Sheraton University

City Hotel

Saturday, May 19, 2018

7:00 am – 4:30 pm

#PennMedMDBR2018 #GGPennRareSymposium

New Approaches and New Approval Pathways to Drug Development

Kristin Smedley

Co-Founder and President

Curing Retinal Blindness Foundation

Lisa Carlton, Ph.D.

Senior Director, Regulatory Affairs

Regenxbio, Inc

Larissa Lapteva, M.D

Associate Director

Division of Clinical Evaluation, Pharmacology, and Toxicology, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and

Research, U.S. Food and Drug Administration

#PennMedMDBR2018 #GGPennRareSymposium

Larissa Lapteva, M.DAssociate Director

Division of Clinical Evaluation, Pharmacology, and Toxicology, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research,

U.S. Food and Drug Administration

New Approaches and New Approval Pathways to Drug Development

Engaging Patients as Partners in Drug Development

Larissa Lapteva, MD, MHS, MBAAssociate Director

Division of Clinical Evaluation and Pharmacology/Toxicology (DCEPT)Office of Tissues and Advanced Therapies (OTAT)

Center for Biologics Evaluation and Research (CBER)US Food and Drug Administration (FDA)

Rare Patient Advocacy Symposium - 2018

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• I do not have any conflicts of interest

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Overview

• FDA’s organizational structure

• Overview of development and regulation of drugs and biological products

• Potential ways to increase patient engagement in product development

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FDA Organization

www.fda.gov

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CBER Organization

www.fda.gov

Center for Biologics Evaluation and

Research

Office of Tissues and Advanced Therapies

(OTAT)

Office of Blood Research and Review

(OBRR)

Office of Vaccines Research and Review

(OVRR)

Office of Compliance and Biologics Quality

(OCBQ)

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INDs with Gene Therapy ProductsSubmitted to OTAT CBER by Year

19

90

19

95

20

00

20

05

20

10

20

15

0

10

20

30

40

50

60

70

80

90

Year

Nu

mb

er

of

Sub

mis

sio

ns

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Product Development Overview

undefined ~5-10 years ~5-10 years ongoing

Basic

Scie

nce

TranslationalP

re-I

ND

Po

st-

mark

eti

ng

Clinical/IND

phases

Ph 1 Ph 2 Ph 3 Ph 4

ND

A/B

LA

Revie

wNIH/Academia

Product Developers

FDA Interactions

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Fast Track (FT) Breakthrough Therapy (BT)

Regenerative Medicine Advanced Therapy (RMAT)

Criteria -Serious condition

AND

-Nonclinical or clinical data demonstrate the potential to address unmet medical need

Note: Information to demonstrate potentialdepends upon stage of development at which FT is requested

-Serious condition

AND

-Preliminary clinicalevidence indicates that the product may demonstrate substantialimprovement overavailable therapy on one or more clinically significant endpoints

-Serious condition

AND

-Preliminary clinical evidence indicates that the product has the potential to address unmet medical need

Note: RMT include cell therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using such therapies or products (gene therapies, including genetically modified cells, that lead to durable modifications of cells or tissues)

Expedited Programs for Product Development

Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics https://www.fda.gov/downloads/Drugs/Guidances/UCM358301.pdfDraft Guidance for Industry: Expedited Programs for RMAT for Serious Conditions https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM585414.pdf

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Expedited Programs for Product Development

Fast Track (FT) Breakthrough Therapy (BT)

Regenerative Medicine Advanced Therapy(RMAT)

FeaturesFrequent meetings

Frequent written communication

Eligibility for *:

Accelerated approval

Priority review

Rolling Review

*if relevant criteria are met

All of FT Features +

Intensive guidance on an efficient drug development program, beginning as early as Phase 1

Organizational commitment

All of BT Features +

Early interactions to discuss any potential surrogate or intermediate endpoints

Statute addresses potential ways to support accelerated approval and satisfy post-approval requirements

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Review is Multidisciplinary

Product

Quality

(CMC)

Clinical Pharmacology

& Biopharmaceutics

Pharmacology &

Toxicology

Clinical

Statistics

Project

Management

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“He who studies medicine without books sails an uncharted sea, but he who studies medicine without patients does not go to sea at all.”

Sir William Osler

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Patient Engagement

• Is important at every stage of understanding diseases and developing novel products

• Patients are best positioned to advocate for raising awareness and improving treatment options for their disease

• Context of the disease and its manifestations

• Clinical meaningfulness (life- or activity- changing impact)

• Endpoints as measures of improvement that are understood by patients in both clinical trials and clinical practice

• Risk tolerance in the context of specific disease and available treatments

• Benefit : Risk Assessment

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Patient-Focused Drug Development Meetings at FDA in FY 2013-2017

Fiscal Year 2013 Fiscal Year 2014 Fiscal Year 2015 Fiscal Year 2016 Fiscal Year 2017

• Chronic fatigue syndrome/ myalgicencephalo-myelitis

• HIV

• Lung cancer

• Narcolepsy

• Sickle cell disease

• Fibromyalgia

• Pulmonary arterial hypertension

• Inborn errors of metabolism

• Hemophilia A, B, and other heritable bleeding disorders

• Idiopathic pulmonary fibrosis

• Female sexual dysfunction

• Breast cancer

• Chagas disease

• Functional gastrointestinal disorders

• Huntington’s disease and Parkinson’s disease

• Alpha-1 antitrypsin deficiency

• Non-tuberculous mycobacterial lung infections

• Psoriasis

• Neuropathic pain associated with peripheral neuropathy

• Patients who have received an organ transplant

• Sarcopenia

• Autism

• Alopecia areata

• Hereditary angioedema

www.fda.gov Office of Strategic Programs, CDER, FDA

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Patient-Focused Product Development

• Sections 3001-3004 of the 21 Century Cures Act

• Patient experience data as part of marketing applications

• Issuance of guidance documents addressing methodological approaches to collecting, analyzing, and submitting patient experience data

• FDA to publish a report on patient experience data

https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM563618.pdf.

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Opportunities To Further Patient Participation

• Learning about and participating in Natural History Studies

• Finding and participating with disease-based patient advocacy organization(s)

• Taking proactive approach to better understand how your condition is evaluated in studies and what symptoms, signs, and improvements are measured

• Collaborating with product sponsors, basic scientists, clinicians, psychometricians, geneticists, and other experts to contribute to the development of trial endpoints and measurements that are meaningful to persons with specific conditions

• Participating in post-marketing studies to help better understand effects of approved therapies

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OTAT Welcomes Opportunities for Patient Engagement

• OTAT fully supports patient participation in development of biological products:

• Meet with patient advocacy organizations» As part of product development

» As outreach at various conferences

• Engage patients in multidisciplinary review of selected IND and BLA applications

• Patient-focused drug development meetings

• Promote inclusion of patient representatives in research teams and product development on sponsor’s side

• Encourage sponsors to include measurements of patient input in clinical studies

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Biologic License Applications Recently Approved by OTAT

• Imlygic (talimogen laherparepvec) – genetically modified oncolytic viral therapy; approved for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery.

• MACI (autologous cultured chondrocytes on porcine collagen membrane – cellular sheet for autologous implantation) approved for the repair of symptomatic, full-thickness cartilage defects of the knee in adult patients.

• Kymriah (tisagenlecleucel) – genetically modified autologous T cell immunotherapy approved for the treatment of patients up to 25 years of age with B-cell precursor Acute Lymphoblastic Leukemia that is refractory or in second or later relapse.

• Yescarta (axicabtagene ciloleucel) – genetically modified autologous T cell immunotherapy approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy.

• Luxturna (voretigene neparvovec) – adeno-associated virus vector type 2, expressing the gene for human retinal pigment epithelial 65kDA protein (AAV2-hRPE65v2) is approved for the treatment of patients with vision loss due to confirmed bi-allelic RPE65 mutation-associated retinal dystrophy.

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Contact Information

Larissa.Lapteva@fda.hhs.gov

Regulatory Questions:

OTAT Main Line – 240 402 8190

Email: OTATRPMS@fda.hhs.gov and

Lori.Tull@fda.hhs.gov

OTAT Learn Webinar Series:

http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/ucm232821.htm

CBER website: www.fda.gov/BiologicsBloodVaccines/default.htm

Phone: 1-800-835-4709 or 240-402-8010

Consumer Affairs Branch: ocod@fda.hhs.gov

Manufacturers Assistance and Technical Training Branch: industry.biologics@fda.hhs.gov

Follow us on Twitter: https://www.twitter.com/fdacber

#PennMedMDBR2018 #GGPennRareSymposium

Lisa Carlton, Ph.D.

Senior Director, Regulatory Affairs

Regenxbio, Inc

New Approaches and New Approval Pathways to Drug Development

#PennMedMDBR2018 #GGPennRareSymposium

The Regenerative Medicines Challenge

An Industry Member’s Perspective

#PennMedMDBR2018 #GGPennRareSymposium

Outline

• Regenerative Medicine Product Development

• Gene therapy

• Rare diseases

• Key challenges

#PennMedMDBR2018 #GGPennRareSymposium

About me…

• Over 18 years industry experience

• ‘Traditional’ drug development in small-to-mid pharma

• Orphan product consulting

• Biotechnology/gene therapy

• Parent to child with a rare disease

Disclaimer: The views and opinions expressed in this presentation arethose of the presenter and do not necessarily reflect the official policy orposition of any company, employer, agency or organization.

#PennMedMDBR2018 #GGPennRareSymposium

Gene Therapy

• Virus is modified to prevent replication

• Delivers functional copy of gene (DNA) to the target cell

• DNA transcribed into RNA

• Functional protein produced / supplied to cell

RNA

GeneVector

• Power: Potentially applicable to thousands of monogenetic diseases, potential to alter disease course

#PennMedMDBR2018 #GGPennRareSymposium

Navigating the Landscape to Obtain Regulatory Approvals

• Traditional drug development mindset

• Lack of regulatory precedent

• Responsibility of health authorities

• Global reach and complex regulatory requirements

• Small populations

• Trial recruitment/Patient identification

• Demonstrating effectiveness

• Limited physicians/sites with expertise

• ‘Meaningful’ outcome measures

• Heath authorities

• Payers

• Patients

Industry Challenges to Developing Regenerative Medicines for Rare Diseases

#PennMedMDBR2018 #GGPennRareSymposium

Shifting the Mindset to Obtain Regulatory Approvals

• Leverage regulatory flexibility

• Orphan product development initiatives

• Regenerative Medicine Advanced Therapy (RMAT) designation

• Heath Authority interactions

• Patient Advocacy

• Creating collaborative industry ‘partners’

• Challenge traditional paradigms and understand health authority perspective

‘External’ Opportunities for Regenerative Medicines / Rare Diseases

#PennMedMDBR2018 #GGPennRareSymposium

Conclusion

• Key considerations

• Disease profile

• Treatment / regulatory landscapes

• Patient need

• Opportunity to partner with physicians, agencies, and especially patients

#PennMedMDBR2018 #GGPennRareSymposium

#PennMedMDBR2018 #GGPennRareSymposium

Kristin Smedley

Co-Founder and President

Curing Retinal Blindness Foundation

New Approaches and New Approval Pathways to Drug Development

Michael & MitchellCRB1-LCA