1) The document discusses the paradigm shift in biomarker development from a "learn and confirm" model to an "identify, confirm, refine, and learn" model to continuously learn from clinical trials. 2) It outlines policies used by the FDA to incentivize orphan drug development, including expedited programs, marketing exclusivity, and fee reductions. International collaboration is important for developing policies tailored to individual countries. 3) Successful partnerships between the FDA, NIH, patient groups, and industry have helped advance rare disease drug development, including through biospecimen repositories and training programs.

1. Clinical Pharmacology Leveraging
Science to Provide Access
孤儿药市场准入的机遇与挑战：中国及其他新兴市场
Challenges and Opportunities for Orphan Drug Access in
China and Emerging Markets
CAPT E. Dennis Bashaw, Pharm.D.
Dir. Division of Clinical Pharmacology-3
Office of Clinical Pharmacology
Office of Translational Sciences
US Food and Drug Administration

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• 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 will be mentioned. No commercial
endorsement is either implied or intended.

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• Pharmacodynamic & Biomarker Development and Qualification
– A Paradigm Shift
• Building the Polices
• Building Partnerships-the US experience

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An International Concern

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PHARMACODYNAMIC & BIOMARKER
DEVELOPMENT AND QUALIFICATION

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A Paradigm Shift
• Since the late 1990s the standard
drug development paradigm has
been “Learn and Confirm”
– Actually “learning vs confirming”
– Implies a deeper examination of
the data beyond the initial analysis
the “deep dive”
• With the need to extract all the
data from patients we need to
move to:
– Identify
– Confirm
– Refine
– Learn

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• Identify
• Incorporate Genomic Models and tools early to develop
candidate biomarkers
• Confirm
• Initial studies should “drill down” on one or two biomarkers
for evaluation
• Refine
• In Phase 2 and 3 test as many doses as possible and challenge
the utility of the biomarker (QUESTION!)
• Learn
• Actually CONTINUOUS LEARNING thru Phase 3 and into Post-
Marketing
• Registry studies

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Biomarkers and Modeling
Adapted from S. McCune, Dep Dir., Office of Translational Sciences, Pediatric Advisory Committee-Neonatal Subcommittee Mtg. March 2013

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Biomarkers Are the Present
and the Future
• Biomarkers
–Expand understanding of the disease and its progression
–Provide insight into FUTURE drug development
–Provide the potential for clinician based individualization (i.e.,
bleeding time vs IL-17A)
–Provide a path forward to a more optimized drug development
program
–Provide opportunities for collaboration with regulatory bodies

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FDA Partnership in Qualification
https://www.fda.gov/drugs/developmentapprovalprocess/drugdevelopmenttoolsqualificationprogram/

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FDA Qualified Biomarkers
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/BiomarkerQualificationProgram/ucm535383.htm

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BUILDING THE POLICIES

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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
Entering Drug
Development cycle
To Market
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

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Use of Special Programs 2016
• 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
73% of all NME Approvals Used One or More Designation

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Lessons to Learn and NOT to Learn
• The mixture of policies and incentives used in the United States
is designed for the particular mix of laws and systems in the
United States
• Each country must develop their own mix of incentives and
policeies to attract researchers, resources, and companies into
the orphan drug/rare disease space
– It must be tailored for each company and not a copy of the US model as
each situation is different
• HOWEVER, what can be learned is that policies can be combined
and run in parallel and not “in series”

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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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BUILDING PARTNERSHIPS
THE US EXPERIENCE

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NIH-Community (Academic and Patient)

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Biospecimen Repositories

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FDA-NIH Collaboration
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FDA-TRND Collaboration
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Partnership Matrix
Ramsey BW et al. N Engl J Med 2017;376:1762-1769
Partnership roles vary for
many reasons including
the state of knowledge of
the disease, the existence
of biomarkers, and the
development of mature
academic research centers
for a particular disease.

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PDUFA-6
FDA Commitment Letter (section 5)
Advancing Development of Drugs for Rare Diseases
• ….The Rare Disease Program staff in CDER will be integrated into review teams for rare disease
development programs and application review to provide their unique expertise on flexible and feasible
approaches to studying and reviewing such drugs to include, for example, innovative use of biomarkers,
consideration of non-traditional clinical development programs, use of adaptive study designs,
evaluation of novel endpoints, application of new approaches to statistical analysis, and appropriate use
of FDA’s expedited development and review programs (i.e., Fast Track, Breakthrough, Priority Review,
and Accelerated Approval). …
• The RDP staff will also continue to provide training to all CDER and CBER review staff related to
development, review, and approval of drugs for rare diseases as part of the reviewer training core
curriculum. The objective of the training will be to familiarize review staff with the challenges
associated with rare disease applications and strategies to address these challenges; to promote best
practices for review and regulation of rare disease applications; and to encourage flexibility and
scientific judgment among reviewers in the review and regulation of rare disease drug development and
application review.
• RDP staff will continue to engage in outreach to industry, patient groups, and other stakeholders to
provide training on FDA’s RDP. The staff will continue to foster collaborations in the development of
tools (e.g., patient reported outcome measures) and data (e.g., natural history studies) to support
development of drugs for rare diseases. In addition, the staff will also facilitate interactions between
stakeholders and FDA review divisions to increase awareness of FDA regulatory programs and
engagement of patients in FDA’s regulatory decision-making.
www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM511438.pdf

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Contact Information
CAPT Edward D. Bashaw, PharmD.
Director, Div. of Clinical Pharmacology-3
US FDA
10903 New Hampshire Ave
Building 51, Rm 3134
Edward.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