This document discusses challenges and solutions for developing orphan drugs and implementing precision medicine programs. It notes that orphan drug development faces resource constraints as trials require more patients than rare diseases have. However, using clinical pharmacology tools allows learning from small populations by incorporating biomarkers, modeling, and innovative designs. The future of drug development lies in going beyond traditional trials to involve patients more and continually learn from individual experiences. Quantitative tools during all stages of development can extract maximum knowledge from minimal data to improve understanding, approval chances, and labeling.

1. Translational Sciences and Clinical
Pharmacology in Orphan Drug Development
精准医学的临床部署：挑战与解决方案
Practical Challenges and Solutions for
Implementing Precision Medicine Programs
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

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 Orphan Drug
Development
• Personalized Medicine and Clinical
Pharmacology
• Problems and Solutions
• Building Knowledge for Tomorrow & Today

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21ST CENTURY CHALLENGES IN
ORPHAN DRUG DEVELOPMENT

5. 5
Lengthy Process to Reach Market
(TIME)

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

7. 7
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
Essentially Orphan Drugs and Rare Diseases are caught in a
“RESOURCE SQUEEZE” that the standard drug development
paradigm is ill-suited for.

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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?)

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Making Every Patient Count

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Orphan Development Paradox
Ironically, given the small absolute number of subjects that
are studied in an orphan product development program,
relative to the TOTAL size of the population the number of
subjects studied is actually a high percentage. Thus, our
understanding of the drug: disease interplay is quite high.
Thus we CAN (and MUST) do MORE with LESS by using
advanced tools.
Photo by kazuend on Unsplash

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PERSONALIZED MEDICINE AND
CLINICAL PHARMACOLOGY

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Personalized Medicine &
Personalized Genomics
• Personalized medicine uses traditional, as well as emerging
concepts of the genetic and environmental basis of disease to
individualize prevention, diagnosis and treatment.
• Personalized genomics builds on principles established by the
integration of genetics into medical practice.
• Principles shared by genetic and genomic aspects of medicine,
include the use of variants as markers for diagnosis, prognosis,
prevention, as well as targets for treatment.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128266/

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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.
• For Rare Diseases successful programs have to incorporate these
concepts at the patient and molecular level.
Huang S-M, Temple R, Clin Pharmacol Ther. 2008

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Personalized Medicine
in the Age of Biomarkers

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Decreased Development Time
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=10588&pubmed-linkout=1
A net decrease in
development time of 34
months or almost 3yrs

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Regulatory Challenge
• Orphan drugs held to same evidentiary standard as non-
Orphan drugs
• To be approved in US, Orphan drugs must:
– Demonstrate substantial evidence of effectiveness/clinical benefit
(21CFR 314.50)
– Substantial evidence of benefit requires:
• Adequate and well-controlled clinical study(ies)
– designed well enough so as to be able “to distinguish the effect
of a drug from other influences, such as spontaneous change…,
placebo effect, or biased observation” (§314.126)

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Challenges in Orphan Drug /Rare Disease
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
Proper deployment of Clinical Pharmacology in orphan drug
development can extract the most amount of knowledge from least
amount of information

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http://www.ctsi.umn.edu/sites/ctsi.umn.edu/files/chris-austin-ncats-presentation-umn-10.21.14.pdf

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Increased Understanding and
A Long Way To Go
http://www.ctsi.umn.edu/sites/ctsi.umn.edu/files/chris-austin-ncats-presentation-umn-10.21.14.pdf

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The Standard Phases of Drug Development
(or the growth of patient involvement)
Building Clinical Pharmacology
INTO A Development Program

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Learn and Confirm
Vs Identify, Confirm, Refine, and LEARN
• 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

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Quantitative Tools During Drug
Development
Tools
Decisions Target ID
ADME, Biomarkers, POC, Dose,
Efficacy, Safety, Approval,
Labeling
Safety, New
Indication
Process Pre-IND
EOP2A
EOP2
NDA/BLA
Quantitative ModelsMechanistic Empirical
Innovative
Designs

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Linkage of Patient Factors
to PK and PD

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BUILDING KNOWLEDGE FOR
TOMORROW & TODAY

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

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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 INVOLVEMENT is also shaping orphan drug development
– Defining expectations
– Advocacy for new methods and policies

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Communicating the Future
• 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
– Biomarkers can spur innovation and extrapolation thru re-
purposing of old drugs into underserved populations
• 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
and an opportunity for that one patient as well

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Combining the Workstreams
and Implementation
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
PATIENT
ENGAGEMENT
Feedback on needs
and expectations

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Development of Safe and Effective Drugs
Requires a Team Effort
30
Academia
Industry
International
Collaboration
Patient
Advocacy
Good Science
& Policy
Benefits
To All

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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

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Acknowledgements
• The Staff of the Division of Clinical Pharmacology-3
• The Office of Clinical Pharmacology
• The Office of Translational Sciences
• The International and Chinese Organization for Rare Disease