Clinical Pharmacology in Orphan Drug Development
-
Upload
e-dennis-bashaw -
Category
Health & Medicine
-
view
155 -
download
2
Transcript of Clinical Pharmacology in Orphan Drug Development
![Page 1: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/1.jpg)
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
![Page 2: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/2.jpg)
2
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.
![Page 3: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/3.jpg)
3
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
![Page 4: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/4.jpg)
4
DRUG DEVELOPMENT AND ORPHAN DRUGS/RARE DISEASES IN THE UNITED STATES: AN OVERVIEW
![Page 5: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/5.jpg)
5
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
![Page 6: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/6.jpg)
6
Chronology of Drug Developmentfor Classical and Orphan Drug
Nature Reviews and Drug Discovery, 2003, Volume 2, Page 71
![Page 7: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/7.jpg)
7
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
![Page 8: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/8.jpg)
8
Updated Drug Development Cost Figures
J Health Econ. 2016 May;47:20-33. doi: 10.1016/j.jhealeco.2016.01.012
![Page 9: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/9.jpg)
9
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
![Page 10: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/10.jpg)
10
Accelerated Pathways Under PDUFA-V
https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm552923.pdf
![Page 11: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/11.jpg)
11
1983 ORPHAN DRUG ACT –PROBLEM SOLVED?
![Page 12: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/12.jpg)
12
The Orphan Drug Act21 CFR314.105
![Page 13: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/13.jpg)
13
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
![Page 14: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/14.jpg)
14
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
*
![Page 15: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/15.jpg)
15
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
![Page 16: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/16.jpg)
16
CHALLENGES AND THE ROLE OF THE REGULATOR:SCIENCE, REGULATION, AND POLICY
![Page 17: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/17.jpg)
17
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)
![Page 18: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/18.jpg)
18
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
![Page 19: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/19.jpg)
19
Rare Disease Guidance-Common Issues
![Page 20: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/20.jpg)
20
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
![Page 21: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/21.jpg)
21
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
![Page 22: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/22.jpg)
22
Trends in Orphan Drug Approvals and Development
Clin Pharmacol Ther. 2012 May;91(5):932-6.
doi: 10.1038/clpt.2012.23.
![Page 23: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/23.jpg)
23
Orphan Drug Approvals (NMEs)by Therapeutic Area
![Page 24: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/24.jpg)
24
A Graphical Perspective on Trends inOrphan Drug Development for NMEs
![Page 25: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/25.jpg)
25
Orphan/Rare Disease NME Approvalsby Cohort
0
5
10
15
20
25
30
2011-2015 2006-2010
![Page 26: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/26.jpg)
26
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
**
![Page 27: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/27.jpg)
27
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
![Page 28: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/28.jpg)
28
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
![Page 29: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/29.jpg)
29
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
![Page 30: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/30.jpg)
30
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
![Page 31: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/31.jpg)
31
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
![Page 32: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/32.jpg)
32
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
![Page 33: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/33.jpg)
33
Impact of PBPK on Labeling
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205494Orig1s000lbl.pdf
![Page 34: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/34.jpg)
34
Impact of PBPK on Labeling
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205494Orig1s000lbl.pdf
![Page 35: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/35.jpg)
35
CONCLUDING THOUGHTS
![Page 36: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/36.jpg)
36
FDA-NIH Collaboration
![Page 37: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/37.jpg)
37
FDA-TRND Collaboration
![Page 38: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/38.jpg)
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
![Page 39: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/39.jpg)
![Page 40: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/40.jpg)
40
An International Concern
![Page 41: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/41.jpg)
41
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
![Page 42: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/42.jpg)
42
International Update (beyond US and APAC)
![Page 43: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/43.jpg)
43
Development of Safe and Effective Drugs For ALL Requires a Team Effort
Academia
IndustryInternational
Collaboration
Patient
Advocacy
FDA Science
& Policy
Benefits
To All
![Page 44: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/44.jpg)
![Page 45: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/45.jpg)
45
Contact Information
CAPT Edward D. Bashaw, PharmD.Director, Div. of Clinical Pharmacology-3US FDA10903 New Hampshire AveBuilding 51, Rm [email protected]
![Page 46: Clinical Pharmacology in Orphan Drug Development](https://reader033.fdocuments.in/reader033/viewer/2022051504/5a64a5c77f8b9a46568b509d/html5/thumbnails/46.jpg)
46
Acknowledgements• The Staff of the Division of Clinical Pharmacology-3
• The Office of Clinical Pharmacology
• The Office of Translational Sciences