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Clinical Pharmacology in
Orphan Drug Development
KoNECT 3rd Regulatory Symposium
CAPT E. Dennis Bashaw, PharmD.
Director, Division of Clinical Pharmacology-3
Office of Clinical Pharmacology
Office of Translational Sciences
CDER/FDA

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Disclaimer: 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.

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Outline
• Drug Development and Orphan Drugs/Rare
Diseases in the United States: An Overview
• 1983 Orphan Drugs Act-PROBLEM SOLVED?
• Challenges And the Role of the Regulator:
Science, Regulation, and Policy
• Bringing Clinical Pharmacology Tools to Bear
• Concluding Thoughts

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DRUG DEVELOPMENT AND ORPHAN
DRUGS/RARE DISEASES IN THE
UNITED STATES: AN OVERVIEW

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Pre Orphan Drug Act: 1982
• 1973-1982: 10 new drugs for rare diseases
– Little economic incentive for large pharmaceutical
companies to pursue rare disease indications
• ≈7,000 rare diseases; 25 million people
– In comparison: 67 million American adults (31%)
have high blood pressure—that’s 1 in every 3
people in this room
(http://www.cdc.gov/bloodpressure/facts.htm)
• ~85% of orphan diseases have a genetic basis
• Increasing by ~100 diseases/year

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Chronology of Drug Development
for Classical and Orphan Drug
Nature Reviews and Drug Discovery, 2003, Volume 2, Page 71

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Trends in Drug Discovery
Scannell, JW, et al “Diagnosing the decline in pharmaceutical R&D efficiency”
Nature Reviews Drug Discovery, 11:191-200 (March 2012)
An unsustainable
trend for an Orphan
Drug

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

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Fast Track Designation
• Drug intended to treat a serious condition
• Nonclinical or clinical data needed to
demonstrate the potential to meet an
unmet medical need.
Breakthrough
• Drug intended to treat a serious condition
• Must be preliminary clinical evidence to
indicate the drug may substantially improve a
clinically significant endpoint compared to
available therapies
Priority Review
• Drug must treat a serious condition and, if
approved, offer a significant improvement in
safety or effectiveness
• Designation assigned only at the time of the
original NDA or efficacy filing
Accelerated Approval
• Drug must treat a serious condition and
generally provide a meaningful advantage over
available therapies
• Must demonstrate an effect on a surrogate
endpoint that is likely to predict a clinical
benefit or on a clinical endpoint
FDA’s “Accelerated” Pathways –
Not Exclusive to Orphan Drugs
Entering Drug
Development cycle
To Market
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

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Accelerated Pathways Under PDUFA-V
https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm552923.pdf

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1983 ORPHAN DRUG ACT –
PROBLEM SOLVED?

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The Orphan Drug Act
21 CFR314.105

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How Well Are We Doing?
• In past few years
– ~1/3 of all NME approvals are Orphan products
– 2/3 of therapeutic biological product approvals
• While there has been progress in the general science and
approval of Orphan Drugs….just like an iceberg much more
lies below the surface to be done.
– 7,000 plus indications
• Since 1983
– 4071* drugs with an orphan designation
– 602* drugs approved……..
*as of 4/23/2017

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NME/NDA Approvals: Total vs Orphan
15
24
33
25
30
33
22
14
3
7
11
8
10
12
9
3
0
5
10
15
20
25
30
35
2010 2011 2012 2013 2014 2015 2016 2017
NME
Orphan NME
*

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NME-BLA Approvals: Total vs Orphan
6 6 6
4
11
12
10
6
3
4
2
1
7 7
5
3
0
2
4
6
8
10
12
14
2010 2011 2012 2013 2014 2015 2016 2017
BLA
Orphan BLA
*
* As of April 25th, 2017

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CHALLENGES AND THE ROLE OF THE REGULATOR:
SCIENCE, REGULATION, AND POLICY

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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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The REGULATORS “DUAL” Role
National
Authority
Regulations
Science
Conservative Innovation
Clinical
Pharmacology
Regulations provide room for flexibility in the review of treatments for rare diseases
and the application of regulatory standards….i.e., good scientific judgment

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Rare Disease Guidance-Common Issues

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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
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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INNOVATIVE ANALYSES
•Improved Computing Resources
•Quantitative drug-disease-trial models
• Exposure-response models
INNOVATIVE TRIAL DESIGNS
• Clinical trial simulations
• Enrichment, adaptive, dose-response
• In Silico
KNOWLEDGE MANAGEMENT
• Leverage prior data
• Locate and observe trends
• Understand the need
Bringing Clinical Pharmacology
Tools to Bear

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Trends in Orphan Drug Approvals and
Development
Clin Pharmacol Ther. 2012
May;91(5):932-6.
doi: 10.1038/clpt.2012.23.

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Orphan Drug Approvals (NMEs)
by Therapeutic Area

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A Graphical Perspective on Trends in
Orphan Drug Development for NMEs

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Orphan/Rare Disease NME Approvals
by Cohort
0
5
10
15
20
25
30
2011-2015 2006-2010

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Orphan Designations vs
TOTAL Orphan Approvals*
195 203
190
231
291
355
333
125
15 26 26 33
49 48 39
12
0
50
100
150
200
250
300
350
400
2010 2011 2012 2013 2014 2015 2016 2017
Orphan Designations
Approvals
470 Requests
(75% Acceptance)
*Includes Orphan Indications for Approved Drugs (re-purposing)
** As of April 25th, 2017
**

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INNOVATIVE ANALYSES
•Improved Computing Resources
•Quantitative drug-disease-trial models
• Exposure-response models
INNOVATIVE TRIAL DESIGNS
• Clinical trial simulations
• Enrichment, adaptive, dose-response
• In Silico
KNOWLEDGE MANAGEMENT
• Leverage prior data
• Locate and observe trends
• Understand the need
Bringing Clinical Pharmacology
Tools to Bear

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Clinical Pharmacology Studies in an NDA
• Bioavailability (Absolute or Relative)
– Radiolabel
• Dose and/or Dosage Form Proportionality
• Single Dose Pharmacokinetics
• Multiple Dose Pharmacokinetics
• Metabolism Studies
– P-450 Isoenzymes
• Special Populations
– Elderly
– Renal Failure/ Hepatic Failure
– Pediatrics
• Misc.
– Formulation Studies
– Bioequivalency (Clinical vs. To-be-marketed)
– Drug Interaction
– Protein Binding
– Mechanism of Action
– Dissolution
 Exposure Response
 Dose Response
 Dose Titration
 Surrogate Endpoint
 Pharmacometrics
 Pharmacogenomics

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Orphan Drug Review at the FDA
Eliglustat for Gaucher’s Disease
• Gaucher disease is a rare, autosomal recessive lysosomal storage
disorder caused by a deficiency in the lysosomal enzyme
glucocerebrosidase (or acid-β glucosidase), which catalyzes the
hydrolysis of glucosylceramide (or GL-1) to glucose and ceramide.
This enzyme deficiency results in the accumulation of GL-1,
especially in the liver, spleen, and bone marrow.
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205494Orig1s000ClinPharmR.pdf

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Eliglustat (Cerdelga®)
• Eliglustat is a selective glucosylceramide synthase inhibitor for
substrate reduction therapy (SRT) to reduce the synthesis and
hence the accumulation of GL-1.
• Received both a Priority Review and Orphan Drug Designation

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Metabolic Information Available on
Eliglustat Prior to PBPK Modeling
• Metabolized by CYP2D6 (~80%) and CYP3A (~20%)
• High clearance, nonlinear PK: time-dependent CYP2D6 inhibitor
• Clinical drug interaction studies
– With strong CYP2D6 inhibitor paroxetine: AUC increased by ~8-fold
– With strong CYP3A inhibitor ketoconazole: AUC increased by ~4-fold
• Pharmacogenetic effects: PM/EM ~ 8-fold

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Combining the Workstreams
Pharmacogenomics
Utilize in vitro systems
to identify relevant CPY
polymorphism
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

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Impact of PBPK on Labeling
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205494Orig1s000lbl.pdf

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Impact of PBPK on Labeling
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205494Orig1s000lbl.pdf

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CONCLUDING THOUGHTS

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FDA-NIH Collaboration

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FDA-TRND Collaboration

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In October 2011, FDA awarded $2 million to launch Centers of
Excellence in Regulatory Science and Innovation at the
University of Maryland and Georgetown University. The
investment is part of FDA’s effort, outlined in the Agency's
strategic plan, to foster a robust, collaborative, regulatory
science culture that enables FDA to address the scientific
challenges presented by revolutions in medical product
development and to improve food safety and quality. In 2014
two new centers were established in collaboration with the FDA.
FDA-Academic Collaboration

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An International Concern

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Policies to Incentivize Orphan Drug
Development - APAC & Major Regions*
POLICY elements USA EU Australia Japan S. Korea Singapore Taiwan
Legal framework 
(1983)

(2000)

(1997)

(1993)

(1998)

(1991)

(2000)
Prevalence
(per 10,000)
7.5 5 1 4 4 36 1
Other criteria
Life-
threatening &
chronically
debilitating
Incurable
disease with no
alternative
treatment
No alternative
treatment
Marketing exclusivity 7 years 10 years - 10 years 6 years§
- 10 years
Tax credit/Grants for R&D  - -  - - -
Accelerated MA procedure   **   ** **
Fee reduction     - - -
Protocol assistance   -  - - 
*Slide modified from David Tsui (Shire Pharmaceuticals
** For life saving drugs where there is no therapeutic alternative
§ proposal to increase to a maximum of 10 years

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International Update
(beyond US and APAC)

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Development of Safe and Effective Drugs
For ALL Requires a Team Effort
Academia
Industry
International
Collaboration
Patient
Advocacy
FDA 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