EEducational Web Seminar

Guidance for Submission of an Initial Investigational New Drug (IND) Application

Tuesday, 10 December 201912:00 PM M –– 1:00 PM ET

Catherine CortezDirector, Office of IND Development and Regulatory Affairs

City of Hope

Carmen Netto-Merced, MS, RACManager, Regulatory Affairs

City of Hope

Revathiswari Tirughana-Sambandan, ACRP-CP, PMPRegulatory Affairs Specialist

City of Hope

Disclosure of Financial RelationshipsIt is the policy of the University Of Minnesota Office Of Continuing Professional Development to ensure balance, independence,objectivity and scientific rigor in all of its educational activities. All individuals (including spouse/partner) who have influence overactivity content are required to disclose to the learners any financial relationships with a commercial interest related to the subjectmatter of this activity. A commercial interest is any entity producing, marketing, re-selling, or distributing health care goods or servicesconsumed by or used on, patients. Disclosure information is reviewed in advance in order to manage and resolve any possible conflictsof interest. Specific disclosure information for each presenter, course director, and planning committee member will be shared with thelearner prior to the presenter's presentation. Persons who fail to complete and sign this form in advance of the activity are not eligibleto be involved in this activity.

Unless otherwise noted, individuals did not indicate any relevant affiliations or financial interests.Presenters

Catherine CortezDirector, Office of IND Development and Regulatory Affairs*No reference, content, or logos regarding INDuarte Consulting are included as part of this speaker’s presentation.

Revathiswari Tirughana-Sambandan, ACRP-CP, PMPRegulatory Affairs Specialist

Carmen Netto-Merced, MS, RACManager, Regulatory Affairs

Planning Committee Members

Laarni Ibenana, MPSProject Manager; The Emmes Company libenana@emmes.com

David H. McKenna, Jr., MDProfessor; Lab Medicine & Pathology, University of MNmcken020@umn.edu

Adrian Gee, MI, BioProfessor; Center for Cell & Gee Therapy, Baylor College of Medicineapgee@txch.org

Linda Kelley, PhDSenior Member; Department of Immunology, Moffitt Cancer Centerlinda.kelley@moffitt.org

Ashraf El Fiky, MDMedical Officer; The Emmes Company aelfiky@emmes.com

Joseph Gold, PhDSenior Director; Manufacturing, Center for Biomedicine & Genetics; City of Hope jogold@coh.org

Aisha Khan, MSc, MBAExecutive Director; Laboratory Operations and Development, University of Miami akhan@med.miami.edu

Accreditation StatementIn support of improving patient care, this activity has been planned and implemented by University of Minnesota,Interprofessional Continuing Education and The Emmes Company. The University of Minnesota, InterprofessionalContinuing Education is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME),the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC),to provide continuing education for the healthcare team.

Credit Designation Statements

American Medical Association (AMA) The University of Minnesota, Interprofessional Continuing Education designates this live activity for a maximum of1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of theirparticipation in the activity.

Laboratory Professionals1.0 hour of P.A.C.E. credit (CEU) through the University of Minnesota Medical Laboratory Sciences Program will be offered for this session.

Florida Clinical Laboratory PersonnelThe University of Minnesota Medical School, Office of Continuing Professional Development has been approved bythe Florida Board of Clinical Laboratory Personnel, CE Provider #50-21144. This activity has been approved by theFlorida Board of Clinical Laboratory Personnel, CE Broker Tracking # 20-749724 and will offer 1.0 hour ofcontinuing education (general).

Other Healthcare Professionals Other healthcare professionals who participate in this CE activity may submit their statement of participation to their appropriate accrediting organizations or state boards for consideration of credit. The participant is responsible for determining whether this activity meets the requirements for acceptable continuing education.

1. Complete the online attendee roster w/in 72 hrs. of the web seminar:https://z.umn.edu/PACTWebSeminarAttendanceRoster

2. Complete the online survey w/in 72 hrs of the web seminar: • Survey will display when you exit the web seminar• Survey link provided in your email reminder sent 10 December 2019

https://www.surveymonkey.com/r/PACTWebinarDecember2019

• PACT website: Education>PACT web seminars>December 10 Web Seminar

CE credit is oonly offered to participants who have attended this llive web seminar.

Each attendee must:

Note: After the web seminar, on-line rosters and surveys have been processed, a Statement of Participation will be issued via email to each participant listed on the attendee rosters requesting CE.

Educational Web Seminar

Guidance for Submission of an Initial IND Application

Tuesday, 10 December 2019

12:00 PM M –– 1:00 PM ET

Provide a general overview of key steps for investigators in preparation for an IND submission.

Describe how to engage the FDA early in development including INTERACT and pre-IND meetings with the FDA.

Identify critical components needed for a complete Chemistry, Manufacturing and Controls (CMC) package (Module 3) for an initial IND application.

Identify the type of data needed in the preclinical package of an IND submission.

Catherine CortezCity of Hope

Director, Office of IND Development & Regulatory Affairs

Planning for an IND Submission

Page 1 of 36

Getting StartedEstablish secure email with the FDA

Contact SecureEmail@fda.hhs.gov

Review relevant FDA Guidance Documents

Seek guidance early in product development process

Commercial INDs require submission in the electronicCommon Technical Document (eCTD) format.

Page 2 of 36

Build Your Team• Preclinical

• Manufacturing• Quality Control (QC)

• Quality Assurance (QA)• Biostatistician

• Protocol Writer• Clinical PI/Clinical study team

• Regulatory• Technology Transfer

Page 3 of 36

INTERACT ProgramThe Initial Targeted Engagement for Regulatory Advice (INTERACT) Program enables sponsors to obtain preliminary, informal, nonbinding advice from the FDA at an early stage of development prior to a pre-IND meeting.

“The program is intended for discussion of innovative investigational products that introduce unique challenges related to unknown safety profiles, complex manufacturing/technology issues, incorporation of innovative devices, or use of cutting edge testing methodologies.”https://www.fda.gov/vaccines-blood-biologics/industry-biologics/interact-meetings-initial-targeted-engagement-regulatory-advice-cber-products

naryy

Page 4 of 36

INTERACT Program (cont’d)

Meeting request and package should include:

Description of the product and disease/condition to be treated or prevented

Summary of information about product

development to date and future development plans

Statement summarizing purpose of the meeting

List of questions to be discussed

Summary of available data to support discussion

An INTERACT meeting request should be submitted only after a Sponsor has identified a specific investigational agent to evaluate in a clinical

study and early proof of concept and feasibility data is available.

Page 5 of 36

INTERACT Program (cont’d)

• Requests should be sent to INTERACT-CBER@fda.hhs.gov

• FDA will respond within 21 days of receipt ofrequest whether meeting request is grantedor denied

• Meeting will be scheduled within 90 days ofreceipt (subject to availability of CBER staff)

• Meeting is held by teleconference only,generally for one hour

Page 6 of 36

Type B Pre-IND Meeting Request21 CFR 312.82

PlanningPrepare Pre-IND Meeting Package

SubmitPre-IND Meeting Request

SubmitPre-IND Meeting Request

Pre-IND Meeting

FDA Response to Meeting Request

• FDA requests the Pre-IND Meeting Package be submitted at least four weeks prior to the scheduled meeting

• Seek guidance early in product development

• Identify key questions to be addressed by the FDA

• Recommend that meeting package is near final prior to submitting a meeting request

• Pre-IND Meeting Request must be submitted to the FDA at least 60 days prior to the desired meeting date

• FDA will respond within 21 calendars from date of receipt of the meeting request

• Prior to the scheduled meeting date/time, FDA will provide preliminary responses and comments

Page 7 of 36

Pre-IND Meetings

What concerns do you have with respect to preclinical data, manufacturing or clinical plan?

If you are asking “Should we bring this up?”This is the time to bring issues forward and discuss with the FDA

Page 8 of 36

Time to SubmitKey Components:

Pharmacology/ToxicologyClinical ProtocolManufacturing Information

Format:Common Technical Document (CTD)

Module 1 - Administrative InformationModule 2 - SummariesModule 3 – QualityModule 4 – Non-Clinical Study ReportsModule 5 – Clinical Study Reports

Page 9 of 36

Tips for Successful IND Filing

• Seek FDA Guidance early in product development process• Meet regularly with your team• Plan accordingly to ensure timely accurate filing

(QC, publishing)• Clear and organized data is critical• Present information clearly and concisely• Review all sections for consistency• Documentation is key through the product and IND life

cycle

Page 10 of 36

Critical Components Needed for a Complete Chemistry, Manufacturing and Control (Module 3)

Carmen Netto-Merced, MS, RACManager, Office of IND Development and Regulatory Affairs

Page 11 of 36

Key Points to be Covered

Introduction

Prior to IND Submission

Module 3 Quality

Key Takeaways

Guidance Documents

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Page 12 of 36

Introduction

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Page 13 of 36

Step 1 – Prior to IND Submission

• Develop a manufacturing platform• How to make the product?• Establish characterization assays• Determine QC criteria• Determine stability of the product• Route of administration• Patient Population

• Validate the manufacturing platform• 3 runs if possible

Page 14 of 36

Module 3 Quality

Main ComponentsBody of Data

Drug Substance

Drug Product

Appendices

Regional Information

Page 15 of 36

Module 3 (Quality)

3.2.S Drug Substance

3.2.S.1 General Information- Name of the DS- Molecular structure and cellular components- Diagram of relevant regulatory elements (e.g. promoter, etc)

3.2.S.2 Manufacture- Facilities involve in the manufacture, testing and storage

3.2.S.3 Characterization

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Page 16 of 36

Module 3 (Quality)

3.2.S Drug Substance Content

• 3.2.S.4 Control of Drug Substance

• 3.2.S.5 Reference Standards or Materials• - Certified reference standard (e.g. USP)• - Commercially supplied reference standards

• 3.2.S.6 Container Closure System• - Determine whether the container closure is compatible

with the DS

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Page 17 of 36

Module 3 (Quality)

•3.2.S.7 Stability•Studies conducted or planned

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Page 18 of 36

Module 3 (Quality)

3.2.P Drug Product Content

3.2.P.1 Description and Composition of Drug Product

3.2.P.2 Pharmaceutical Development

3.2.P.3 Manufacture

3.2.P.4 Control of Excipients

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Page 19 of 36

Module 3 (Quality)

3.2.P Drug Product Content

3.2.P.5 Control of Drug Product

3.2.P.6 Reference Standards or Materials

3.2.P.7 Container Closure System• Description and materials• How is the container sterilized• Provide 510k (k number) if cleared by the

FDA

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Page 20 of 36

Module 3 (Quality)

3.2.P.8 Stability

• Studies conducted• Protocols• Results – also provide a prospective

plan to collect stability data. The results can be submitted in the annual report.

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Page 21 of 36

Module 3 (Quality)

3.2.A. Appendices

3.2.A.1 Facilities and Equipment

3.2.A.2 Adventitious Agents Safety EvaluationNon-viral adventitious agentsViral adventitious agents

Page 22 of 36

Key Takeaways

• The sponsor is responsible for the safety of the subjects in the clinical study (21CFR312.3), therefore the FDA recommends that the sponsor and the CMO understand and document your respective responsibilities for ensuring product quality.

• Changes made to the manufacturing process that impact product safety, identity, quality, purity, potency or stability should be submitted to the FDA prior to implementation.

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Page 23 of 36

Guidance Documents

• FDA Guidance for Industry M4Q: The CTD Quality

• Chemistry, Manufacturing Control Information for Human Gene Therapy Investigational New Drug Applications

Page 24 of 36

Revathi Tirughana ACRP-CP,PMPRegulatory Affairs Specialist

Office of IND Development and Regulatory Affairs

Preclinical Data Required for an IND

Page 25 of 36

Overview

DefinitionsPreclinical data required

Product development Preclinical animal studies

Tips for Good Preclinical Data Key Takeaways

Page 26 of 36

DefinitionsGood Documentation Practices (GDP) are methods for

recording, correcting and managing data, documents and records, toensure the reliability and integrity of information and datathroughout all aspects of a product's lifecycle

o“Attributable, legible, contemporaneously recorded, original or atrue copy, and accurate (ALCOA)”

Good Laboratory Practice (GLP) is a quality system concernedwith the organizational process and the conditions under whichnon-clinical health and environmental safety studies are planned,performed, monitored, recorded, archived and reported. (21CFRPart58)

Page 27 of 36

Preclinical Study Data Required

Product Development Product characterization Manufacturing platform development

Preclinical Animal StudiesTo assess product safety To assess product potency or efficacy

Page 28 of 36

Product Characterization

• Conduct extensive characterization studies• “Know thy product”• Use similar class reference, FDA guidance docs

• Identify product’s quality attributes (QAs) and potential impact to product potency• chemical, physical, biological and microbiological attributes

• Identify key product specific assays to be used for product release testing or biomarker assays to be used in clinical studies.• Potency assay development

Page 29 of 36

Manufacturing Platform Development

• Establish manufacturing platform parameters• Identify cell culture conditions, limitations, and susceptibility• Consider scale-up and new technology in the future• Qualification runs

• Identify critical reagents and back-up sources • Research vs GMP grade products• Performance comparability, cost, & reliable supplier

• Assess how the product will be used • Product administration, concentration, formulation, and

delivery systems

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Page 30 of 36

Preclinical Animal Studies ddddddiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiieeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeessssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss Types of Animal Studies Required

Proof of Concept/ Efficacy data (Pharmacology)Biodistribution (Pharmacokinetics)Safety/toxicology data (GLP)Tumorgenicity

• Key ConsiderationsModel selection: Species, disease type, tumor burden, Biological system compatibility Study design comparability: Treatment regimen, Dosing

• Product used in the in-vivo studies should be manufactured and tested as per the proposed investigational product to support product safety/efficacy.

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TIPS for G Preclinical Data

• Identify studies that may support a future IND applicationand incorporate GDP prospectively.

• Strong data integrity = strong data quality.• Incorporate quality by design (QbD) as much as possible

when planning preclinical studies.• Practice transparency in preclinical research reporting.• Any data that supports an IND application is subjected to

critical review by the FDA.• Consider using Laboratory Management

systems (LIMS), Electronic lab notebook or databaseswhich allow for controlled document storage.

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Why Does Preclinical D Matter?

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FDA Statement excerpt: “ However, the integrity of the product testing data used in the development of the product’s manufacturing process is still a matter that we are continuing to evaluate and take very seriously.”

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Why Does Preclinical Data Matter?

All data that is used to support an IND may have an impact on human subject.

• Animal data showed some promise.• Clinical trial was completed with 412

patients in a randomized placebocontrolled study.

• Patients treated with investigationalproduct failed more rapidly than thoseon placebo. (Gordon et al, 2007)

• Alluded to issues with transgenicmouse model selection

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Key Takeaways

Robust preclinical testing serves a fundamental role incharacterizing the potential risks associated with aninvestigational product.

Recognizing pitfalls and addressing them earlier on indrug development will pay off in the long run.

Quality of preclinical data is integral in translationalresearch and subsequently has real life implications.

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References

1. Gordon, P., Moore, D., Miller, R., Florence, J., Verheijde, J., Doorish, C., Hilton, J., Spitalny, G., MacArthur, R., Mitsumoto, H., Neville, H., Boylan, K., Mozaffar, T., Belsh, J., Ravits, J., Bedlack, R., Graves, M., McCluskey, L., Barohn, R. and Tandan, R. (2007). Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. The Lancet Neurology, 6(12), pp.1045-1053.

2. US-FDA, CBER Directors (2019) https://www.fda.gov/news-events/press-announcements/statement-data-accuracy-issues-recently-approved-gene-therapy

3. US-FDA,(2018). Section 1. Modernize Toxicology to Enhance Product Safety. [online] U.S. Food and Drug Administration. Available at: https://www.fda.gov/science-research/advancing-regulatory-science/section-1-modernize-toxicology-enhance-product-safety-strategic-plan-regulatory-science [Accessed 5 Dec. 2019].

4. Keown, A. (2019). FDA Says Some Preclinical Data was Manipulated for Novartis’ $2.1 Million Gene Therapy Drug | BioSpace. [online] BioSpace. Available at: https://www.biospace.com/article/some-preclinical-data-was-manipulated-in-novartis-2-1-million-sma-gene-therapy/ [Accessed 5 Dec. 2019].

Page 36 of 36

Guidance for Gu dance forSubmission of an SSuuubbmm ssss ooon oooff aan

Initial IND Application

Speaker Contact aker ConEmail

Catherine Cortezcacortez@coh.org

Carmen Netto-Mercedcmerced@coh.org

Revathi Tirughanartirughana@coh.org

CE Credit

1. Complete the online attendee roster w/in 72 hrs. of the web seminar:https://z.umn.edu/PACTWebSeminarAttendanceRoster

2. Complete the online survey w/in 72 hrs of the web seminar: • Survey will display when you exit the web seminar• Survey link provided in your email reminder sent 10 December 2019

https://www.surveymonkey.com/r/PACTWebinarDecember2019

• PACT website: Education>PACT web seminars>December 10 Web Seminar

CE credit is oonly offered to participants who have attended this llive web seminar.

Each attendee must:

Note: After the web seminar, on-line rosters and surveys have been processed, a Statement of Participation will be issued via email to each participant listed on the attendee rosters requesting CE.

Onn--demand Webb Seminars

Today’s web seminar (presentation slides, audio/video recording) and previous web

seminars are available publicly at www.pactgroup.net

Select EEducation PACT Web Seminars

Thank you for attending!

To register for updates on upcoming web seminars visit us on the web at:

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