IND Preparation, Submission, shepherding through approval, and subsequent care and

feeding…

William E. Janssen (session chair)

Cynthia Walker

Getting from the bench to the bedside with any new therapeutic agent…

• Pre-clinical – in vitro and animal studies (GLP?)

• Phase I – first in human studies, MTD and toxicity studies

• Phase II – efficacy used along side existing therapeutics

• Phase III – placebo or standard of care controlled randomized trial

• Licensure

• Phase IV – extended studies, added indications

Several hurdles to get over,

PRE-CLINICAL BENCHWORK

CLINICAL TRIALS

INVESTIGATIONAL NEW DRUGS

• PARTS OF IND APPLICATION – Investigational Plan

– Investigator’s Brochure

– Clinical Trial(s) protocol(s)

– Chemistry Manufacturing and Control (CMC)

– Pharmacology & Toxicology

– Previous human experience with agent

– Other relevant information

• LIFECYCLE OF THE IND – Development of product

• Data to efficacy > toxicity

– Pre-IND preparations • Meetings with FDA

– IND Application and Approval • Clinical Holds

– Conduct of Clinical Trials • Safety reports

• Annual reports

– IND Withdrawal • Conditions to close

INVESTIGATIONAL NEW DRUGS

• PARTS OF IND APPLICATION – Investigational Plan

– Investigator’s Brochure

– Clinical Trial(s) protocol(s)

– Chemistry Manufacturing and Control (CMC)

– Pharmacology & Toxicology

– Previous human experience with agent

– Other relevant information

• LIFECYCLE OF THE IND – Development of product

• Data to efficacy > toxicity

– Pre-IND preparations • Meetings with FDA

– IND Application and Approval • Clinical Holds

– Conduct of Clinical Trials • Safety reports

• Annual reports

– IND Withdrawal • Conditions to close

We will be focusing primarily on:

BEFORE THE IND APPLICATION…

• Begin with the end in mind

• Talk to the FDA early

BEGIN with the END

• TARGET PRODUCT PROFILE

– Tool for preparing CMC section of IND

– Start with clear picture of what your product will look like and how it will be used, then work backwards

– Described in FDA guidance and also in FDA produced webinar

– Sample formats available also

TPP

• http://www.fda.gov/downloads/drugs/ guidancecomplianceregulatoryinformation/ guidances/ucm080593.pdf

• http://adrclinresearch.com/ Issues_in_Clinical_Research_links/ Target%20Product%20Profiles_v041009.pdf

FDA and TPP

• The FDA strongly advocates the use of a TPP although it does not mandate it

• The FDA has prepared a Template that is included in the draft guidance document just discussed

• For each element of the label, the template proposes – Target: Language in the Package Insert that the sponsor hopes to achieve – Annotations:Summary information regarding completed or planned

studies – Comments: To provide clarity

• The TPP template in the guidance has hyperlinks with each labeling concept to a specific study or other source of data

Label Elements in FDA TPP Template

• Product Milestones • Indications and Usage • Dosage and Administration • Dosage Forms and Strengths • Contraindications • Warnings and Precautions • Adverse Reactions • Drug Interractions • Use in Specific Populations • Drug Abuse and Dependence • Overdosage • Description

• Clinical Pharmacology • Non-clinical Toxicology • Clinical Studies • References • How Supplied/Storage and

Handling • Patient Counseling Information

• The TPP is a living document,

some elements aren’t known yet, some are not applicable – complete what you can and use the blanks to guide your development

How does this look?

• Note that the milestones table at the top is not fully complete – the TPP shell is created before anything else gets done, and then gets filled in as you go

• Comments are additional information that does not fit into the ‘Target’ or ‘Annotation’ fields.

• The TPP can (and should) be submitted along with briefing documents for pre-IND meetings

Comments: The proposed biomarkers included in Protocol-XXX-02 and Protocol-XXX-03 are acceptable to the DMEP. Protocol XXX-003 will be submitted for special protocol assessment.

Talk to the FDA early (and often?)

• Pre-IND meetings – Type B Meeting - scheduled at critical

milestones in new drug lifecycle • Pre-investigational new drug application

(pre-IND) meetings (21 CFR 312.82) • Certain end-of-phase 1 meetings (21 CFR

312.82) • End-of-phase 2 and pre-phase 3

meetings (21 CFR 312.47) • Pre-new drug application/biologics

license application meetings (21 CFR 312.47)

– Type B meeting requirements: • Requested in writing • Scheduled within 60 days of request

FDA Guidance Document

• http://www.fda.gov/downloads/Drugs/.../ Guidances/ucm153222.pdf

Pre-IND meetings

• Lay out proposed content of IND

• Sponsor specific questions regarding proposed IND, including – Design elements of clinical trial such as stopping rules, correlative studies,

patient assessments and frequency

– Manufacturing details such as release criteria, early phase assays earmarked as potential potency assays

• Agency will review pre-meeting briefing materials (don’t forget TPP), and may respond to some questions in writing in advance of meeting

• Remainder of material for discussion at meeting

Special offer ONLY AVAILABLE at OCTGT

• Pre-Pre-IND Meeting

– Informal meeting not identified as A, B or C type

– Still requires request in writing - approximately 45 days in advance

– Purpose is to identify pre-clinical study pathway that

• Is least burdensome to sponsor

• Provides essential data FDA will require for pre-IND meeting and for IND review

– Submit TPP when requesting pre-pre-IND meeting too

FDA Guidance Document

• http://www.fda.gov/downloads/ BiologicsBloodVaccines/ GuidanceComplianceRegulatoryInformation/ Guidances/CellularandGeneTherapy/ UCM376521.pdf

Pre-pre-IND meeting

• Questions that may be resolved – Animal studies

• How safety and efficacy of proposed agent to be measured

• How many animal species and which ones

– 3R (reduce, refine, replace) considerations vis a vis animal studies

– In vitro data • Tests of specific manufacturing methodologies if not in common use – e.g. a

novel way to eliminate RBCs from collected blood

• Methodology for release assays – validation and relevance

• Use this information to update TPP!

PUTTING IT ALL TOGETHER – THE FINAL IND APPLICATION

• Follow The Format

• Be detailed in brief

Follow the Format All of the required sections and the order they should come in is right there at the top of 2nd page of form 1571

… and make sure that this form is filled out correctly too!

Preparing IND

• Format is also very clearly laid out in 21CFR312.23

• Make sure that all elements are present, and that all information asked for has been presented

• USE YOUR TPP to help with preparation of the CMC section

• If you have been using TPP diligently, the information needed will be at your fingertips

Be detailed, in brief

• A picture (or table) can be worth a thousand words

– Tables of • Starting materials and qualification

– Cell source

– Ancillaries

• Equipment employed

• Safety and release assays

– Flowcharts to show manufacturing processes

• Include justifications in the form of data

– Reference pre-clinical studies from TPP and pre-pre-IND discussions

And don’t forget

• Send the correct number of copies (3)

• Make sure pages are properly bound so that they do not come apart in transit

• FDA has 30 days to review starting on the day your application is logged into their receiving office

– Be available to discuss your IND with reviewers during that time (don’t take a two week vacation trekking in the Andes)

CONGRATULATIONS!!!

• YOUR IND HAS BEEN APPROVED

• The FDA says that your study may begin

• You are all done now, sit back, roll in your subjects, and start writing the Nature Medicine article that you certainly will have coming, right?

• WRONG – Cynthia Walker will now pick up and explain why up to here has been the easy part…