Talk given at the 25th Anniversary Celebration of the Chinese University of Hong Kong School of Pharmacy

1. Translation of Orphan Disease
Trial Design into
General Drug Development
E. DENNIS BASHAW, PHARM.D.

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.
This presentation is being made in my private capacity and not as an
employee of the US FDA or the US Government
Throughout the talk, representative examples of commercial products
will be mentioned. No commercial endorsement is either implied or
intended.

3. DRUG DEVELOPMENT IN THE US

4. Idealized Drug Development in the US
Nature Reviews and Drug Discovery, 2003, Volume 2, Page 71

5. Lengthy Process to Reach Market
(TIME)
http://phrma.org/sites/default/files/pdf/biopharmaceutical-industry-profile.pdf

6. Drug Development Cost Figures
(MONEY)
J Health Econ. 2016 May;47:20-33. doi: 10.1016/j.jhealeco.2016.01.012
22.39 Billion HK$

7. The Cost of Research vs Ease of Conduct
High
Low
Single Center Randomized Trials
Hard
Case Reports
Cohort Studies
Case-Control Studies
Case Series
EasyEase of conduct
Multi-Center Randomized Trials
CostThe ease of conduct is directly related to cost and inversely
related to the relative informational value of the study

8. National Academies of Science
Workshop Series
“The clinical trials system is “broken” and there needs to be new ways to
collect and utilize patient data”
-Janet Woodcock, MD, Director of FDA’s Center for Drug Evaluation and Research
https://endpts.com/fdas-janet-woodcock-the-clinical-trials-system-is-broken/

9. Beyond the Randomized Clinical Trial
N Engl J Med 2017;377:465-75. DOI:10.1056/NEJMra1614394

10. Orphan Disease
and Drug Development
A MODEL FOR INNOVATION

11. Challenges in Orphan Disease/
Rare Drug Development
Large heterogeneity in disease pathophysiology
Poorly understood natural histories and progression
Few patients are available conducting clinical trials
Uncertain appropriate duration of treatment
Lack appropriate endpoints that predict outcomes
Large heterogeneity in treatment effects
Require compromise, innovation and trade-offs
Make difficult decisions in absence of ideal information

12. Total NME’s Approved - 22
Priority – 15
Orphan Drugs – 9
Fast Track – 8
Breakthrough – 7
Accelerated – 6
Two - 5
Three - 4
Four - 4
Five - 1
https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM536693.pdf
Orphan Drug Approvals 2016
New Molecular Entities

13. Clinical Pharmacology and
Precision Medicine
•Clinical Pharmacology as a science encompasses both
classical pharmacokinetics (drug measurement in the body)
but also the internal (INTRINSIC) and external (EXTRINSIC)
factors that cause variability in drug response (both safety
and efficacy).
•Precision Medicine MUST encompass the tools and science
of Clinical Pharmacology to allow right drug for right
patient.
Huang S-M, Temple R, Clin Pharmacol Ther. 2008

14. Oncology and Orphan Drugs
ORPHAN DRUG APPROVALS (NMES)
BY THERAPEUTIC AREA
•Since 2011, over 50% of all Orphan
Drugs approved have been in the
oncology and hematology area.
•Patients in these groups represent
• A large degree of heterogeneity in
disease pathophysiology
• Poorly understood natural histories
and progression. . . . .

15. Challenges in Orphan Disease/
Rare Drug Development
Large heterogeneity in disease pathophysiology
Poorly understood natural histories and progression
Few patients are available conducting clinical trials
Uncertain appropriate duration of treatment
Lack appropriate endpoints that predict outcomes
Large heterogeneity in treatment effects
Require compromise, innovation and trade-offs
Make difficult decisions in absence of ideal information

16. CLINICAL TRIAL DESIGN
https://irb.research.chop.edu/study-design

17. Making Every Patient Count

18. How Many Patients are Enough?
Population Size Affected
◦ 74.5 million Hypertension
◦ <200,000-10,000 Juvenile Rheumatoid Arthritis (150,000)
◦ <10,000-1,000 Pompe Disease (7,300)
◦ <1,000 N-acetylglutamate Synthase Deficiency (<200?)

19. Enrichment Trial Design
Ann Intern Med. 2016;165:270-278. doi:10.7326/M15-2413
• Can be viewed as a modification of a
standard trial design where patients
screened for trial enrollment are
evaluated for a specific mutation prior to
treatment randomization
• Those with the mutation are then
randomized to therapy
• Those without the mutation are removed
from the trial
• Following screening the population
remaining in the trial is “enriched”
towards responding rather than a naive
randomization without screening

20. Umbrella Trials
Ann Intern Med. 2016;165:270-278. doi:10.7326/M15-2413
• An umbrella trial is restricted to patients with
a single primary site or histologic type of
cancer.
• Those with “actionable” mutations are
grouped together by mutation and are
randomly assigned to therapy that is mutation
“specific”.
• Those without actionable mutations are
removed from the trial.
• The leverage here is that more than one drug
or treatment regimen can be evaluated based
on the observed mutations.

21. Basket Trials
Ann Intern Med. 2016;165:270-278. doi:10.7326/M15-2413
• Patient eligibility is based on a defined
genomic alteration rather than on primary
site.
• They can be nonrandomized or randomized
and can include more than one drug
• In a multi-drug basket study, for each drug
studied, all of the patients share a common
mutation but have different primary disease
sites. The primary disease site deter-mines
the cell type of the tumor, and this may
influence responsiveness to a drug in
addition to mutations present in the tumor.

22. Adaptive Trial Designs
Adaptive aspects can be incorporated into most trial designs,
including the standard cross-over and parallel designs.
It incorporates intermediate looks at the defined times during the
trial and then re-adusting the trial by:
◦ Enrolling more patients
◦ Re-evaluating dosing levels
◦ Changing treatments
◦ Evalutaing multiple biomarkers

23. Real World Evidence
It refers to information on health care that is derived from multiple sources
outside typical clinical research settings, including electronic health records
(EHRs), claims and billing data, product and disease registries, and data
gathered through personal devices and health applications
Real-world evidence can inform therapeutic development, outcomes
research, patient care, research on health care systems, quality
improvement, safety surveillance, and well-controlled effectiveness
studies.
DOI: 10.1056/NEJMsb1609216

24. Quo Vadis
(Where are you going?)

25. Drug Development and Change
•The historical models of drug development have been very
successful
• Decreased rate of death and improved quality of life
•The models did rely on big numbers of patients and a
“regression to the mean approach”
• That is the treatment of the “average patient” guided
patient dosing and drove the need for dose ranging in
Phase 2 and Phase 3 trials (which raised the cost)

26. Orphan Drug Development Model
•Orphan Diseases are those that affect a discrete population
in whom large numbers of subjects cannot be assembled
• Standard drug development models (large, multi-
centered, replicate trials) are inefficient and unfeasible in
this area.
• Orphan Drug Development hinges upon the leveraging of
new sciences and data management strategies
Pharmacogenomics
Physiologically Based Pharmacokinetic (PBPK) Modeling
Innovative Trial Design
Accommodation of REAL WORLD EVIDENCE
•Thus they represent INNOVATION and the FUTURE which
you are entering into professionally thru training

27. PBPK Modeling
Build models based on
observed knowledge with a
“learn and confirm” strategy.
Biomarker Selection
Utilize in vitro and in
vivo systems to probe
and qualify biomarkers
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
PATIENT
ENGAGEMENT
Feedback on needs
and expectations

28. Enhancing Value of Clinical Pharmacodynamics in
Oncology Drug Development: An Alliance Between
Quantitative Pharmacology and Translational Science
The role of the pharmacist in
drug research, development, and
regulation is wide open.
Pharmacists play a vital role in
maintaining and extending the
therapeutic armentarium
Thirty years ago none of these
terms were applied to pharmacists
In my career I have done all of
these roles and more to come.
Clinical Pharmacology & Therapeutics
Volume 101, Issue 1, pages 99-113, 25 NOV 2016 DOI: 10.1002/cpt.544
Pharmacy & Pharmacists

29. Acknowledgements
The Organizing Committee for the 2017 White Coat
Ceremony and Symposia
Dr. ZUO Zhong, Joan
Dr. LEE Hon-Leung, Vincent
29

30. Contact Information
linkedin.com/in/e-dennis-bashaw-82b54276