Orphan Drugs and Rare DiseasesPointing the Way With Clinical Pharmacology

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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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 Indicationis 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 theirpharmacologic, therapeutic or toxic response in animals andman.”

“Clinical pharmacology is the science of drugs and their clinicaluse. It is underpinned by the basic science of pharmacology,with added focus on the application of pharmacologicalprinciples and methods in the real world. It has a broad scope,from the discovery of new target molecules, to the effects ofdrug 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 drugdevelopment can extract the most amount of knowledgefrom 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 sciencetook off as the computational toolsand expanded analysis becameavailable.

• Rare Diseases (as a search term) hasparalleled the appearance of ClinicalPharmacology in the literature.

• While this is not evidence of a directlinkage, the two areas are highlycorrelated in that much of theknowledge we have today of RareDiseases is due to the toolsdeveloped 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 BasedDecision Tree for Orphan Drugs

• Building on 30yrs of ClinicalPharmacology experience one can drawdevelopmental lessons from oursuccessful development of bothoncologic and pediatric drugs.

– These models leverage both know routesof drug development an leverageinformation

• Reducing uncertainty is a key effort ofClinical Pharmacology research.

– Uncertainty in the clinical setting

– Uncertainty in “go-no go” decision-making

Drug for Orphan Indication

New Molecular Entity

Studies in HealthySubjects

Follow ModifiedOncology Model

Patients Only

Oncology Model

Re-Purposed505(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

IndustryInternational

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-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 Chinese Organization for Rare Disorders