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 PharmacologyOffice of Translational Sciences

US Food and Drug Administration

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• The presentation today should not beconsidered, in whole or in part as beingstatements of policy or recommendationby the US Food and Drug Administration.

• Throughout the talk, representativeexamples of commercial products will bementioned. No commercial endorsementis either implied or intended.

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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

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Lengthy Process to Reach Market(TIME)

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Drug Development Cost Figures(MONEY)

J Health Econ. 2016 May;47:20-33. doi: 10.1016/j.jhealeco.2016.01.012

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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

CostEssentially 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 thatare studied in an orphan product development program,relative to the TOTAL size of the population the number ofsubjects studied is actually a high percentage. Thus, ourunderstanding of the drug: disease interplay is quite high.Thus we CAN (and MUST) do MORE with LESS by usingadvanced 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 emergingconcepts of the genetic and environmental basis of disease toindividualize prevention, diagnosis and treatment.

• Personalized genomics builds on principles established by theintegration 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 andPrecision 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 drugdevelopment can extract the most amount of knowledge from leastamount of information

19http://www.ctsi.umn.edu/sites/ctsi.umn.edu/files/chris-austin-ncats-presentation-umn-10.21.14.pdf

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Increased Understanding andA 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 PharmacologyINTO A Development Program

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Learn and ConfirmVs 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-INDEOP2A

EOP2NDA/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 Workstreamsand Implementation

Biomarker SelectionUtilize in vitro and in

vivo systems to probe

and qualify biomarkers

PBPK ModelingBuild models based on

observed knowledge with a

“learn and confirm” strategy.

Classical PK/PDSynthesize the

available PK/PD data

on Drug Metabolism

Develop

Actionable

InformationInformed labeling for the

prescriber

PharmacogenomicsUtilize in vitro systems

to identify relevant

genetic factors to

enhance patient safety

and selection

Patient SelectionUnderstand 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

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Academia

IndustryInternational

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-3US FDA10903 New Hampshire AveBuilding 51, Rm 3134Edward.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