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 PharmacologyOffice of Translational Sciences

US Food and Drug Administration

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• The presentation today should not be considered, inwhole or in part as being statements of policy orrecommendation by the US Food and DrugAdministration.

• Throughout the talk, representative examples ofcommercial products will be mentioned. No commercialendorsement 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 cycleTo 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 PARTNERSHIPSTHE 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 formany reasons includingthe state of knowledge ofthe disease, the existenceof biomarkers, and thedevelopment of matureacademic research centersfor a particular disease.

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PDUFA-6FDA 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-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