Translation of Orphan Disease Trial Design into

General Drug DevelopmentE. DENNIS BASHAW, PHARM.D.

The presentation today should not be considered, in whole or in part asbeing statements of policy or recommendation by the US Food and DrugAdministration.

This presentation is being made in my private capacity and not as anemployee of the US FDA or the US Government

Throughout the talk, representative examples of commercial productswill be mentioned. No commercial endorsement is either implied orintended.

DRUG DEVELOPMENT IN THE US

Idealized Drug Development in the US

Nature Reviews and Drug Discovery, 2003, Volume 2, Page 71

Lengthy Process to Reach Market(TIME)

http://phrma.org/sites/default/files/pdf/biopharmaceutical-industry-profile.pdf

Drug Development Cost Figures(MONEY)

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

22.39 Billion HK$

The Cost of Research vs Ease of Conduct

High

Low

Single Center Randomized Trials

Hard

Case Reports

Cohort Studies

Case-Control Studies

Case Series

EasyEase of conduct

Multi-Center Randomized Trials

CostThe ease of conduct is directly related to cost and inversely related to the relative informational value of the study

National Academies of Science Workshop Series

“The clinical trials system is “broken” and there needs to be new ways to collect and utilize patient data”

-Janet Woodcock, MD, Director of FDA’s Center for Drug Evaluation and Research

https://endpts.com/fdas-janet-woodcock-the-clinical-trials-system-is-broken/

Beyond the Randomized Clinical Trial

N Engl J Med 2017;377:465-75. DOI:10.1056/NEJMra1614394

Orphan Diseaseand Drug DevelopmentA MODEL FOR INNOVATION

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

Total NME’s Approved - 22

Priority – 15

Orphan Drugs – 9

Fast Track – 8

Breakthrough – 7

Accelerated – 6

Two - 5

Three - 4

Four - 4

Five - 1

https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM536693.pdf

Orphan Drug Approvals 2016 New Molecular Entities

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.

Huang S-M, Temple R, Clin Pharmacol Ther. 2008

Oncology and Orphan Drugs

ORPHAN DRUG APPROVALS (NMES)BY THERAPEUTIC AREA

•Since 2011, over 50% of all Orphan Drugs approved have been in the oncology and hematology area.

•Patients in these groups represent • A large degree of heterogeneity in

disease pathophysiology

• Poorly understood natural histories and progression. . . . .

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

CLINICAL TRIAL DESIGN

https://irb.research.chop.edu/study-design

Making Every Patient Count

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?)

Enrichment Trial Design

Ann Intern Med. 2016;165:270-278. doi:10.7326/M15-2413

• Can be viewed as a modification of astandard trial design where patientsscreened for trial enrollment areevaluated for a specific mutation prior totreatment randomization

• Those with the mutation are thenrandomized to therapy

• Those without the mutation are removedfrom the trial

• Following screening the populationremaining in the trial is “enriched”towards responding rather than a naiverandomization without screening

Umbrella Trials

Ann Intern Med. 2016;165:270-278. doi:10.7326/M15-2413

• An umbrella trial is restricted to patients witha single primary site or histologic type ofcancer.

• Those with “actionable” mutations aregrouped together by mutation and arerandomly assigned to therapy that is mutation“specific”.

• Those without actionable mutations areremoved from the trial.

• The leverage here is that more than one drugor treatment regimen can be evaluated basedon the observed mutations.

Basket Trials

Ann Intern Med. 2016;165:270-278. doi:10.7326/M15-2413

• Patient eligibility is based on a definedgenomic alteration rather than on primarysite.

• They can be nonrandomized or randomizedand can include more than one drug

• In a multi-drug basket study, for each drugstudied, all of the patients share a commonmutation but have different primary diseasesites. The primary disease site deter-minesthe cell type of the tumor, and this mayinfluence responsiveness to a drug inaddition to mutations present in the tumor.

Adaptive Trial Designs

Adaptive aspects can be incorporated into most trial designs, including the standard cross-over and parallel designs.

It incorporates intermediate looks at the defined times during the trial and then re-adusting the trial by:◦ Enrolling more patients

◦ Re-evaluating dosing levels

◦ Changing treatments

◦ Evalutaing multiple biomarkers

Real World Evidence

It refers to information on health care that is derived from multiple sources outside typical clinical research settings, including electronic health records (EHRs), claims and billing data, product and disease registries, and data gathered through personal devices and health applications

Real-world evidence can inform therapeutic development, outcomes research, patient care, research on health care systems, quality improvement, safety surveillance, and well-controlled effectiveness studies.

DOI: 10.1056/NEJMsb1609216

Quo Vadis(Where are you going?)

Drug Development and Change

•The historical models of drug development have been very successful• Decreased rate of death and improved quality of life

•The models did rely on big numbers of patients and a “regression to the mean approach”• That is the treatment of the “average patient” guided

patient dosing and drove the need for dose ranging in Phase 2 and Phase 3 trials (which raised the cost)

Orphan Drug Development Model

•Orphan Diseases are those that affect a discrete population in whom large numbers of subjects cannot be assembled• Standard drug development models (large, multi-

centered, replicate trials) are inefficient and unfeasible in this area.

• Orphan Drug Development hinges upon the leveraging of new sciences and data management strategiesPharmacogenomics

Physiologically Based Pharmacokinetic (PBPK) Modeling

Innovative Trial Design

Accommodation of REAL WORLD EVIDENCE

•Thus they represent INNOVATION and the FUTURE which you are entering into professionally thru training

PBPK ModelingBuild models based on

observed knowledge with a

“learn and confirm” strategy.

Biomarker SelectionUtilize in vitro and in

vivo systems to probe

and qualify biomarkers

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

Enhancing Value of Clinical Pharmacodynamics in Oncology Drug Development: An Alliance Between Quantitative Pharmacology and Translational Science

The role of the pharmacist in drug research, development, and regulation is wide open.

Pharmacists play a vital role in maintaining and extending the therapeutic armentarium

Thirty years ago none of these terms were applied to pharmacists

In my career I have done all of these roles and more to come.

Clinical Pharmacology & TherapeuticsVolume 101, Issue 1, pages 99-113, 25 NOV 2016 DOI: 10.1002/cpt.544

Pharmacy & Pharmacists

Acknowledgements

The Organizing Committee for the 2017 White Coat Ceremony and Symposia

Dr. ZUO Zhong, Joan

Dr. LEE Hon-Leung, Vincent

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Contact Information

linkedin.com/in/e-dennis-bashaw-82b54276