Clinical Pharmacology in Orphan Drug Development

KoNECT 3rd Regulatory Symposium

CAPT E. Dennis Bashaw, PharmD.Director, Division of Clinical Pharmacology-3

Office of Clinical PharmacologyOffice 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 Developmentfor 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 cycleTo 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 Act21 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

810

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

1112

10

6

34

21

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

ClinicalPharmacology

Regulations provide room for flexibility in the review of treatments for rare diseasesand 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 inorphan drug development can extract the mostamount of knowledge from least amount ofinformation

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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 inOrphan Drug Development for NMEs

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Orphan/Rare Disease NME Approvalsby Cohort

0

5

10

15

20

25

30

2011-2015 2006-2010

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Orphan Designations vs TOTAL Orphan Approvals*

195 203190

231

291

355333

125

15 26 26 3349 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 FDAEliglustat 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

PharmacogenomicsUtilize in vitro systems

to identify relevant CPY

polymorphism

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

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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

In October 2011, FDA awarded $2 million to launch Centers ofExcellence in Regulatory Science and Innovation at theUniversity of Maryland and Georgetown University. Theinvestment is part of FDA’s effort, outlined in the Agency's

strategic plan, to foster a robust, collaborative, regulatoryscience culture that enables FDA to address the scientific

challenges presented by revolutions in medical productdevelopment and to improve food safety and quality. In 2014two 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

IndustryInternational

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-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