This document discusses orphan drugs and rare disease drug development. It outlines the challenges in developing drugs for rare diseases, including small patient populations and lack of knowledge. The role of clinical pharmacology in drug development is described, including use of innovative analyses, trial designs, and knowledge management to help overcome challenges. Clinical pharmacology can point the way by applying lessons from oncology and pediatric drug models to the orphan drug context. Collaboration across different stakeholders is needed to develop safe and effective drugs for rare diseases.

1. Orphan Drugs and Rare Diseases
Pointing the Way With Clinical Pharmacology
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

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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.
Throughout the talk, representative examples of
commercial products or software may be given to
illustrate a methodology or approach to problem
solving in drug development. No commercial
endorsement is implied or intended.
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Outline
• The Current State of Orphan Drug Development in the US
• Challenges in Orphan Drug Development
• The Role of Clinical Pharmacology in Drug Development
– Standard Development
– Orphan/Rare Disease Paradigms
• Clinical Pharmacology-Pointing the Way

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THE CURRENT STATE OF
ORPHAN DRUG DEVELOPMENT IN THE US

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FDA Drug Approvals 1980-2015
http://phrma.org/sites/default/files/pdf/biopharmaceutical-industry-profile.pdf

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World-Wide Drug Development Targets

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How Well Are We Doing in the
United States?
• 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
– 3575 drugs with an orphan designation
– 522 drugs approved……..

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Orphan Designations vs
TOTAL Orphan Approvals*
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*Includes Orphan Indications for Approved Drugs (re-purposing)

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CHALLENGES IN ORPHAN DRUG DEVELOPMENT

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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
• (http://www.cdc.gov/bloodpressure/facts.htm)
• ~85% of orphan diseases have a genetic basis
• Increasing by ~100 diseases/year

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The Orphan Drug Act-Jan. 4th, 1983
• While the ODA does NOT comment on the
issue of informational needs or reviewing
standards, it defines what an Orphan Indication
is and provide incentives for the developer.
• “…FDA is required to exercise its scientific
judgment to determine the kind and quantity
of data and information an applicant is
required to provide for a particular drug to
meet the statutory standards…”
The Code of Federal Regulations
(21 CFR314.105)

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Drug Development in the
United States
Nature Reviews and Drug Discovery, 2003, Volume 2, Page 71

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Actual Drug Development
 Although mapped as a linear process,
in reality drug development is
distinctly non-linear
 Even within a drug class, different
approaches can be used to satisfy the
regulatory burden
 Science is not static and can change within
the time period of a drug development
timeline.

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The Challenge and Cost of Development

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 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
Reasons for Lack of Success in
Drug Discovery
These factors are true for most therapeutic areas.
They are also factors that Clinical Pharmacology can impact.
Williams, Michael & Enna, S J “Prospects for neurodegenerative and psychiatric
disorder drug discovery” Expert Opin. Drug Discov. (2011) 6(5):457-463

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THE ROLE OF CLINICAL PHARMACOLOGY IN
DRUG DEVELOPMENT
Any sufficiently advanced technology is indistinguishable from magic.
-Arthur C. Clarke

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Pharmacokinetics vs. Clinical Pharmacology
“Pharmacokinetics is the study of the kinetics of absorption,
distribution, metabolism and excretion of drugs and their
pharmacologic, therapeutic or toxic response in animals and
man.”
“Clinical pharmacology is the science of drugs and their clinical
use. It is underpinned by the basic science of pharmacology,
with added focus on the application of pharmacological
principles and methods in the real world. It has a broad scope,
from the discovery of new target molecules, to the effects of
drug usage in whole populations.” R.E. Notari

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Clinical Pharmacology as a Science
• Clinical Pharmacology is Composed of Many Elements
– Classical Pharmacokinetics
– Classical Pharmacodynamics
– Pharmacometrics
– Pharmacogenomics
– Physiologically Based PK Modeling
– Pharmacovigilance
– And many more….
Image credit: <a href='http://www.123rf.com/photo_10976401
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Clinical Pharmacology and Drug Development
• Clinical Pharmacology plays a crucial role in drug
development
– Enable a better understanding of the disease
– Early candidate and target identification
– Building drug’s entire “story”
• PK/PD, dose identification, biomarkers at all phases of
development
• Support evidentiary standards
– Contribute to the science thru presentation and
publication of results and collaboration

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What is the Role of Clinical Pharmacology
in Orphan/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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The Growth of Clinical Pharmacology
and Research in Rare Diseases
1982 Orphan Drug Act Signed
• Clinical Pharmacology as a science
took off as the computational tools
and expanded analysis became
available.
• Rare Diseases (as a search term) has
paralleled the appearance of Clinical
Pharmacology in the literature.
• While this is not evidence of a direct
linkage, the two areas are highly
correlated in that much of the
knowledge we have today of Rare
Diseases is due to the tools
developed for Clinical Pharmacology.
Report run Sept. 2016

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Innovation & Re-Purposing
• Drugs for Orphan or Rare Disease are developed
along two distinct pathways
– Innovation
• The identification of candidate drugs and their
development along standard tracks
– Re-Purposing
• The identification of drugs that were previously approved
for (usually) a non-Orphan/Rare indication and have
promise in treating a rare disease

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Developmental Paradigms
• Innovation Route
– 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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Developmental Paradigms (cont’d)
• Re-purposing Route
– As used here it is the development of an already approved
drug for use in an orphan indication.
– The use of knowledge of related disease/drug mechanisms
to identify potential drug candidates at any stage of
development
– Generally allows the fastest route for a drug as the initial
mass-balance, animal safety, drug interaction, and special
population work is already done.
– Development program is targeted to the orphan
populations needs in terms of dose and any potential
intrinsic factors that may affect drug disposition.

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Developmental Paradigms
• Both the “innovation” and “re-purposing” route have
parallels in standard drug development
– Oncologic (Innovation)
• Using a combination of small numbers of patients with appropriate use
of animal and other collateral data along with pharmacometric tools to
assess dose/concentration response features.
– Pediatric (Re-purposing)
• Using data from adult subjects to define metabolism, dose response,
drug interactions and allowing us to focus on the pediatric aspects.

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Oncologic Drug Development Model
(Innovation)
• Basic Clinical Pharmacology
• Pre-Clinical
• Mass Balance
• Use of Animal Models
• Biomarker Development
• Characterize Pharmacokinetics in Patients With
Population Based Tools
• Special Populations Within Orphan Population
• Prioritize Drug-Drug Interaction Studies Based
on Mechanism

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Pediatric Drug Development Model
(Re-Purposing)
• Drug already approved for use in an Adult
population
– Basic Pharmacokinetic Properties and Clinical
Pharmacology studies already conducted and can be
“borrowed” to support use in pediatric patients.
• For an Orphan Disease
– Dose response (efficacy) relationship needs to be
established
– Safety in targeted population
– Biomarker Development and Qualification
• Clarify Pharmacodynamics

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CLINICAL PHARMACOLOGY POINTING THE WAY

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Moving Forward
• Developing drugs for rare diseases presents unique
challenges
– Small patient population
– Uncertain biomarkers
– Lack of good animal models
• The development of new methods of analysis and
new tools has allowed us to move forward in
seeking cures and mitigating symptoms
• Clinical Pharmacology as a science is uniquely
qualified to operate in the area of Orphan/Rare
Disease drug development

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INNOVATIVE ANALYSES
• Quantitative drug-disease-trial models
• Exposure-response models
INNOVATIVE TRIAL DESIGNS
• Clinical trial simulations
• Enrichment, adaptive, dose-response
KNOWLEDGE MANAGEMENT
• Leverage prior data
Bringing Clinical Pharmacology Tools to Bear
DRUGS@FDA

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A Clinical Pharmacology Based
Decision Tree for Orphan Drugs
• Building on 30yrs of Clinical
Pharmacology experience one can draw
developmental lessons from our
successful development of both
oncologic and pediatric drugs.
– These models leverage both know routes
of drug development an leverage
information
• Reducing uncertainty is a key effort of
Clinical Pharmacology research.
– Uncertainty in the clinical setting
– Uncertainty in “go-no go” decision-
making
Drug for Orphan
Indication
New Molecular
Entity
Studies in
Healthy
Subjects
Follow Modified
Oncology Model
Patients Only
Oncology Model
Re-Purposed
505(b)(2) or
NDA Supplement
Follow Modified
Pediatric
Strategy

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New Ideas-New Perspectives
• At ASCPT in March a symposia was held
focused on Orphan Drug Development
entitled
– “Don’t Do Different Things…Do Things Differently”
• It brought together industry, patient
advocates, the FDA, and academics to
discuss and challenge the drug
development paradigm
– The symposia is being reported out in the October
2016 issue and is available on-line
• The thesis is we must not abandon the
science that brought us here, but we
must adapt it to the questions and
realities of working in the orphan/rare
disease area. doi:10.1002/cpt.427

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

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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 Chinese Organization for Rare Disorders