Regulatory IND Process James Ault, RAC, RQAP-GLP VP Quality and Regulatory Affairs Ricerca Biosciences, LLC May 23, 2007 Quality and Regulatory Affairs

Regulatory IND Process So, you’ve got the next Blockbuster Product! What now? PROVE IT!

So, you’ve got the next Blockbuster Product!

What now?

PROVE IT!

Regulatory IND Process Overview/Summary Requirements for a regulatory submission Regulatory strategy IND application contents Reasons for clinical hold Interaction with the regulators/meetings

Overview/Summary

Requirements for a regulatory submission

Regulatory strategy

IND application contents

Reasons for clinical hold

Interaction with the regulators/meetings

Fundamental Principle No medical product can be marketed in the United States until “substantial evidence” of the safety and effectiveness has been provided to the FDA’s satisfaction

No medical product can be marketed in the United States until “substantial evidence” of the safety and effectiveness has been provided to the FDA’s satisfaction

What is “Substantial Evidence”? Test product in animals and humans; see if it works and if it does any harm Use “controlled conditions of testing” to eliminate possibility that results are wrong Apply rigorous scientific, medical and regulatory standards throughout Assure identity, quality, purity, strength, reproducibility of manufacturing and ability to pass an FDA inspection

Test product in animals and humans; see if it works and if it does any harm

Use “controlled conditions of testing” to eliminate possibility that results are wrong

Apply rigorous scientific, medical and regulatory standards throughout

Assure identity, quality, purity, strength, reproducibility of manufacturing and ability to pass an FDA inspection

Here’s What the FDA Wants from You Description of the product How do you make the product? What does your product do? How do you know? How did you test it? - animals and humans Did you follow ALL the regulations? Show us the data! ALL the data We may need to inspect - for cause

Description of the product

How do you make the product?

What does your product do? How do you know?

How did you test it? - animals and humans

Did you follow ALL the regulations?

Show us the data! ALL the data

We may need to inspect - for cause

When Do You File an IND? Whenever clinical studies are initiated: on a new drug or biologic in the US for a new indication or different route of administration of an already approved drug

Whenever clinical studies are initiated:

on a new drug or biologic in the US

for a new indication or different route of administration of an already approved drug

Regulatory Strategy A regulatory strategy is a reverse-engineered document. Start from the outcome desired and work backward through a schedule of key pieces that are necessary to realize that outcome. The key pieces are: Indication Route of administration Dose Safety data

A regulatory strategy is a reverse-engineered document. Start from the outcome desired and work backward through a schedule of key pieces that are necessary to realize that outcome.

The key pieces are:

Indication

Route of administration

Dose

Safety data

Regulatory Strategy The regulatory strategy is developed by key players in the development process. Each area needs planning and coordination with the other players to ensure that the required information or materials are assembled and available at the appropriate times. The key players are Chemical Syntheses, Toxicology/Biology, Clinical and Regulatory.

The regulatory strategy is developed by key players in the development process. Each area needs planning and coordination with the other players to ensure that the required information or materials are assembled and available at the appropriate times. The key players are Chemical Syntheses, Toxicology/Biology, Clinical and Regulatory.

Regulatory Strategy Chemistry – necessary components Route of synthesis – identify the RSM Specifications – for Raw Mats and Product Reference standards Analytical Methods – Release and In-Process Quantity needed? GLP and Clinical? Formulation Stability

Chemistry – necessary components

Route of synthesis – identify the RSM

Specifications – for Raw Mats and Product

Reference standards

Analytical Methods – Release and In-Process

Quantity needed? GLP and Clinical?

Formulation

Stability

Regulatory Strategy Biology – necessary components Preliminary pK/TK, in-vitro data Species and duration based on intended clinical dose and duration GLP Toxicology studies, two species Schedules – animals, rooms, test material availability, pathology and reporting

Biology – necessary components

Preliminary pK/TK, in-vitro data

Species and duration based on intended clinical dose and duration

GLP Toxicology studies, two species

Schedules – animals, rooms, test material availability, pathology and reporting

Regulatory Strategy Clinical – necessary components Route of administration – oral, IV, topical Lead clinician selected Phase I protocol developed Previous human experience (if any) Clinical sites? International will require BSE/TSE Certifications and Quality Person to release in EU

Clinical – necessary components

Route of administration – oral, IV, topical

Lead clinician selected

Phase I protocol developed

Previous human experience (if any)

Clinical sites? International will require BSE/TSE Certifications and Quality Person to release in EU

Regulatory Strategy Regulatory – necessary components Form 1571 – IND Application Draft Introductory Statement CMC writing – copies of labeling for clinic and environmental waiver Toxicology/Pharmacology writing – data summaries Clinical Protocol Investigator Brochure Form 1572 – Statement of Investigator Format? FDA or CTD Accommodation for Annual reports that are required

Regulatory – necessary components

Form 1571 – IND Application

Draft Introductory Statement

CMC writing – copies of labeling for clinic and environmental waiver

Toxicology/Pharmacology writing – data summaries

Clinical Protocol

Investigator Brochure

Form 1572 – Statement of Investigator

Format? FDA or CTD

Accommodation for Annual reports that are required

IND Application Content and Format Cover Sheet (Form FDA 1571) Table of Contents Introductory Statement General Investigational Plan Investigator’s Brochure Clinical Protocols Chemistry, Manufacturing and Controls Data Pharmacology and Toxicology Data Previous Human Experience Additional Information

Content and Format

Cover Sheet (Form FDA 1571)

Table of Contents

Introductory Statement

General Investigational Plan

Investigator’s Brochure

Clinical Protocols

Chemistry, Manufacturing and Controls Data

Pharmacology and Toxicology Data

Previous Human Experience

Additional Information

IND Item 7: Chemistry, Manufacturing and Controls Introductory Statements Includes signals of known potential risks: chemistry and manufacturing differences between the drug product for clinical use and drug substance used in toxicology trials…. How they affect the safety (impurity) profile

Introductory Statements

Includes signals of known potential risks: chemistry and manufacturing differences between the drug product for clinical use and drug substance used in toxicology trials…. How they affect the safety (impurity) profile

IND Item 7: Chemistry, Manufacturing and Controls Drug Substance Description of the properties, formula, structure, and reference standards Name of Manufacturer Synthesis or formulation Specifications/Methods used Stability (some data on representative lots)

Drug Substance

Description of the properties, formula, structure, and reference standards

Name of Manufacturer

Synthesis or formulation

Specifications/Methods used

Stability (some data on representative lots)

IND Item 7: Chemistry, Manufacturing and Controls Drug Products List of componentsquantitative composition Name and address of Manufacturer Method of manufacture and packaging (brief) Specifications/methods (usually tentative) Stability (general) Investigational labeling Placebo information Environmental Assessment (request Exemption)

Drug Products

List of componentsquantitative composition

Name and address of Manufacturer

Method of manufacture and packaging (brief)

Specifications/methods (usually tentative)

Stability (general)

Investigational labeling

Placebo information

Environmental Assessment (request Exemption)

What is cGMP? Good Manufacturing Practices Shipping/Receiving Raw Mats/Supplies Quarantine-Test-Release Processing - batch records Validated facilities/equip. Good documentation Test product Documentation reviewed by QA - Release/Reject Label and ship to client Archive data and records Wait for FDA to appear

IND Item 8: Non-clinical Pharmacology and Toxicology Pharmacology Description of pharmacological effects and mechanisms of action - intended use general safety In Vitro and In Vivo Extrapolation to humans

Pharmacology

Description of pharmacological effects and mechanisms of action

- intended use

general safety

In Vitro and In Vivo

Extrapolation to humans

IND Item 8: Non-clinical Pharmacology and Toxicology Toxicology: Integrated Summary Description of design and dates when conducted Systematic presentation of findings from animal toxicology and toxicokinetic studies - related to any risks Signatures, testing locations and compliance statements (GLP)

Toxicology: Integrated Summary

Description of design and dates when conducted

Systematic presentation of findings from animal toxicology and toxicokinetic studies - related to any risks

Signatures, testing locations and compliance statements (GLP)

IND Item 8: Non-clinical Pharmacology and Toxicology Toxicology - Full Data Tabulations For each toxicology study that is intended to support safety of the proposed clinical investigation: Full tabulation of data suitable for detailed review - line listings - methods description or study protocol

Toxicology - Full Data Tabulations

For each toxicology study that is intended to support safety of the proposed clinical investigation:

Full tabulation of data suitable for detailed review

- line listings

- methods description or study protocol

What is GLP? Good Laboratory Practices Adequate Facility Qualified Personnel - Technical and Quality Unit Protocol and SD Unique Suitable Test Systems Characterized Test Materials/Controls Effective SOPs Accurate/Timely Data Accurate/Complete Report Secure Archives

FDA’s Role Reviewing IND Submissions Regulatory/Scientific Role in Assuring Safety of Subjects/Patients Adequate clinical program/protocol design Quality and integrity of the data

Regulatory/Scientific Role in Assuring

Safety of Subjects/Patients

Adequate clinical program/protocol design

Quality and integrity of the data

Grounds for IND Clinical Hold Clinical trial or program can be placed on hold for the following reasons: IND does not contain enough data to assess safety Human subjects are exposed to unreasonable risk Investigators not qualified Investigator’s brochure is incorrect, misleading, erroneous, or materially incomplete

Clinical trial or program can be placed on hold for the following reasons:

IND does not contain enough data to assess safety

Human subjects are exposed to unreasonable risk

Investigators not qualified

Investigator’s brochure is incorrect, misleading, erroneous, or materially incomplete

Causes for Rejection No. 1 cause - safety or excessive risk to patients Inadequate or incomplete manufacturing description Premature submission - not all data or protocols provided Inadequate reports of previous studies Inadequate investigational plan

No. 1 cause - safety or excessive risk to patients

Inadequate or incomplete manufacturing description

Premature submission - not all data or protocols provided

Inadequate reports of previous studies

Inadequate investigational plan

FDA’s Regulatory Aspect - IND Will the product expose human subjects to unreasonable risks when used in limited, early-stage clinical studies? Animal pharmacology and toxicology studies Manufacturing information Clinical protocols and investigator information

Will the product expose human subjects to unreasonable risks when used in limited, early-stage clinical studies?

Animal pharmacology and toxicology studies

Manufacturing information

Clinical protocols and investigator information

Agency Interaction/Meetings As currently codified, there are three meetings that can be requested: Pre-IND (PIND) submission meeting – to clarify potential questions concerning any part of the application End of Phase II (EOPII) – to develop Phase Three protocol Pre-NDA review – to clarify expectations of upcoming submission

As currently codified, there are three meetings that can be requested:

Pre-IND (PIND) submission meeting – to clarify potential questions concerning any part of the application

End of Phase II (EOPII) – to develop Phase Three protocol

Pre-NDA review – to clarify expectations of upcoming submission

Agency Interaction/Meetings In FDA speak: Communicate early and often – don’t need to have a formal meeting to get advise Agency open to novel approaches to development – witness the GMPs for the 21 st Century initiative, especially risk management approaches in ICH documents Honesty – put problems “out there”; they will likely find them anyway and you will lose the “trust” of the reviewers Don’t bring your lawyers – the regulators have more than you do!

In FDA speak:

Communicate early and often – don’t need to have a formal meeting to get advise

Agency open to novel approaches to development – witness the GMPs for the 21 st Century initiative, especially risk management approaches in ICH documents

Honesty – put problems “out there”; they will likely find them anyway and you will lose the “trust” of the reviewers

Don’t bring your lawyers – the regulators have more

than you do!

Regulatory IND Process Thank you for your invitation to present at your meeting. Are there any questions that I may address?

Thank you for your invitation to

present at your meeting.

Are there any questions that I may address?