![Page 1: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/1.jpg)
Translation of Orphan Disease Trial Design into
General Drug DevelopmentE. DENNIS BASHAW, PHARM.D.
![Page 2: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/2.jpg)
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.
![Page 3: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/3.jpg)
DRUG DEVELOPMENT IN THE US
![Page 4: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/4.jpg)
Idealized Drug Development in the US
Nature Reviews and Drug Discovery, 2003, Volume 2, Page 71
![Page 5: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/5.jpg)
Lengthy Process to Reach Market(TIME)
http://phrma.org/sites/default/files/pdf/biopharmaceutical-industry-profile.pdf
![Page 6: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/6.jpg)
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$
![Page 7: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/7.jpg)
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
![Page 8: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/8.jpg)
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/
![Page 9: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/9.jpg)
Beyond the Randomized Clinical Trial
N Engl J Med 2017;377:465-75. DOI:10.1056/NEJMra1614394
![Page 10: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/10.jpg)
Orphan Diseaseand Drug DevelopmentA MODEL FOR INNOVATION
![Page 11: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/11.jpg)
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
![Page 12: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/12.jpg)
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
![Page 13: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/13.jpg)
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
![Page 14: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/14.jpg)
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. . . . .
![Page 15: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/15.jpg)
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
![Page 16: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/16.jpg)
CLINICAL TRIAL DESIGN
https://irb.research.chop.edu/study-design
![Page 17: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/17.jpg)
Making Every Patient Count
![Page 18: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/18.jpg)
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?)
![Page 19: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/19.jpg)
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
![Page 20: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/20.jpg)
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.
![Page 21: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/21.jpg)
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.
![Page 22: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/22.jpg)
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
![Page 23: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/23.jpg)
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
![Page 24: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/24.jpg)
Quo Vadis(Where are you going?)
![Page 25: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/25.jpg)
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)
![Page 26: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/26.jpg)
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
![Page 27: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/27.jpg)
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
![Page 28: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/28.jpg)
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
![Page 29: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/29.jpg)
Acknowledgements
The Organizing Committee for the 2017 White Coat Ceremony and Symposia
Dr. ZUO Zhong, Joan
Dr. LEE Hon-Leung, Vincent
29
![Page 30: Translation of Orphan DiseaseTrial Design into General Drug Development](https://reader030.vdocument.in/reader030/viewer/2022021801/5a64a5c77f8b9a46568b5093/html5/thumbnails/30.jpg)
Contact Information
linkedin.com/in/e-dennis-bashaw-82b54276