Quality and Regulatory Affairs

Regulatory IND ProcessJames 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!


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

What is “Substantial Evidence”?

• Test product in animals and humans; see if it worksand 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

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

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

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.

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

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

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

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

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

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


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 Products• List of components\quantitative 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


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 - 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

RHFH6Klm8

36mikrojoul

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

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

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

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

Agency Interaction/Meetings

As currently codified, there are three meetingsthat 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 21st 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!


Thank you for your invitation to

present at your meeting.

Are there any questions that I may address?

Business

Quality and Regulatory Affairs