From Bench to the Clinic: Regulatory and Clinical Drug Development StrategiesJ Margaretha Oortgiesen

14 May 2013

AgendaBACKGROUND Early discovery - Proof of concept Clinical Development US FDA

TACTICAL REGULATORY CONSIDERATIONS IND Applications Marketing Applications

STRATEGIC CONSIDERATIONSRegulatory mechanismsWorking with the FDA

Clinical Development

From nonclinical discovery Towards clinical data

Towards licensing or marketing

Safety Early stage

Marketing

Pharmacokinetics

Pharmacodynamics

Proof of Concept

Proof of Efficacy

Clinical Development Phases Phase 1 - First in humans

Healthy volunteers/patients

Safety

PK

Phase 2

Safety

PK/PD

Proof of concept

Exploratory

Phase 3 (pivotal)

Confirmation of efficacy

Extended safety

Clinical Strategies

Clinical development plan with end in mind >> label

Regulatory pathway Input from:

KOLs

Patient advocacy groups

Previously approved products

Products under development

Regulated Clinical Development Highly regulated

FDA

ICH

Local ethics

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Food and Drug Administration

US FDA

Part of US Department of Health & Human Services

Website: www.fda.gov

FDA Mission and Activities

MISSION: To promote and protect the public health (helping

safe and effective products reach the market in a timely way).

To monitor products for continued safety (post-authorization)

To advance public health (helping to speed innovations that make medicines more effective, safer and more affordable)

To help the public receive accurate science-based information (to improve their health)

ACTIVITIES: New Product Review - Review of Data Keeping Watch - Safe manufacturing, distribution

and handling Keeping Watch – Monitoring for New Risks Standards and Regulations Research Enforcement: Actions to Protect Public Health

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Scope of Products Regulated

Drugs (Prescription and Over-The-Counter)

Biologics Vaccines

Blood products

Biotechnology products, cell products, and gene therapy

Medical Devices

Food

Veterinary products

Consumer and Medical Radiation Products

Cosmetics

How does FDA achieve its mission?• For prescription drug/biologics

products:

IND regulatory process

NDA/BLA regulatory process

Postmarketing surveillance of drug safety

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FDA Organization and Centers

Eight Centers/Offices:• Center for Biologics Evaluation and Research

(CBER)

• Center for Drug Evaluation and Research (CDER)

• Center for Devices and Radiological Health (CDRH)

• Office of the Commissioner (OC)

• Office of Regulatory Affairs (ORA)

• Center for Food Safety and Applied Nutrition (CFSAN)

• Center for Veterinary Medicine (CVM)

• National Center for Toxicological Research (NCTR)

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Center for Drug Evaluation and Research (CDER)

CENTER DIRECTOR: Janet Woodcock, M.D. (DBNA)

Offices:

• OFFICE OF REGULATORY POLICY

• OFFICE OF MANAGEMENT

• OFFICE OF COMMUNICATIONS

• OFFICE OF COMPLIANCE

• OFFICE OF MEDICAL POLICY

• OFFICE OF TRANSLATIONAL SCIENCES

• OFFICE OF EXECUTIVE PROGRAMS

• OFFICE OF COUNTER-TERRORISM AND EMERGENCY COORDINATION

• OFFICE OF SURVEILLANCE AND EPIDEMIOLOGY

• OFFICE OF NEW DRUGS

• OFFICE OF PHARMACEUTICAL SCIENCE

• OFFICE OF PLANNING AND INFORMATICS

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Center for Biologics Evaluation and Research (CBER)

CENTER DIRECTOR: Karen Midthun, M.D.

Offices:

• OFFICE OF MANAGEMENT

• OFFICE OF COMPLIANCE AND BIOLOGICS QUALITY

• OFFICE OF BLOOD RESEARCH AND REVIEW

• OFFICE OF CELLULAR, TISSUE, AND GENE THERAPIES

• OFFICE OF VACCINES RESEARCH AND REVIEW

• OFFICE OF COMMUNICATION, OUTREACH AND DEVELOPMENT

• OFFICE OF BIOSTATISTICS AND EPIDEMIOLOGY

                                                                                               

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Center for Devices and Radiological Health (CDRH)

Devices: primary intended purposes not through chemical action within or on the body Classification (I – II – III)

510K

PMAs

Radioactive products Diagnostics

Companion diagnostics

Combination products Drug-device combination products

Biologics-device combination products

Food Product Categories

• Food

• Foods for Special Dietary Uses

Infant formulas, weight loss products

• Medical Foods

Specific dietary management of a disease

Nutritionally complete products, oral rehydration formulas

• Dietary Supplements

Vitamins, minerals, botanicals

• Nutraceuticals*

• Functional Foods*

*These terms are widely used in the marketplace. Such foods are regulated by FDA under the authority of the FD&C Act, even though they are not specifically defined by law.

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FDA Regulations & Guidances

• Food, Drug, and Cosmetic (FD&C) Act

Federal Law; sets broad legal requirements

• Regulations (21 CFR)

Prescribes specific legal requirements; codified in Code of Federal Regulations. The CFR presents the official and complete text of the Agency’s regulations into an organized publication

– IND (Title 21 CFR 312)

– NDA/BLA (Title 21 CFR 314/601)

– ANDA (Title 21 CFR 320)

– 505(b)(2) (Title 21 CFR 314.107)

– PMA (Title 21 CFR 814)

• Guidances

Represent FDA’s current thinking on a given subject

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TACTICAL CONSIDERATIONS

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IND Clinical Trial/Program Initiation

Investigational New Drug (IND) Application• An IND to test the diagnostic or therapeutic potential of an

investigational new drug/biological in a clinical investigation

New Chemical Entity (NCE)

Approved Drug

• New indication

• Unapproved doses

• New dosage form

• Change in route of administration

• Change in dose regimen

• IND: Described in 21 CFR Part 312 (Investigational New Drug Application)

• Pre- IND Meeting: Opportunity to have early discussion with FDA on your product, the preliminary development plan and any issues you would like to obtain guidance/advice – Nonclin, CMC, Clin, Reg

What is an IND?

• Document through which the drug sponsor alerts the FDA of its intention to conduct clinical studies with an investigational drug. Summation of data to support clinical exposure for

drug not previously authorized for marketing in the U.S.

Promise of compliance and to do no harm

• In legal terms, the IND is a request for an exemption from the federal statue that prohibits an unapproved drug from being shipped in interstate commerce

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IND Clinical Trial/Program Initiation

Types of INDs Sponsor (Company/Corporate) IND

Investigator (Research) IND (named investigator is Sponsor)

Emergency Use IND (named patient/compassionate use, bypasses IRB)

Treatment IND (multiple patients for an indication being studied under ‘regular’ IND)

Exploratory IND (micro-dosing in Phase 0)

Initiation of Clinical Trials Sponsor (company) may begin trials 30 days after filing

IND, unless otherwise notified by FDA

During development, maintain ongoing communication with FDA to help guide the program (e.g., EOP 1/2 meetings)

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IND Application

IND Content Paper or electronic

CTD or 21 CFR 312 format

Form FDA 1571 Contains the signature of the Sponsor or the Sponsor’s

authorized representative

Typical IND for a NCE: ~ 2,800 – 3,200 pages

IND: Scientific Technical Sections

Chemistry,Manufacturing &

Controls

Microbiology

Human Pharmacokineticsand Bioavailability

Statistics

Clinical

Pharmacology &Toxicology

Drug RegulatoryApplication

eCTD Structure Overview

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Sponsor Obligations

• Sponsor Person who takes responsibility for an IND to initiate

a clinical investigation

Signed off on Form FDA 1571

• General Sponsor Responsibilities: Select qualified investigators; provide them with

information they need to conduct investigation properly

Ensure proper monitoring of the investigation(s)

Ensure that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the IND

Maintain an effective IND

Comply with safety reporting requirements

IND Review Process Summary

• FDA does not approve INDs

• IND is “in effect” after 30 days (unless placed on clinical hold) Based on calendar – no holidays allowed!

Clock begins when submission is logged into FDA Document Control Room

• Clinical hold may occur at any point in the life of the IND and may affect a single study or the entire IND

• FDA Communication May occur at any time during the course of the IND review

Clarifications are usually sought during the review process with the goal of avoiding clinical hold

Comments are advisory unless accompanied by a clinical hold order

Maintaining the IND

• Must be updated continually Safety Information

Ongoing clinical trials

• Types of modifications to IND Protocol Amendments

• Change in previously submitted protocol

• Add new protocol to original IND

• IRB approval required prior to implementation

Maintaining the IND (2)• Types of modifications to IND - continued

Information Amendments

• IB updates

• New information about study drug

– CMC information, nonclinical studies, final clinical study report

• Report new information not ordinarily included in protocol or IND safety report submissions

– Changes/updates to contact information

– FDA Form 1572s

– Letter of cross reference

IND Safety Reports

• Serious and unexpected Adverse Events (AEs)

• Inform FDA and all participating investigators

Annual Reports

• Yearly submission

• Within 60 days of “effective IND” anniversary date

• Includes enrollment, demographic and conduct status information for each study

• AE summaries (safety reports, deaths, dropouts)

• Preclinical study status

Marketing Applications

• New Drug Application (NDA)

• Biologics Licensing Application (BLA)

• Premarket Approval Application (PMA)

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Marketing Application - FDA Review

When to file NDA: File at completion of all 3 phases (with exception of accelerated approval)

21 CFR Part 314 (Application for FDA Approval to Market a New Drug)

21 CFR Part 601 (Licensing)

FDA has 60 days to accept or refuse to file.

FDA assembles the Review Team

Role of an Advisory Committee – To provide Independent advice that will contribute to the quality of the agency’s regulatory decision-making and lend credibility to the product review process.

Do the benefits outweigh the risks?

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NDA/BLA Review Actions

► Refusal to File <60 days after submission

► Not Approvable letter List deficiencies in application why product can not be

approved based on current submission

► Approvable letter Signals that product ultimately can be approved. Lists

minor outstanding deficiencies (i.e., label, Phase 4 commitments

► Approval letter

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STRATEGIC CONSIDERATIONS

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Approval/Review Pathways► Type of approval

‘Regular’ Approval

Accelerated Approval

► Filing/review type Fast Track Designation

Priority Review

Standard Review

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‘Regular’ Approval

On completion of Phase 3 clinical studies

Full data packageApplication with sufficient data to

demonstrate

Safety and Efficacy

Clinical Benefit

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Accelerated Approval

► Intended to make promising products for life threatening diseases available on the basis of preliminary evidence prior to formal demonstration of patient benefit

Under Subpart H (21CFR314.510) & 21CFR 601.41

► Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity

A measurement that is considered likely to predict patient benefit

► Considered provisional approval with a written commitment to complete clinical studies that formally demonstrate patient benefit

If studies don’t confirm the initial results, the FDA can withdraw approval

Post-marketing studies should be underway. Sponsor needs to show diligence in completing studies in a timely manner. Status update may be requested to report at Advisory meeting

If confirmatory study shows clinical benefit, FDA will grant ‘regular’ approval

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Fast Track

► Fast Track is a process designed to facilitate the development and expedite the review of new drugs that are intended to treat serious or life threatening conditions fill an unmet medical need

► Applies to the product and the indication

► May be requested at any time during development. An applicant must submit a request ( 60 days review)

► Emphasizes the close and early communication between the FDA and sponsor to improve the efficiency of product development

► Benefits include

“Rolling submission" for a marketing application

More frequent meetings with FDA to discuss development plans and ensure collection of appropriate data needed to support approval

The option of requesting evaluation of studies using surrogate endpoints (Accelerated Approval)

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Priority Review

► Priority Review designation is given to drugs that offer major advances in treatment or provide a treatment where no adequate therapy exists

► The goal for completing a priority review is 6 months (versus standard review period of 10 months)

► A request for priority review is made by the Sponsor at the time of the NDA filing, and the FDA will determine within 60 days whether a priority or standard review designation will be assigned

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Other considerations: Orphan Drugs To treat a rare disease or condition which

affects fewer than 200,000 people nationwide (e.g., cystic fibrosis, Lou Gehrig’s, Tourette’s syndrome, certain cancers)

Congress passed the Orphan Drug Act (ODA) in 1983 Applies to drugs and biologics

Provides financial incentives, including tax credits for cost of clinical research

Seven years exclusivity if approved first (from approval of NDA/BLA)

FDA Assistance with Protocol Development

Application for Orphan Drug Designation can be filed at anytime during the drug development process (60 days review)

May receive Priority Review

Other Considerations: Animal Rule

► Human clinical trials are not ethical or feasible, approval based on nonclinical evidence of efficacyBiodefensePoisoning antidotes

► A type of surrogate endpointRequires postmarketing studies to

confirm efficacy observed in animals

Target Product Profile (TTP)

Development tool to strategize towards product label

Tracking document containing Development steps towards an approved product

Requirements towards with the proposed label (package insert)

Presented in annotated, key sections of label

Dynamic document during development

May be shared with FDA

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WORKING WITH THE FDA

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FDA Project Manager

► Main contact at FDA – important to establish an open communication and a good working relationship with your key contact at the Agency (email, telephone)

► FDA Project Managers assigned for IND - by class of drug or based on project workload

► Role: Logs submissions and distributes for review;

coordinates formal FDA meetings; generates FDA official minutes

Handles Compassionate Use IND, Research IND

Addresses questions/queries from sponsors

CDER Office of New Drugs

- Office of Antimicrobial Products (OAP)- Office of Drug Evaluation I

Division of Cardiovascular and Renal Products (DCaRP)Division of Neurology Products (DNP) Division of Psychiatry Products (DPP)

- Office of Drug Evaluation II Division of Anesthesia, Analgesia, and Addiction Products (DAAAP)  Division of Metabolism and Endocrinology Products (DMEP)Division of Pulmonary, Allergy, and Rheumatology Products (DPARP)

- Office of Drug Evaluation IIIDivision of Dermatology and Dental Products Division of Gastroenterology and Inborn Errors Products Division of Reproductive and Urologic Products

- Office of Drug Evaluation IV Division of Medical Imaging Products

Radioactive Drug Research Committee (RDRC) Program- Office of Hematology and Oncology Drug Products

Where to submit IND?

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Types of FDA Meetings

► Type A: A critical path meeting (eg. Clinical Hold issue)

Scheduled to occur within 30 days of FDA’s receipt of request

► Type B: Pre-IND meetings, certain End of Phase 1, meetings, End of

Phase 2 / pre-Phase 3 meetings, and pre-NDA / BLA meetings.

Should be scheduled to occur within 60 days of FDA’s receipt of request

► Type C: Any meetings other than a Type A or Type B meeting.

Scheduled to occur within 75 days of FDA’s receipt of request

Note: no charge to FDA

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FDA Meeting Process

► Give careful consideration to your selection of the proposed date(s) to optimize your choice

► Consider the merits of Face-to-Face meeting versus Teleconference

► Attendees from company/advisors/experts/KoLs

► Meetings are allocated 1 to 1.5 hours maximum Use allocated time effectively with careful

preparations/rehearsals

Summarize clearly the agreements and actions to avoid misunderstanding later

► FDA’s minutes are official and binding version Sponsor may submit minutes

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Advisory Committees

► Public meetings to review: New NDAs, BLAs, new indications for approved

products

New guidelines relating to therapeutic areas

Development issues during INDs (closed session if proprietary information discussed)

► Non-FDA Members generally academic, mainly MDs plus statisticians and consumer representatives

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FDA: General Principles -1 ► FDA is scientific and very data driven

► Pre-plan interaction(s) to increase efficiency. Be specific in your requests or issues Advice from FDA is only as good as the background

information provided

► Work with FDA in partnership Early discussions to guide the development program

► Company drug experts – FDA’s extended knowledge (i.e., access to a lot of data on a large number of drugs)

► FDA Terminology – advise, recommend, suggest, should = must

► Document interactions with FDA to ensure understanding and for appropriate follow-up, as needed

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FDA: General Principles - 2

► Start discussions with FDA early in your development program. Effective use of FDA meetings, e.g. Pre-IND, EOP 1

and EOP 2

Use various FDA review process to obtain guidance (e.g., Request for SPA)

► Regulatory advice normally given in a structured way, in a structured process and generally, within a definitive timeframe

► FDA has a large number of opinion leaders; seek expert advice to refine your program (particularly important at AdCom time)

► US is an important market – impact of global climate

Thank You

Questions:

Marga Oortgiesen

Email: marga.Oortgiesen@gmail.com

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FDA WEBSITES/REFERENCE

S

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FDA Homepage

http://www.fda.gov/default.htm

About the FDA

http://www.fda.gov/opacom/hpview.html

Overview of the FDA: Choose Short Course- A Tour of the FDA

http://www.fda.gov/opacom/hpview.html

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FDA Internet Address

CDER Home Page

http://www.fda.gov/cder

CBER Home Page

http://www.fda.gov/cber

CDRH Home Page

http://www.fda.gov/cdrh

Code of Federal Regulations

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfsearch.cfm

Federal Register Notices

http://www.accessdata.fda.gov/scripts/oc/ohrms/index.cfm

CDER Guidelines

www.fda.gov/cder/guidance/index.htm

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FDA Internet Addresses (contd) CBER Guidelines

www.fda.gov/cber/guidelines.htm Freedom of Information

http://www.fda.gov/foi/fola2.htmEnforcement ReportsGuide to InspectionsInvestigators Operations ManualRegulatory Procedure ManualWarning Letters, etc

Advisory Committee Meeting Transcripts

http://www.fda.gov/oc/advisory/default.htm

http://www.wakeforestinnovations.com/