgements
• The Staff of the Division of Clinical
Pharmacology-3
• The Office of Clinical Pharmacology
• The Office of Translational Sciences
• The Drug Information Association-China